Physiological Reviews Review Article

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ITCH

GRAPHICAL ABSTRACT AUTHORS
Ferda Cevikbas and Ethan A. Lerner

CORRESPONDENCE
elerner@mgh.harvard.edu

KEYWORDS
atopic dermatitis; itch; neurogenic
inflammation; pruritus; quality of life

CLINICAL HIGHLIGHTS
• Scratching an itch can be intensely pleasurable, yet chronic
itch is a disease that impacts quality of life to the same
extent as pain.
• Signals between the environment, skin, immune cells, and
afferent nerve fibers funnel into the spinal circuitry and
brain to relay the sensation of itch, which promotes
scratching.
• The mechanisms that underlie itch and opportunities for
targeting this unmet need are reviewed.

Ferda Cevikbas and Ethan A. Lerner, 2020, Physiol Rev 100: 945–982
December 23, 2019; © 2020 the American Physiological Society
https://doi.org/10.1152/physrev.00017.2019
Downloaded from journals.physiology.org/journal/physrev (119.235.208.254) on January 3, 2023.
 Physiol Rev 100: 945–982, 2020
First published December 23, 2019; doi:10.1152/physrev.00017.2019

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ITCH

Ferda Cevikbas and Ethan A. Lerner

Dermira, Inc., Menlo Park, California; and Harvard Medical School and the Cutaneous Biology Research Center
at Massachusetts General Hospital, Charlestown, Massachusetts

Cevikbas F, Lerner EA. Physiology and Pathophysiology of Itch. Physiol Rev 100: 945–982, 2020.
First published December 23, 2019; doi:10.1152/physrev.00017.2019.—Itch is a topic to which
everyone can relate. The physiological roles of itch are increasingly understood and appreciated.
The pathophysiological consequences of itch impact quality of life as much as pain. These dynamics
have led to increasingly deep dives into the mechanisms that underlie and contribute to the
sensation of itch. When the prior review on the physiology of itching was published in this journal in
1941, itch was a black box of interest to a small number of neuroscientists and dermatologists.
Itch is now appreciated as a complex and colorful Rubik’s cube. Acute and chronic itch are being
carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. New
mediators are being identified. Mechanisms blur boundaries of the circuitry that blend neurosci-
ence and immunology. Measures involve psychophysics and behavioral psychology. The efforts
associated with these approaches are positively impacting the care of itchy patients. There is now
the potential to markedly alleviate chronic itch, a condition that does not end life, but often ruins it.
We review the itch field and provide a current understanding of the pathophysiology of itch. Itch is
a disease, not only a symptom of disease.

atopic dermatitis; itch; neurogenic inflammation; pruritus; quality of life

I. INTRODUCTION 945 I. INTRODUCTION

II. GLOSSARY 947
III. SENSORY NEURONS 947 “Itching is an unpleasant sensation which provokes the de-
IV. LABELED LINE FOR ITCH... 950 sire to scratch.” So began the previous review on the phys-
V. NEUROANATOMY 950 iology of itching in this journal in 1941, written by the
VI. HUMAN VERSUS MOUSE NEURONS 951 father of investigative dermatology, Stephen Rothman.
VII. CIRCUITRY AND GATING OF ITCH 951 This definition was penned by Samuel Hafenreffer in 1660,
VIII. GLIA NEURON INTERACTION 953 with pruritus, an identical term, in place of itch. The defi-
IX. SENSITIZATION IN ITCH 955 nition continues to appear regularly at the beginning of
X. ITCH IN THE BRAIN 956 manuscripts. Why such reinforcement occurs, unique to
XI. G PROTEIN-COUPLED RECEPTORS 956 this topic, is indicative of the fascination that surrounds
XII. TRP CHANNELS 963 itch. Scratching an itch can also be pleasurable (269). The
XIII. VOLTAGE-GATED SODIUM... 965 poet Ogden Nash wrote that happiness is to have a scratch
XIV. CYTOKINES AND ITCH 965 for every itch. The sensation may be unpleasant, the
XV. OTHER CYTOKINES AND THEIR... 968 scratching response rewarding, but patients who suffer
XVI. MODELS AND TECHNIQUES 969 from acute or chronic itch, which affects 15% of the pop-
XVII. CONTAGIOUS ITCH 971 ulation, are miserable.
XVIII. CLINICAL ITCHES 971
XIX. TARGETING ITCH 972 Rothman’s review was prescient. The complete overlap be-
XX. FUTURE DIRECTIONS 973 tween areas in which itch and pain were felt was indicative
of shared neuronal pathways but could not explain the
distinct motor responses of scratching an itch versus with-
drawal from a painful stimulus. The triple response of Sir
• Scratching an itch can be intensely pleasurable, yet chronic Thomas Lewis, manifest by vasodilatation, flare, edema
itch is a disease that impacts quality of life to the same extent
as pain. and associated itch attributed to a “H-substance” not nec-
• Signals between the environment, skin, immune cells, and essarily exclusive to histamine, was consistent with media-
afferent nerve fibers funnel into the spinal circuitry and brain tors aside from histamine. Itch associated with systemic
to relay the sensation of itch, which promotes scratching.
• The mechanisms that underlie itch and opportunities for tar- processes including cholestasis and hematological condi-
geting this unmet need are reviewed. tions was noted to be distinct from histamine, consistent
with current understanding that clinical itches are driven

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 FERDA CEVIKBAS AND ETHAN A. LERNER

primarily by mediators and pathways that are independent
from histamine. The concepts of central inhibitory path-
ways and central sensitization were introduced.
Why do we have the sensation of itch? Conventional think-
ing has been that the major role of the sensation of itch and
the subsequent motor response of scratching is to remove
environmental insults from the skin, especially arthropods.
Hence, itch is considered a protective sensation and re-
sponse to the environment. More recent thinking is that in
addition, scratching damages the epidermal barrier and fa-
cilitates an appropriate physiological cascade associated
with sensing the insult (FIGURE 1). This cascade includes
multidirectional communication between the nervous and
immune systems within the skin, perhaps primarily directed
against components of the microbiota, which can evoke itch
and pain (FIGURE 1). The pleasure that accompanies
scratching may serve to reinforce the motor activity to fur-
ther ensure neuroimmune communication.
Depending on the insult, such as a contact allergen, or in
association with a disease, for example atopic dermatitis
or cholestasis, a pathophysiological itch may develop.
Our goal is to provide an understanding of the overall
physiology and associated pathophysiology of itch. We
focus on neuronal aspects, as a nervous system is needed
to have the sensation of itch, as well as the multidirec-
tional connections between the nervous and immune sys-
tems that impact itch transmission from the skin into the
spinal cord. These areas are the ones most supported by
objective data indicative of mechanisms, and it is appre-
ciated that an understanding of central itch circuitry in
the mouse is advancing rapidly.
Itch is rarely a pure sensation. Instead, itch typically in-
cludes degrees of burning, prickling, and stinging. This de-
lineation is of importance because experimental stimuli as
well as clinical conditions manifest such differences, which
can overlap with pain. Atopic dermatitis (AD), for which
itch is a sine qua non, often has a degree of pain, and
Staphylococcus aureus, which is resident in AD skin, can
evoke pain and itch. Our peripheral neurosensory-immune
system together with central circuitry is able to differentiate
between itch and pain. This observation leads to the long-
standing question of whether or not there is specific neuro-

BRAIN

ITCH ALLERGENS, PRURITOGENS, IRRITANTS

THALAMUS

EPIDERMIS

MAST
CONTRALATERAL
CELLS DERMIS
STT ASCENDS TO HISTAMINE
THE THALAMUS
NEUROPEPTIDES CD4+ T CELLS
PROTEASES IL-4, IL-13, IL-31
DORSAL-ROOT CYTOKINES
GANGLION NON
HISTAMINERGIC
NEURON HISTAMINERGIC
NEURON NEUROPEPTIDES

ITCH SENSORY
SPINAL NEURONS
CORD

FIGURE 1. Initiation of itch. Allergens, pruritogens, and irritants are exogenous substances which interface
with the skin in acute and chronic itch. Branching terminal fibers of afferent neurons which sense these
substances reach the epidermis, the uppermost viable layer of skin immediately below the stratum corneum
barrier. The sensory neurons are considered histaminergic or non-histaminergic. Neural activity drives the
recruitment of immune cells, including mast cells and CD4⫹ T cells among others. These cells release
mediators that activate cognate receptors on sensory neurons to release neuropeptides to contribute to the
itch-scratch cycle. Messages are relayed from the peripheral afferents to their cell bodies in dorsal root or
trigeminal ganglia followed by synapsing with second-order neurons in the spinal cord. The thalamus then
assists in the interpretation of messages encoding itch. IL, interleukin; STT, spinothalamic tract.

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 ITCH

nal coding for itch. An extension of this topic is whether the Psychogenic itch: having a psychosomatic or psychiat-
sensation of itch is restricted to skin or if other organs get ric origin, e.g., delusions of parasitosis.
itchy. We are accustomed to associating pain with visceral
organs, but there is a developing consensus that processes
B. Selected Definitions and Terminology
associated with removal of material from any epithelia, be it
the bladder, gut, or respiratory system, including cough,
Allodynia: pain or itch from what is normally a nonpain-
may be equivalent to itch (205).
ful or itchy stimulus. It is associated with central sensiti-
zation.
A plethora of discoveries is shaping our understanding and
Alloknesis: triggering of itch from what is normally a
helping us to understand itch. A critical caveat of ongoing
nonpruritogenic stimulus includes itch.
research is the need to use experimental species and the
Atmoknesis: itch that occurs when skin is exposed to air,
challenge to translate findings from mice, canines, and non-
such as when clothing is removed.
human primates into the human condition. Scratching be-
Central sensitization: increased responsiveness of no-
havior in animals is considered to relate to human itch,
ciceptive neurons in the central nervous system to their
although there is no objective method of asking if a non-
normal or subthreshold afferent input. It is often asso-
human itches, nor is there an objective measure of human
ciated with peripheral injury or inflammation, such
itch. If itch depends on the ability to scratch, then from an
that persistent stimulation of nociceptors or pruricep-
evolutionary standpoint, it can be argued that itch devel-
tors leads to increased excitability of central pathways,
oped in conjunction with receptors that first appear in
decreased activity of inhibitory pathways, and chronic
tetrapods (29). However, if scratching is considered a
pain or itch.
behavioral response manifest by rubbing following injec-
Dysesthesia: an abnormal sensation, often including
tion of a channel activator, then fish may have the sensa-
some components of burning, itch, pain, pins and nee-
tion of itch (80).
dles, and touch. It can occur anywhere on the skin but
is often associated with the scalp.
In the clinic, itch is considered either acute or chronic.
Neurogenic inflammation: inflammation associated
Acute itch is defined as an itch that lasts less than 6 wk,
with the release of mediators, particularly substance P
whereas chronic itch persists for 6 wk or longer and is
(SP) or calcitonin gene-related peptide (CGRP), from
experienced by 15% of the population. A variety of ani-
peripheral afferent neurons, which then impact the im-
mal models are considered proxies for chronic itch by
mune system.
some investigators, but given the brevity of these models,
Sensitive skin: a widely used term that has defied an
we have difficulty making that connection. Information
objective definition or pathophysiology. It can occur in
is lost in translation between models and human physi-
the setting of specific diagnoses, including atopic der-
ology, modulating the perspectives between the bench
matitis, less well-defined conditions such as fibromyal-
and bedside, while promising findings in mouse models
gia, or it can refer to itching, burning, pricking sensa-
(104) have often failed in the clinic (28). At the same
tions, or dysesthesias of unknown cause.
time, appreciation of the impact of itch together with the
fascinating physiology underlying this sensation is driv-
ing therapeutic success and improved quality of life for III. SENSORY NEURONS
those who itch.
Itch is sensed by cutaneous nerve fibers called pruriceptors.
These primary afferent fibers serve as antennae and con-
II. GLOSSARY
stantly sample the environment of the skin to detect and
respond to cues. Signals are propagated along neural path-
A. Types of Itches ways to the spinal cord and brain for interpretation and
response. Analogous to itch, algogenic (painful) stimuli,
Acute itch: itch lasting less than 6 wk. heat, and cold are sensed by nociceptors. It is possible that
Chronic itch: itch lasting 6 wk or longer (under causes, all pruriceptors function as nociceptors in humans but
note that it can be a chronic acute mechanism). whether the reverse is true remains to be clarified. There are
Neurogenic itch: induced by mediators but in the ab- data in mice that support the concept of a small number of
sence of neural damage. As the mediators of neuro- uniquely pruriceptive fibers. Nociceptors are categorized
genic itch are defined, it is likely that neurogenic itch into two biophysically distinct major afferent classes, thinly
will fall under pruritoceptive itch. myelinated A␦ and unmyelinated C-fibers. A␦ are 2–5 ␮m in
Neuropathic itch: associated with damaged neurons, diameter and have a conduction velocity of up to 8 m/s.
e.g., post-herpetic neuralgic itch or small fiber neurop- C-fibers average 0.2–1.5 ␮m in diameter and have a con-
athy. duction velocity less than 2 m/s. Sensory nerves do not
Pruritoceptive itch: itch associated with pruritogen ac- function in isolation but are part of an interactive milieu.
tivation of sensory fibers. This milieu includes a plethora of mediators generated from

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 FERDA CEVIKBAS AND ETHAN A. LERNER
the sensory neurons themselves, neighboring cells, the bar-
rier, and the microbiome. These mediators range in size
from ions to proteins, include pH, and may include local-
ized cell or tissue tension. Each neuronal population is het-
erogeneous and polymodal, meaning that it has more than
one detection property, often associated with specific ion
channels that detect, for example, heat, cold, acid, and
whether they respond to cellular stretch or a light touch
from a cellular probe, being mechanically sensitive, or in-
sensitive, and the yet ill-defined milieu that is generated by
tissue inflammation. These neurons are pseudounipolar,
with cell bodies residing in dorsal root (or trigeminal) gan-
glia. The peripheral branch of the axon extends to the
skin while the central branch synapses with first-order
neurons in the dorsal horn of the spinal cord. These
proceed to interact with second-order neurons that com-
prise excitatory and inhibitory circuits that project to the
parabrachial nucleus of the thalamus for processing, in-
terpretation in additional brain regions, and a resultant
motor response of scratching. C-fibers, and to a lesser
extent A␦-fibers, are responsible for itch sensing. It is not
yet known if the recently described specialized glial cells
that form a meshlike network near the dermal-epidermal
junction and initiate the sensation of pain contribute to
the sensation of itch (1).
Itch fibers comprise fewer than 10% of the C-fibers in skin.
Diversity in the C-fiber population has long been recog-
nized, is manifest in several ways, is dynamic, and evolves
postnatally in mice and possibly in humans. Rather than
being strictly absolute, C-fibers can be distinguished by
markers and by function, often illustrated via Venn dia-
grams. Single-cell RNA sequencing has led to even further
subdivisions, but whether these are static is not known.
“Silent” nociceptors constituting almost a quarter of C-fi-
bers in human skin have been described (246). These me-
chanically insensitive but heat-responsive C-afferents or
silent nociceptors biophysically transition to mechani-
cally responding fibers in the setting of injury. A conven-
tional distinction between C-fibers, although not abso-
lute, is by peptidergic versus nonpeptidergic markers.
Peptidergic markers include SP and CGRP which are re-
leased by these fibers. They also express the nerve growth
factor (NGF) receptor and tropomyosin (or tyrosine) re-
ceptor kinase A (TrkA) and somatostatin (SOM). Non-
peptidergic markers include the c-Ret neurotrophin re-
ceptor as well as artemin. In general, the c-Ret⫹ neurons
express the isolectin IB4, a lectin that binds to nonpepti-
dergic neurons.
With an unbiased RNA profiling analysis that combined
neuronal information with functional impact, four nonpep-
tidergic (NP 1– 4) itch-specific classes were identified. NP1
is considered to mediate neuropathic pain and itch. NP2
and NP3 are also involved in itch sensation with NP3 re-
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sponsible for the transduction of inflammatory itch (293).
These data suggest that there is a neuronal segregation be-
tween chemical and acutely induced and inflammatory-me-
diated itch (FIGURE 2).
Another, and particularly useful discriminator between itch
sensory neuron function, is between fibers that are either
mechanosensitive or mechanoinsensitive (151). The two
prototypic substances that evoke itch in human subjects are
histamine and spicules of the bean plant Mucuna pruriens.
The plant and its spicules are colloquially referred to as
cowhage and informally known as itching powder. The
sensations elicited by cowhage were known even to Roth-
man to be independent of histamine. Electrophysiologi-
cal recordings from human and mouse primary afferents
revealed that histamine acts on a subset of mechanoin-
sensitive C-fibers that also respond to heat and capsaicin.
In contrast, cowhage activates mechanosensitive fibers in
humans. Possible differences of signal intensity carried
via mechano-sensitive or -insensitive neurons may be ac-
counted for by the diameter of the respective cutaneous
receptive fields. A cutaneous receptive field is defined as
the area within the skin activated by a stimulus and con-
currently evoking action potential (132). The activation
of the receptive fields by histamine or cowhage spicules
seem to differ from each other, which may be explained
by distinct and overlapping C-fibers that convey different
stimuli, the pruritogens themselves, or the mode of ap-
plication, spicules for cowhage, and injection for hista-
mine.
A. Transmission of Messages
All primary afferents project into the dorsal horn of the
spinal cord. Peptidergic and nonpeptidergic neurons target
distinct areas of the superficial laminae in the dorsal horn.
The peptidergic C-afferents project into the outer region of
lamina I and lamina II, whereas the nonpeptidergic subset
targets the inner region of lamina II. This segregation within
the spinal cord maintains functional distinction of the C-
afferents. A␦ nociceptors target lamina I and deeper lamina
V of the spinal cord. Low-threshold C-mechanoreceptors
venture to the inner ventral part of lamina II where protein
kinase C (PKC)-␥-expressing interneurons are concen-
trated. Deeper dorsal horn contains the wide-range dy-
namic projection neurons that respond to innocuous and
nociceptive stimuli. Projection neurons that carry the mes-
sages beyond the spinal cord comprise 2–5% of the neuro-
nal population, which mostly projects to the parabrachial
(PB) nucleus of the dorsolateral brain stem. Within this
small population, 80% express the neurokinin 1 receptor
(NK1R) and likely connect with SP⫹/GABA– interneurons
(46, 180), a neuronal population considered a fine-tuning
gate of messages. This neuronal circuit is (68, 283) impli-
 ITCH

MrgprA1
MrgprA3
PRURITOGENS MrgprC11
Histamine receptors
IL-4R/IL-13R

NP2
ITCH
Nppb NPR1 GRP GRPR ?
MrgprD NP1 NP3 5-HT receptors
IL-4R/IL-13R ITCH Histamine receptors
IL-31R
RECEPTOR IL-4R/IL-13R
AFFERENTS
GLYCINE
ENK
SOM
B5-I Enkephalin GABA
DYNORPHIN

Glycine
MECHANICAL ? ?
ITCH NEURON MECHANICAL
NPY ITCH
SCN CONTAGIOUS
GRPR ITCH?

SKIN DRG DORSAL HORN THALAMUS

FIGURE 2. Itch circuitry from the periphery to the brain. Itch-related G protein-coupled receptors (GPCRs)
and cytokine receptors on sensory neurons from the skin to the spinal cord are categorized as NP1, NP2, and
NP3 neurons. Some receptors are expressed in all NP1–3 neurons, whereas MrgprA3, an itch specific
marker, is present only in the NP2 population. The natriuretic peptide Nppb acts on its receptor NPR1 to link
transmission between dorsal root ganglion (DRG) and spinal neurons. Complex inhibitory and excitatory
interneuron activity modulates the signal that will be projected to the brain. Gastrin releasing peptide (GRP) and
GRP receptor (GRPR) are each key to excitatory itch circuits in the spinal cord. Inhibitory basic helix loop helix
5 interneurons (B5-I) and somatostatin (SOM) interneurons have inhibitory function. Loss of inhibition either by
neuronal depletion of B5-I interneurons or the inhibitory neurotransmitters GABA, glycine, or dynorphin results
in intensified itch. This pattern most likely occurs in chronic itch conditions. Enkephalinergic interneurons are
important in the gate control between intense pain and itch sensation. Mechanical itch is transmitted through
a different, so far unclassified, neuron population and second-order neurons in the spinal cord. The circuitry
does not involve excitatory GRP but includes the inhibitory neuropeptide NPY (neuropeptide Y). Contagious itch
in mice is relayed through GRPR⫹ neurons in the suprachiasmatic nucleus. [Modified from Dong and Dong
(71), with permission from Elsevier.]

cated in coping behavior associated with sustained pain and
itch (120).
The above-mentioned interneurons are the gate-keepers of
neuronal activity that modulate afferent input carried to the
projection neurons. Morphologically, interneurons show
heterogeneous features from islet, central, radial, and ver-
tical cells (41, 99). Readers are referred to excellent articles
that discuss interneuron morphology and function in detail
(317, 318). Biochemical characterization somewhat simpli-
fied the interneurons into the excitatory interneurons which
express vesicular glutamate transporter VGLUT2 (20, 243)
and neurochemical markers including PKC-␥, neurotensin,
and somatostatin, which also serve to define certain sub-
populations of excitatory interneurons (228, 229, 282).
The testicular orphan nuclear receptor 4 (TR4) is part of the
excitatory interneuron circuitry involved in the transmis-
sion of itch and pain (298). Selective deletion of TR4 in the
central nervous system resulted in loss of excitatory in-
terneurons in the superficial dorsal horn. Phenotypically,
TR4 mutant mice had increased mechanical responses but
reduced responses to heat and lack of responses to various
pruritogens. These findings favor the theory of converging
itch and pain circuitry in the spinal cord. Gastrin releasing
peptide (GRP), considered an itch-specific neurotransmitter
and its corresponding receptor GRPR, are in the excitatory
interneuron population (271, 272, 298) and may label an
itch-specific circuit, at least in mice. Ablation of GRPR⫹
interneurons affected itch behavior but not pain responses,
suggesting a distinction between pain and itch circuitry.
Peptidergic C-fiber input to the excitatory interneurons ap-
pears to engage the neurotransmitter natriuretic polypetide
b (Nppb) that is present in the TRPV1⫹ afferent neuronal
subset (186). Initially, GRP was identified as an itch-specific
neuropeptide released upon activation of peptidergic C-af-
ferents by pruritogens which led to activation of its cognate
receptor GRPR in the spinal cord (271, 272). The relative
roles of Nppb and GRP in the periphery have led to a
dynamic discussion in field of itch research. Currently, the
integrated concept is that Nppb is released from peripheral
afferents and induces GRP to be transmitted from spinal
cord interneurons. In accordance with its itch-specific role,
Nppb is expressed in the TRPV1⫹ subset that also coex-
pressed the members of the itch-associated mas-related G
protein-coupled receptor family members MrgprA3 and
MrgprC11 (170, 171). Hence, the neurons that express the
receptor for Nppb, namely, natriuretic peptide receptor
(Npr), are the first level of spinal cord neurons responsible

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 FERDA CEVIKBAS AND ETHAN A. LERNER
for the neural itch circuitry. In summary, the excitatory itch
circuit includes the peripheral release of Nppb, spinal GRP
and GRPR activation in spinal interneurons that are TR4⫹.
Complementary to the TR4⫹ interneurons, inhibitory in-
terneurons express the transcription factor Bhlhb5. Loss of
Bhlhb5 in basic helix loop helix 5 interneurons (B5-I) inhib-
itory interneurons results in excessive scratching without
alteration of pain responses (229). The majority of inhibi-
tory Bhlhb5 interneurons produce the neurotransmitter
␥-aminobutyric acid (GABA), which is diminished in
chronic conditions of itch and pain (FIGURE 2).
IV. LABELED LINE FOR ITCH IN MICE
In mice, acute itch is transmitted via pruritoceptive neurons
that respond to chemical stimuli. These neurons express
TRPV1⫹ and MrgprA3⫹ and fall predominately into the
NP2 and to a small extent the NP3 populations (FIGURE 2).
Acute and chronic itch are both relayed through this neu-
ronal populations (71) consistent with a specific “itch” la-
beled line in this species. Whether the labeled line transmis-
sion continues in pathological conditions has not been ad-
dressed. In general, itch-specific receptors discussed above
are all present in the NP2/NP3 population, including those
for interleukin (IL)-31, IL-4, and IL-13 (FIGURE 2). Capsa-
icin activates all TRPV1⫹ neurons, including the itch-spe-
cific MrgprA3⫹/TRPV1⫹ neurons. The NP1 population,
which is positive for MrgprD, is polymodal, responding to
itch, pain, mechanical, and thermal stimuli. That this pop-
ulation does not show overlap with NP2 or NP3 suggests
the existence of an additional line that imparts itch. In the
central nervous system, as discussed above, complex cir-
cuits encode itch. Briefly, this circuitry includes Vglut2⫹
neurons. Itch signaling is associated with the release of
Nppb, at least in the NP3 population. Since Nppb was not
detected in NP2 itch neurons, NP2 and NP3 populations
engage separate or overlapping circuitry for itch. In NP3
neurons, Nppb engages with its receptor NPRA followed by
communication to GRPR via GRP release in the spinal cord
(FIGURE 2). Mechanical itch is most likely transmitted
through low-threshold mechanoreceptors in which skin
structures such as Merkel cells might be involved (FIGURE
2). The mechanical itch-sensitive neurons have been shown
to connect to spinal NPY⫹ inhibitory interneurons that
receive low-threshold mechanical input. The circuitry of
contagious itch requires the presence of GRPR⫹ neurons as
discussed later (see sect. XVII).
V. NEUROANATOMY
Primary sensory neurons absorb information from the pe-
riphery to inform the spinal cord where somatosensory pro-
cessing continues. In general, the circuitry is spatially orga-
nized, with nociceptive and thermosensitive afferents enter-
ing the superficial spinal cord whereas the cutaneous and
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proprioceptive afferents target the ventral regions of the
spinal cord. Here, attention is directed towards embryolog-
ical development and organization in the spinal cord as
related primarily to pruritoceptive primary afferents and
spinal cord segments responsible for transmission and mod-
ulation of itch.
A. Development of the Spinal Anatomy
The spinal cord is generated from the vertebrate neural
plate that also gives rise to neural crest cells from which
most neurons and glia originate. The neural plate thickens
and invaginates, resulting in the rostro-caudal neural tube
formation. Expansion of the neural tube in the head region
leads to formation of the brain, whereas more caudally the
same neural tube expansion forms the spinal cord. The
neural tube closes along the entire body axis and neural
crest cells transition from epithelial to mesenchymal cells
migrating into distal parts of the embryo (159). The periph-
eral nervous system (PNS) is formed by cranial neural crest
cells and ectodermal placodes (30). Neural crest cells give
rise to dorsal root ganglia (DRG) neurons and sympathetic
ganglia of the PNS. The DRG neurons form bilaterally
along the developing spinal cord to innervate the skin and
various organs. Remaining neural tube elements generate
the truncal spinal cord which consists of only a single cell
layer (10). These cells of the epithelium divide and become
progenitor cells for the neural and glial cells within the
spinal cord which subsequently undergo cell differentiation
to form the grey and white matter of the spinal cord.
1. Laminar organization of the spinal cord
At different positions of the spinal cord, distinct neuronal
types are present along the dorsal-ventral axis, which re-
sults in the laminar organization of specific neurons accord-
ing to their functional and physiological properties (41, 99).
Laminar segregation of the neuronal functions within the
spinal cord segregate cells of motor function more ventrally
while cells mediating sensory information are present in the
dorsal horn. Lamina I–X in the adult spinal cord are deter-
mined by cytoarchitectonic parameters. Broadly, pain, ther-
mosensitive afferents, so called C- and A␦-fibers from the
dorsal root ganglion, innervate the lamina I–II, touch-sen-
sitive afferents enter the lamina II inner (i) to lamina V, and
lastly, proprioceptive afferents such as A␤ and A␦ target the
more ventral spinal cord including the motor neuron (MN)
region. A different labeling for Rexed laminae regions are as
following: marginal layer (ML) for lamina I, substantia ge-
latinosa (SG) for lamina II, nucleus propius (NP) for lamina
III–V, and MN for lamina IX (281). Various transcription
factors (TF) define during development the cytoarchitecture
and diversity of neurons in the spinal cord. The itch-specific
C-pruritoceptor fibers represent a subpopulation of the C-
nociceptors.
 ITCH
2. Spinal transcription factors and neuronal cell
development
The distinct combination and interplay of signaling path-
ways with homeodomain and basic helix-loop-helix
(bHLH) transcription factors (229) regulate neurogenesis
and define cellular identity in a tightly timed choreography
during development of the spinal cord (150). In the ventral
neural tube homeodomain, TFs are the drivers of neuronal
fate mapping during development (150). The expression
and presence of TFs during developmental stages is dy-
namic and often transient, i.e., bHLH factors ASCL1 and
ATOH1 and NEUROG1 appear in proliferating progenitors
but disappear during differentiation and once cells become
postmitotic. The lineage of pruritoceptors in the spinal cord is
presumably dependent on the proneural NEUROG1 which
has been described for their DRG development (175). In the
spinal cord, the same proneural lineage might represent
the precursors of itch-specific neurons. For itch circuits, the
bhlhb5 TF is developmentally crucial in determining the
itch-inhibitory interneurons (229). The transcription fac-
tors PAX2 and TLX3 are postmitotic and remain in post-
natal stages and are used as lineage markers for neuron
populations. A recent publication suggested that most in-
terneurons that receive pruritoceptive input lack PAX2 la-
beling (100). Sonic hedgehog is a morphogen that is crucial
for the patterning of the dorsoventral axis of the spinal cord
by either activating or repressing TFs (43, 97). Notch sig-
naling maintains cell proliferation while bHLH influences
cell differentiation. A concentration gradient of sonic
hedgehog regulates the TF expression which is later cross-
regulated by the bone morphogenetic proteins (BMP) and
WNT signaling for the generation of the dorsal cell types
(79, 241). BMP and WNT are instrumental in the genera-
tion of dorsal interneurons. The rostrocaudal axis is pat-
terned and positioned via the interplay of graded concen-
trations of fibroblast growth factor (FGF), retinoic acid
(RA), and transforming growth factor (TGF)-␤ member
GDF11 which regulate the expression of homeobox (HOX)
TFs in progenitor and postmitotic cells. Detailed discus-
sions of the developmental fate and signaling pathways in-
fluencing the neuronal map during development are avail-
able (45, 128, 161, 187, 292). Terminal neuronal pheno-
types are regulated by the expression of transcription
factors such as LHX2 and LHX9 which also promote ax-
onal guidance. Transiently expressed TFs such as bHLH
members ATOH1, PTF1A, and ASCL1 directly influence
gene regulation for the terminal fate of neuronal pheno-
types (37, 236). GABAergic neurons, enzymes, and inhibi-
tory neuron circuits, for example, are regulated by PTFA1
(37). These inhibitory neurons are fundamental to the pro-
cessing of itch signals in the developed spinal cord. Neurons
derived from the dorsal and ventral horns remain in their
original segments although the laminar structure is modi-
fied as the spinal cord neuronal map is finalized.
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VI. HUMAN VERSUS MOUSE NEURONS
Comparisons between mouse and human neurons have
now been made with respect to the peptidergic population
of nociceptors (231). Given that pruritoceptive neurons
form a small subset within the nociceptors, it may be rea-
sonable to consider that the similarities and differences are
transferable to the itch-specific population. Somata size and
neurochemical characterization by TrkA, a small diameter
neuron marker, as well as TrkB and TrkC which label larger
diameter neurons were similar between mouse and human.
In contrast, 50% of human neurons express TrkA⫹ and Ret
during adulthood, whereas the expression profile for Ret
and TrkA undergoes developmental changes in mice. Addi-
tionally, human TrkA⫹ neurons are colabeled with
TRPV1. Perhaps these double positive neurons have an evo-
lutionary advantage, to provide protection coverage during
heat or inflammation. It is speculated that the TrkA/TRPV1
neuron cluster responds to acute and highly localized pain-
ful stimuli. Perhaps a small subset of these double positive
neurons is responsible for itch transmission in humans. Hu-
man and mouse DRG neurons differ in their expression
profile and number of positive neurons responsible for the
transmission of itch and pain.
VII. CIRCUITRY AND GATING OF ITCH
The circuitry that controls itch transmission encompasses a
dense network of neurons within the superficial dorsal
horn, which is innervated by C- and A␦-fibers. Noxious and
pruritic stimuli are processed mostly in the superficial dor-
sal horn, whereas deeper dorsal horn neurons receive noci-
ceptive and pruritic input via polysynaptic innervation. In-
terplay between inhibitory and excitatory interneurons sets
the tone for the spinal input/output and sensitivity of the
message. The interneurons are defined by their neurochem-
ical and neuropeptidergic signatures (281), including the
expression of marker molecules SOM, neuropeptide Y
(NPY), and parvalbumin (PV) (317, 318). Generally, the
gross differentiation of interneurons into excitatory or in-
hibitory subsets is according to neurochemical and neuro-
peptidergic characterization. For example, SOM⫹ in-
terneurons excite neurons in the mechanical pain circuit by
two distinct mechanisms: 1) the superficial SOM⫹ in-
terneurons receive monosynaptic A␦- and C-fiber input to
process acute mechanical pain, and 2) the second SOM⫹
population in the deeper layers of the spinal cord receives
polysynaptic input that is modulated by intermediate inhib-
itory interneurons. These are engaged by A␤ afferents,
which are responsible for the transmission of nonpainful
mechanosensation. For this reason, activation of SOM⫹
interneurons directly results in spontaneous pain and de-
creased mechanical pain thresholds (58, 73). Additionally,
SOM⫹ interneurons broadly overlap with the expression of
excitatory mediators such as vesicular glutamate trans-
porter 3 (VGluT3) and calretinin (CR) which are known to
951
 FERDA CEVIKBAS AND ETHAN A. LERNER
amplify nociceptive messaging (257). In contrast to the
function of the second SOM⫹ population, inhibitory in-
terneurons in the superficial dorsal horn are essential for
controlling sensitivity to painful and itchy stimuli. Approx-
imately 40% of interneurons located in lamina I–III contain
the inhibitory neurotransmitter GABA, and defined as
GABAergic. In a subpopulation, the GABAergic neurons
coexpress, and most likely co-release glycine, the other ma-
jor inhibitory neurotransmitter. Within the deeper lamina
of the spinal cord, GABAergic interneurons are key factors
in the Gate Control Theory (183).
The Gate Control Theory introduced by (183) explains the
mechanism of control mediated by nociceptive and non-
nociceptive neuronal input. Lifting of this control leads to
peripheral and central sensitization processes seen in in-
flammation and pathological conditions of itch and pain.
The theory provides that non-nociceptive large-diameter
neurons “close” the gate by activating interneurons in the
spinal cord which in turn “inhibit the activation of projec-
tion neurons as crucial neuronal connectors to the supraspi-
nal nervous system” (41, 99). Noxious input is transmitted
by the nociceptors which are mostly peptidergic or nonpep-
tidergic, unmyelinated, slow conducting C-fiber afferents
and by a subset of myelinated A␦-fibers. Activation of the
nociceptors “opens” the gate and excites the projection
neurons and “turns off” the inhibitory interneurons. Essen-
tial players in the Gate Control Theory are morphologically
and neurochemically diverse inhibitory interneurons that
release inhibitory neurotransmitters to modulate pain mes-
sages (41, 99). It has long been acknowledged that loss of
inhibitory circuitry due to cellular and molecular changes
results in chronic pain and amplification of pain signals to
the brain. More recently, inhibitory interneurons were re-
ported to also control itch messages (58, 73). One of the
major neurotransmitters is GABA, which controls the sen-
sory gating of itch and pain transmission in the spinal cord
and marks the population of inhibitory interneurons (FIG-
URE 2). Besides GABA, inhibitory interneurons express
NPY, dynorphin (DYN), and galanin (155, 301). A subset
of DYN⫹ interneurons which also express glycine⫹ and
GABA⫹ might modulate the signal transmission by co-re-
lease of these neurotransmitters. However, it is unclear if
these neurotransmitters are differentially employed for the
inhibition of itch and pain messages.
The role of GABA in itch transmission has gained attention
in the last few years. Briefly, GABA signals via two distinct
types of receptors. GABA-A receptors are ligand-gated ion
channels that exist in pentameric structures. These also
serve as receptors for benzodiazepines and ethanol.
GABA-B receptors are metabotropic glutamate receptors
and belong to the group C family of G protein-coupled
receptors (GPCRs) (39, 40). The initial work on the role of
GABA and glycine in itch circuitry suggested that strych-
nine, a glycine-receptor antagonist, was more effective than
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GABA receptor antagonists in disinhibiting the sponta-
neous firing in the paws of itchy mice (6). A different
approach suggests GABA as a major inhibitory transmit-
ter in a mouse model of neuropathic itch as well as in-
flammatory chronic itch. With a cellular approach in
which medial ganglionic eminence (MGE) cells of the
forebrain are transplanted into the mouse spinal cord,
the group tested whether rescue of GABAergic control
impacted different itch phenotypes. In bhlhb5 mutant
mice, MGE transplantation of GABAergic cells resulted
in improvement of neuropathic itch (42). When tested in
IL-31TG mice, the MGE-GABAergic cell transplants also
successfully rescued the GABAergic tone and subse-
quently reduced the phenotypical severe itch (54).
The above-mentioned bhlhb5⫹ interneurons (B5-I) are cru-
cial in the control of itch. B5-I neurons receive input from
neurons that are activated by itch counterstimuli such as
menthol and capsaicin and act rather anti-pruritic. B5-I
neurons inhibit the excitation of the itch specific GRPR⫹
interneurons (discussed further below), which are activated
by pruritogen-specific circuitry. Dynorphin, a kappa-opioid
agonist, marks the B5-I interneurons (139). Dynorphin
might be the neurotransmitter that blocks itch mediated by
chemical counterstimuli, whereas GABA might be relevant
in blocking itch counterstimuli associated with scratching
(mechanical input).
In terms of excitatory circuitry specific for itch, the identi-
fication of GRP has gained attention. The recent attention
to GRP builds on work from Alan Cowan who demon-
strated in 1983 that bombesin, a peptide with tight se-
quence homology to GRP, caused scratching when injected
intrathecally (96). GRP has been reported to be expressed
in peptidergic DRGs, released upon pruritic stimuli, and
then communicates via GRPR in the spinal cord (271,
272). GRP was thus identified as the first itch-specific
neuropeptide engaged in the transmission from the pe-
riphery to the central nervous system. The details of this
role have been questioned (259). Newer studies describe
the release of Nppb from DRG neurons which induces
GRP circuitry in the spinal cord in response to multiple
pruritogens (186). Moreover, the GRP⫹ neurons are pre-
sumably excitatory interneurons. In summary, these find-
ings led to the current modality-specific circuit from
Nppb, Nppb-receptor (Npra), GRP, and finally GRPR. In
a different study, GRP-positive interneurons were found
to receive noxious input and gate nociceptive informa-
tion in the superficial dorsal horn. However, intense no-
ciceptive stimulation of the GRP⫹ interneurons recruits
enkephalinergic interneurons which in turn results in in-
hibition of the intense nociception (270). A “leaky gate
model” was described in which GRP⫹ interneurons code
itch but also receive nociceptive input and are thus
strongly activated by intense pain, triggering enkephalin
release which in turn inhibits pain.
 ITCH
Insight into the functional segregation of peripherally and
spinally expressed somatostatin uncovered the role of SOM
in itch modulation (119). It was demonstrated that optoge-
netic stimulation of SOM⫹ sensory neurons was sufficient
to evoke itch. In addition, SOM in combination with Nppb
or GRP potentiated the itch induced by pruritogens. Itch
induced by intrathecal SOM was attenuated by the release
of DYN from B5-I interneurons. This finding led to the
suggestion that itch induced by SOM was mediated via
inhibition of DYN⫹ neurons and subsequent disinhibition
of GRPR⫹ neurons. Additionally, SOM released by pri-
mary afferents suppresses pain, leading to the possibility
that at least SOM-modulated forms of itch might also in-
hibit pain, extending the concept of somatosensory regula-
tion by counterstimuli.
VIII. GLIA NEURON INTERACTION
Glia are implicated in chronic itch, consistent with their
involvement in inflammatory and neuropathic pain (13,
286 –288). Glia, from the Greek, meaning glue, were dis-
covered by Rudolph Virchow, the German anatomist. Vir-
chow suggested that glia provided a matrix for neurons to
be embedded in the brain. Glia have gained attention as
important modulators and communicators within the ner-
vous system in healthy and diseased tissue. In the periphery,
Schwann cells, or neurilemma, produce myelin sheets
around neuronal axons. Schwann glial cells (SGC) express
transient receptor potential (TRP) channels and modulate
neurogenic inflammation, pain, and eventually itch.
Schwann cells express TRPA1, which is linked to neuroin-
flammation (146). Silencing of TRPA1 in nociceptors
yielded mechanical allodynia attenuation without influenc-
ing microglia infiltration, whereas TRPA1 silenced in SGC
resulted in reduction of allodynia and signs of neuroinflam-
mation. The underlining mechanism of SGC-expressed
TRPA1 is speculated to occur via CCL2 release, which
serves as a chemoattractant for macrophages. SGC-specific
TRPA1 may function separately from TRPA1 on itch-spe-
cific neurons. Further studies are required to detail the im-
pact of SGC on inflammatory and chronic itch (FIGURE 3A).
Such studies may be of particular importance in light of the
identification of a mesh network comprised of specialized
cutaneous Schwann-glial cells that are essential for sensing
noxious (1).
Microglia, astrocytes, and oligodendrocytes are the neuro-
glia in the central nervous system (232). As with pain, acti-
vation of central glial cells has been reported to contribute
to itch in Nc/Nga mice, a mouse strain available in Japan
that is prone to develop itch under non-pathogen-free hous-
ing conditions (252). Astrogliosis, an abundance of reactive
astrocytes, was a feature involved in chronic itch. To ex-
plore the hypothesis of glial contribution to chronic itch,
morphological changes of astrocytes have been observed
over time. As compared with healthy, non-itchy mice, the
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astrocytes in the itchy mice were characterized by enlarged
bodies and aberrant arborized processes, a sign of astroglio-
sis.
Lipocalin (LCN), akin to some other glial transmitters such
as ATP, is linked to neuronal inflammation and in the mod-
ulation of neuronal excitability. In addition, intrathecal co-
injection of LCN2 together with GRP enhanced GRP-elic-
ited itch, suggesting that LCN2 plays a role in itch progres-
sion and the maintenance of chronic itch (FIGURE 3B).
Aligned with these findings, serum LCN2 levels are high in
atopic dermatitis and psoriasis patients (290), suggesting
that LCN2 might serve as a biomarker.
Toll-like receptor-4 (TLR4) expressed in astrocytes has also
been linked to chronic itch (172). TLR4 is a member of the
TLR family responsible for innate immunity, recognizing
exogenous ligands and pathogen-associated molecular pat-
terns (PAMP) in the course of viral or bacterial infections
(173, 174). They react also to endogenous ligands and dan-
ger-associated signals during tissue injury. Liu et al. (172)
showed that TLR4 knockout (KO) mice are characterized
by reduced spontaneous scratching and touch-evoked
scratching in models of dry skin and contact dermatitis. The
reduced behavior in the mice correlated also with less acti-
vated GFAP⫹ astrocytes in the spinal dorsal horn in
chronic itch mice. Of note, acute itch as induced by com-
pound 48/80 and chloroquine (CQ) were unaffected in
TLR4 KO mice. Activation of TLR4 by intrathecal lipo-
polysaccharide indeed evoked pain and suppressed itch but
still enhanced alloknesis and chronic itch, accompanied by
reduced astrogliosis. Astrocyte-expressed TLR4 may thus
contribute to the maintenance and sensitization of chronic
itch.
Microglia constitute another type of glial cell and surpass
neurons in number. They are derived from myeloid precur-
sors, constantly screen the environment for danger, and
have been implicated in maintenance of neuropathic pain
(284). Scratching triggered by compound 48/80 activates
microglia in the spinal cord (322). Like neuropathic pain,
activation of microglia occurs within minutes. This scratch-
induced microglial activation was detected with colabeling
for microglia (CD11b) and phosphorylation of p38. Inhibi-
tion of the scratching by nalfurafine, a ␬-opioid receptor
agonist, resulted in diminished microglial p38 phosphory-
lation. Unlike in pain, reactive microglia are not limited to
the dorsal horn of the cervical spinal cord. Glutamate or
ATP released by pruritoceptors might activate microglia or
itch-specific neurotransmitters such as GRP or Nppb,
which may then turn on microglial activation. Furthermore,
mast cells are essential to the recruitment of glial cells in the
spinal cord in neuropathic and neurodegenerative diseases
(95, 108).
953
 FERDA CEVIKBAS AND ETHAN A. LERNER

CYTOKINES / PROTEASES
NEUROPEPTIDES
TH2

BASOPHILS
CYTOKINES

SGC
MAST
CELLS

PROTEASES /
NEUROPEPTIDES

SCHWANN
CELL ITCH RESPONSES
TRPA1 SP
& SENSITIZATION

NEUROPEPTIDES

CCL2 PRURICEPTOR

B SPINAL DORSAL HORN

STAT3
itch signaling activation Activated
from periphery astrocyte

Pruriceptive
primary afferent LCN2

Aδ myelinated Central
fibers GRPR+ neuron

p38 MAPK
activation
Activated Itch
C-Nociceptors microglia signaling

C-Pruriceptors IIo

GRP
GABA / glycine dynorphin
IIi

III-IV

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 ITCH

IX. SENSITIZATION IN ITCH
Patients suffering from chronic itch, analogous to those
with chronic pain conditions, perceive intensified responses
to mild pruritic stimuli. This phenomenon is referred to as
sensitization. Dysesthesia, the Greek term for abnormal
sensation, captures the altered perception and somatosen-
sory changes occurring in itch and pain. Alloknesis in itch
and allodynia in pain are comparable terms describing the
dysesthesia in patients to non-itchy/painful stimuli such as
to fabrics. Exacerbated itch and pain to stimuli are catego-
rized under the terms hyperknesis for itch and hyperalgesia
for pain conditions. Some of the molecular and cellular
processes described above contribute to the sensitization
processes: loss of inhibitory control, activation of glial and
immune cells, and increase of excitatory activity in sensory
neurons. Touch-evoked pain is a concern in 50% of neuro-
pathic pain patients (127). It is not clear if touch-sensitive
neurons are responsible or whether touch-specific C-fibers
are switched on in neuropathic pain and increase the sensi-
tivity to message pain for touch.
Alloknesis has been defined as itch occurring to innocuous
but dynamic tactile stimuli, which can be mildly painful
(208) or above the activation threshold of mechanosensitive
C-nociceptors (38). The classic concept of alloknesis by
touch has been extended to itch sensitization by innocuous
warmth or noxious heat (12). Another phenomenon in AD
patients is cross-modality, where painful stimuli can en-
hance the itch sensation (114, 123). This form of dysesthe-
sia may be termed “algoknesis” (12). Akiyama et al. (5)
asked whether pruritogens cross-sensitize with respect to
behavioral and neuronal responses of cultured DRG neu-
rons. When bovine adrenal medulla 8 –22 (BAM8-22) was
injected, the group observed an enhancer effect on scratch-
ing behavior when followed by a second injection of
BAM8 –22 or the pruritogenic hexapeptide SLIGRL. DRG
neurons did not respond by mirroring the behavioral re-
sponses, suggesting a different cellular mechanism of the
ongoing behavioral effects (5). In contrast, SLIGRL appli-
cation induced cross-sensitization for BAM8 –22 which was
also reflected in increased neuronal activity of DRGs, not
only in the mean peak response but also the increase in the
number of responsive cells. SLIGRL reduced serotonin (5-
hydroxytryptamine or 5-HT) evoked scratching but did not
influence histamine. Histamine cross-sensitized behavioral
responses to BAM8 –22 but failed to induce increased neu-
ronal activity similar to the effects observed for BAM8-22.
One might speculate that neuronal changes as observed for
SLIGRL are upon effects on subsequent signaling elements
employed by the subsequent pruritogen. For example, ac-
tivity modulation of the respective receptor and/or the sig-
nal transduction receptors, such as TRPA1, on DRG neu-
rons might explain the cross-sensitization triggered by SLI-
GRL. These findings highlight the concept of peripheral
sensitization. However, these are limited to an acute setting
(immediate application of pruritogens) in mice, and how
these observations translate to humans is not clear.
The effects of continuous exposure to mediators on hyper-
knesis, alloknesis, and algoknesis remain to be determined.
In a dry skin model, Akiyama et al. (3) addressed the ques-
tion whether chronic itch cause sensitization of itch path-
ways. In this model, SLIGRL as well as 5-HT injection into
the dry skin caused hyperkinetic itch responses. These be-
havioral responses were also reflected by enhanced neuro-
nal activity of isolated DRG neurons from the itchy mice,
suggesting a peripheral sensitization for hyperknesis in the
dry skin model (3). Protease activated receptor (PAR)-2
mediated effects could result from other cellular sources
than DRGs in the phenomenon of hyperknesis given that
SLIRGL-mediated effects in itch versus pain have been dis-
puted (3, 105). Of note, other mediators and neuroactive
cytokines such as IL-31 or NGF might impact neuronal
activity, receptor distribution, as well as nerve fiber density
in an inflammatory setting such as in AD or other inflam-
matory conditions. For instance, in human surrogate mod-
els, intradermal injections of NGF had limited impact on
chemical itch sensitization, but were reported to induce hy-
persensitivity to pinprick (15). Sensitivity to pinprick has
been defined as hyperknesis which seems to be relayed by
polymodal C-fibers, whereas when occurring secondary to
an itch provocation, type I A␦-fibers relay through central
mechanisms the hyperknesis (14). In ultraviolet B-induced
inflammation, it is speculated that mechanically insensitive
fibers and mechano-nociceptors respond with higher inten-
sity to stimulation, implying that heightened activity has
been set through peripheral and central processes. A similar
contribution of peripheral and central sensitization is as-
sumed to occur in itchy lesions of AD patients to pinprick-
evoked hyperknesis (14). MrgprD-labeled C-fibers inner-
vating the superficial layers of the epidermis and transmit-
ting non-histaminergic itch, in this context of more
importance, are sensitized to punctate stimuli in a mouse

FIGURE 3. Glia-neuron interaction. A: in the periphery, Schwann cells are thought to modulate itch via TRPA1 channels and the release of
CCL2. While expressed in neurons and Schwann glial cells (SGC), silencing of TRPA1 in the latter resulted in reduction of sensitization and signs
of inflammation. B: spinal cord glia comprises microglia, astrocytes, and oligodendrocytes. Pruriceptors, a subpopulation of nociceptors, target
lamina II inner (IIi). Activated microglia as detected by increased p38 mitogen-activated protein kinase (MAPK) signaling (323) might modulate
the pruriceptors and the gastrin releasing peptide receptor (GRPR) neurons (itch signaling second-order neurons). The close proximity of GRPR
and gastrin releasing peptide (GRP) in spinal cord neurons enables direct interaction. Itch signaling and amplification of the itch signal might
result in a decrease of the inhibitory neurotransmitters (GABA, dynorphin, glycine) and simultaneously increase the excitatory activity via GRP.
Activated astrocytes (astrogliosis), detected by increased signal transducers and activators of transcription 3 (STAT3) immunolabeling, release
lipocalin 2 (LCN2) which plays a major role in itch progression and maintenance of chronic itch.

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 FERDA CEVIKBAS AND ETHAN A. LERNER
model of contact dermatitis (215). An underlying cause for
pinprick-induced hyperknesis may be the loss of polymodal
C-fibers and/or the sensitization of the remaining or a cer-
tain subset of them. However, one cannot exclude the cen-
tral component of sensitized pathways such as loss of de-
scending control from supraspinal levels and enhanced ex-
citement of spinothalamic tract (STT) neurons. For
instance, STT neurons respond more intensely to “normal”
input from pruritoceptive afferents (12) which results in
alloknesis or hyperknesis (12, 151). The discovery that
pain-related dysesthesias observed in patients are indepen-
dent from capsaicin-sensitive C-fibers, segment-restricted,
as well as myelinated-fiber modulated suggests a complex
interplay and synaptic connections, which might be similar
in itch-experienced dysesthesias. Another observation re-
lated to sensitization made in chronic itch is that innocuous
thermal stimuli affect serotonin-mediated but not histamin-
ergic itch (14). In general, there seems to be limited sensiti-
zation to histaminergic itch, but increased responses to
cowhage-induced itch in chronic itch patients. Addition-
ally, noxious heat and other algogenic stimuli, i.e., acetyl-
choline and bradykinin, evoke itch rather than pain in
chronically suffering patients (114, 123), suggesting that
tachyphylaxis does not occur with itch.
X. ITCH IN THE BRAIN
The brain represents the final station for the somatosensory
processing of itch. After the spinal coding of itch under
acute or sensitized conditions, the signals are transferred via
projection neurons, likely NK1R⫹ neurons, which connect
to the STT. The parabrachial nucleus (PBN) is the next
supraspinal itch processing station, which branches into
different brain regions. Most activated regions in the hu-
man brain are the primary and secondary somatosensory
cortex (S1-S2) as detected with functional magnetic reso-
nance imaging. In chronic itch patients, the cingulate and
prefrontal cortex reveal a more robust activity as compared
with healthy controls when each group is treated with his-
tamine. Descending control from higher brain regions mod-
ulates responses in the spinal cord (6). Serotoninergic neu-
rons from the nucleus raphe magnus (NRM) have been
shown to directly connect with GRPR⫹ neurons and to
potentiate itch. Noradrenergic neurons in the locus coer-
uleus modulate inhibitory interneuron activity in the spinal
cord. The periaqueductal gray (PAG) is activated during
scratching and was considered as an itch suppressing brain
area. Tachykinin-1 (Tac1) labeled neurons in the PAG fa-
cilitate itch since their ablation significantly abolishes itch
behavior in acute and chronic models. Direct activation of
the Tac1⫹ neurons causes itch behavior in mice (92). This
descending faciliatory pathway from Tac1⫹ PAG neurons
was not linked to serotoninergic control.
The pleasure of scratching an itch is processed in the mid-
brain reward center. GABAergic and dopaminergic (DA)
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neurons in the ventral tegmental area (VTA) partake a role
in the central processing of itch. In general, DA neurons are
key neuronal elements in motivation and reward systems
(66b), whereas GABA neurons are believed to drive aver-
sion and disrupt reward processes (277). VTA GABA neu-
rons are activated in acute itch and show an intensified
activation when scratching is prevented, suggesting a func-
tion in processing the aversive and unpleasant components
of the itch sensation. Intriguingly, DA neurons in the VTA
are activated temporally delayed, and the activation is
linked to the scratching behavior of the tested animals.
These data support the concept that the midbrain VTA DA
neurons might transfer the central pleasure component of
scratching an itch. Chronic itch processing in the VTA was
demonstrated to occur via DA and GABAergic neurons,
suggesting a general function of the midbrain region to
control acute and chronic itch. Another center in the brain
is responsible for the integration of the affective component
of itch. As shown for pain (325), the amygdala links anxiety
and stress affections to chronic itch (242). Even though
both sensory modalities converge in shared central regions,
pain and itch are discernable from each other. The central
pathways and circuits that differentiate itch from pain over-
lap anatomically, and the mechanisms by which these sen-
sations are distinguished remain to be determined. Central
mechanisms of contagious itch relay via the GRP-GRPR
axis in the suprachiasmatic nucleus (SCN) in mice as dis-
cussed in section XVII.
XI. G PROTEIN-COUPLED RECEPTORS
7-Transmembrane receptors or GPCRs are exquisitely associ-
ated with itch arising in the periphery. Their ligands are direct
mediators of itch when the cognate receptors are expressed on
neurons and indirect when the receptors are expressed on non-
neuronal cells. Extensive tables that list GPCRs associated
with itch have been published, yet data supporting the impor-
tance of any particular GPCR in any acute or chronic clinical
itch are remarkably limited. GPCRs that are most strongly
associated with human itch are discussed, including mem-
bers of the Mas-related G protein-coupled receptor (Mrgpr)
family.
Itch arising in the periphery can be divided into two broad
categories: histamine dependent and histamine indepen-
dent. Clinical itches associated with histamine are now con-
sidered limited primarily to some patients with urticaria
and drug reactions with a lesser role for histamine in AD
and other conditions. This limitation accounts for the rela-
tive ineffectiveness of antihistamines in itch. It follows that
histamine-independent itch is the primary driver of itch that
arises in the periphery. The foundation for this understand-
ing is built on a number of observations. These observations
include the identification of mechanosensitive C-fibers re-
sponsive to cowhage but not histamine (132), that the active
component of cowhage stimulates Mrgprs, and that addi-
 ITCH

tional substances that evoke itch in humans and scratching distribution limited primarily to sensory neurons and mast
in mice stimulate specific GPCRs unrelated to histamine cells, together with the appearance of Mrgprs in tetrapods.
receptors. It is now recognized that the large number of Mrgpr genes
in mice, due to a retrotransposon insert was the exception,
as other rodents had fewer, and humans have eight. Mrgprs
A. Mrgprs
were divided into subclasses based on sequence homology.
Mice have A, B, and C subclasses, which correspond loosely
Mrgprs have risen to prominence with respect to itch that is
to human X1– 4 while both species have D, E, F, and G
independent of histamine. This prominence is manifest in a
(FIGURE 4). Ironically, canines, considered excellent at
number of ways and provides a basis for the discussion
here. First, Mrgprs respond to a variety of pruritogens, and scratching, were found to have only a single Mrgpr, homol-
these links are examined (FIGURE 4). Second, the expression ogous to X2. These confounding observations raised the
of Mrgprs is limited primarily to sensory neurons impli- possibility that while most GPCRs were activated by a small
cated in itch as well as mast cells, long implicated in itch and number of ligands, perhaps Mrgprs were broad sensors,
allergy, and is also discussed. Neurons and mast cells are in which turns out to be the case.
close proximity and are considered to interact directly in
epithelia where neuroimmune interactions are prominent A role for Mrgprs in itch was first suggested in 2009 when
and where neurogenic inflammation takes root. it was found that CQ induced scratching in mice that was
dependent on MrgprA3 and that CQ could also activate
Mrgprs comprise a family of orphan GPCRs identified early human MRGPRX1. The year before, Reddy, Lerner, and
in this century by an academic group led by Xinzhong Dong co-workers (224) isolated mucunain, a cysteine protease
(72) while a postdoctoral fellow with David Anderson at that was the active component of cowhage. While we found
Caltech and now at Johns Hopkins, and a group led by that mucunain, and subsequently the endogenous cysteine
Paola Lembo and Sultan Ahmad, at Astra Zeneca (163). protease cathepsin S associated with itch and inflammation,
The respective groups referred to the receptors as Mrgprs could activate protease-activated receptors, further studies
and sensory neuron-specific receptors. The encoding of ~50 revealed that these proteases targeted Mrgprs (222, 224).
Mrgprs in the mouse indicated initially that only olfactory The surprising finding that a protease could evoke itch via
receptors were more numerous. A potential role in sensing activation of a Mrgpr served to inform further studies that
was appreciated given the additional combinations of tissue would explain a long-standing discrepancy between mouse

MOUSE CHROMOSOME 7
A6 A9 A11 A1 A10 A2 A14 A3 A12 A16 A19 A4 C11 B5 B4 B6 B8 B1 B10 B2 B3 B11 E G F D
,
Der p1, cowhage, Bam8-22

ns
ge
co w h

SP
er

,4
ch

all

8/8
lo

ag e,

do

0,
ro

LL
eu
qu

- 37
ps
in

Cat S
e

e
in,
bi l

in
ox

an
ir u

, SLIG

∂t

al
bin

ph

β
ta
,S
RL

80
bi l
e

8/
ac

,4
ids

SP

E G X3 X4 X1 X2 D F

HUMAN CHROMOSOME 11

FIGURE 4. Mrgpr gene loci and receptor ligands in mice and humans. All Mrgpr genes are located on
chromosome 7 in the mouse and chromosome 11 in humans. While still considered orphan receptors,
substances known to activate specific mouse and human Mrgprs are indicated. Note that some substances
which activate a single human receptor interact with more than one mouse Mrgpr. Similarly, some substances
which activate a single mouse Mrgpr interact with more than one human receptor.

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 FERDA CEVIKBAS AND ETHAN A. LERNER
and human studies involving SP. Specifically, SP is linked to
itch, pain, and neurogenic inflammation. A series of publi-
cations revealed that the peripheral actions of SP are medi-
ated via Mrgprs, throwing a wrench into the conventional
view that NK1 was the primary receptor for SP. NK1 an-
tagonists were developed in the 1990s and found to be
effective in mouse models of itch and inflammation but
failed in the treatment of inflammation in humans. Prelim-
inary results from uncontrolled studies suggested that oral
administration of the NK1 antagonist aprepitant might be
useful for the treatment of chronic itch. These results could
not be confirmed in controlled studies (285). Topical appli-
cation of aprepitant was also ineffective in itch (296). More-
over, NK1 mutant mice still scratched when injected with
SP (28). In contrast, Mrgpr cluster ⌬⫺/⫺ mice, which lack
12 Mrgprs but retain mast cell SP-responsive MrgprB2, did
not scratch. SP-evoked scratching was found to be depen-
dent on neuronally expressed murine MrgrpA1 while SP
activated human MRGPRX2 (27), a finding that has re-
cently been extended to pain (98). The explanation for the
conflicting findings between mice and human turns out to
be simple: The NK1 antagonists were also antagonizing
mouse Mrgprs but had no impact on human Mrgprs. These
observations make Mrgprs interesting therapeutic targets
for the treatment of itch.
As there are more Mrgprs in mice relative to humans, map-
ping with respect to ligand specificity would not be expected
to be one-to-one, and it is not (FIGURE 4). Several itch me-
diators as well as substances implicated in allergy, pseudo-
allergy, and inflammation activate only individual human
MRGPRs, but some of these substances activate more than
one mouse Mrgpr. Linking a specific endogenous substance
with a pathological itch has now occurred. Bile acids acti-
vate human MRGPRX4 (182) and can account for choles-
tatic itch. That cholestatic itch does not occur readily in
either mice or canines is consistent with the lack of a
functionally homologous receptor in these other species.
It is not much of a speculation to think that the itch of
chronic kidney disease, which is limited to humans, may
also result from an endogenous ligand activating a
Mrgpr. Three receptors in humans, MRGPRX1,
MRGPRX2, and MRGPRX4, are thus considered to fulfill
the roles of the A, B, and C subclasses of Mrgprs while
␤-alanine activates MrgprD in both species.
With respect to cellular expression, in humans, MRGPRX1
and MRGPRX4 are expressed only on sensory nerves.
MRGPRX2 is expressed on mast cells but has also been
identified on DRG neurons (226, 311). While MRGPRX2 is
not readily identified in neurons based on RNAseq of rest-
ing neurons, expression has not been considered during the
process of neurogenic inflammation, a critical knowledge
deficit in the context of intercellular and mediator crosstalk.
With respect to expression in mice, MrgprB2 is limited to
mast cells and considered generally homologous to human
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MRGPRX2. The Mrgprs A1, A3, and C11 are limited to
sensory nerves. While MrgprA1 is highly expressed only
during development, the low level of expression in adult
mice retains function, as mice scratch to bilirubin.
The affinity for ligand receptor interactions is critical. Thus
SP activates MrgprB2, MrgprA1, and MRGPRX2 (FIG-
URES 4 AND 5). MrgprB2 is still present in the Mrgpr cluster
⌬⫺/⫺ but SP does not cause scratching in these mice. Thus,
in mice, SP causes itch by activating MrgprA1 on sensory
nerves rather than activating MrgprB2. In humans, if
MRGPRX2 is only on mast cells, then SP evokes itch by
stimulating mast cells. In this scenario, the mouse receptors
MrgprA1 and MrgprB2 share functional homologies with
human MRGPRX2. This concept is consistent with single
human receptors sharing function with multiple mouse
Mrgprs as noted in FIGURE 4. This concept is supported
further by the following observations. SLIGRL, the hexa-
peptide derived from PAR-2, but which stimulates Mrg-
prC11 on sensory nerves in mice to evoke itch, also acti-
vates MRGPRX2, while the potent itch inducer compound
48/80 activates Mrgprs expressed on mast cells and neu-
rons. Returning to cysteine protease activation of Mrgprs,
while cathepsin S activates MrgprC11 and MRGPRX2, the
dust mite cysteine protease Der p1 associated with allergy
and inflammation, but not itch, activates MrgprC11 and
MRGPRX1 while cowhage activates human MRGPRX1
and MRGPRX2. Finally, vancomycin which is implicated
in red man syndrome and staphylococcal delta toxin which
is associated with atopic dermatitis, and thus itch, activate
MRGPRX2 (213).
Neuronal expression of Mrgprs has allowed these receptors
to serve as markers or fluorescent tags that have been used
to trace pathways of itch in mice. Of particular importance,
MrgprA3 fibers were found to innervate the epidermis ex-
clusively and respond to mechanical stimuli, noxious heat,
and a number of pruritogens (103). These are features of
non-histaminergic, polymodal itch fibers. Ablation of these
fibers with the aid of diphtheria toxin resulted in decreased
scratching behavior from a range of pruritogens while pain
sensations were intact. Evaluation of dry skin and allergy in
these mice, considered chronic models of itch, were also
modulated. Mice were engineered further to express
TRPV1 only in MrgprA3 neurons, and then treated with
capsaicin. Scratching but no pain behavior was evoked.
These studies established the existence of a labeled line for
itch, at least in mice, in contrast to the prevailing intensity
theory of itch versus pain.
A number of areas of Mrgpr biology in general and itch in
particular remain to be clarified. 1) Beyond bile acids, what
are the physiological endogenous or exogenous ligands for
Mrgprs, and what might that imply about Mrgpr biology in
humans versus mice, canines or non-human primates? 2)
Do human Mrgprs of the E, F, or G subclasses have rele-
 ITCH

ION CHANNELS
BILIRUBIN/SP
TRPA1
MrgprA1 TRPV1
G PROTEIN CHLOROQUINE
COUPLED
RECEPTORS MrgprA3

VOLTAGE-GATED
CYSTEINE PROTEASES ? REQUIRE SODUM
BAM8-22 BOTH NaV 1.7 /1.9
Gβy CHANNELS
MrgprC11

GDq
PLCβ

MAPK IL-31RD
GDs cAMP ERK
SEROTONIN H7R
IL-31
PLA2 OSMR
PLCβ JAK/STAT
GDq PKC IL-4RD
CYTOKINE
RECEPTORS
IL-4
IL-13RD1 IL-13
H1R/H4R

HISTAMINE

FIGURE 5. Sensory neuronal receptors and signaling molecules for the transduction of itch. Sensory
afferents express a multitude of receptors, providing redundancy to ensure the transmission of acute and
chronic itch signaling. A number of these receptors are depicted here, including serotonin-5-hydroxytryptamine
receptors (5-HTRs), promiscuous murine itch receptors MrgprA1/A3/C11, cytokine signaling receptor
complexes interleukin (IL)-31RA, oncostatin M receptor ␤ (OSMR␤), and IL-4Ra and IL-13R and voltage-gated
sodium channels (Nav). A plethora of downstream signaling molecules link receptor activation with generation
of action potentials, the details of which remain to be determined. In persistent itch, signaling might increase
receptor expression, including the itch-related signaling transducer channels TRPV1 and TRPA1. It remains to
be investigated whether downstream signaling mediators such as the mitogen-activated protein kinase (MAPK)
and Janus activated kinase (JAK)/signal transducers and activators of transcription (STAT) acutely alter
itch-relevant receptors via sensitization or on transcriptional levels. BAM8-22, bovine adrenal medulla 8-22;
PKC, protein kinase C; PLA, phospholipase A; PLC, phospholipase C; SP, substance P.

vance to itch? 3) Since MrgprA3 neurons are considered
nonpeptidergic but respond to SP, can peptidergic and non-
peptidergic neurons communicate directly? 4) Is expression
of neuronal Mrgprs inducible during the course of neuro-
genic inflammation? 5) While CQ induces scratching in
mice and can activate human MRGPRX1, hydroxychloro-
quine, a derivative, is used widely in the therapy of autoim-
mune conditions but rarely triggers itch. Therefore, might
the itch associated with CQ in Africans be linked to a Mrgpr
polymorphism? 6) As elevated levels of MRGPRX2 on mast
cells correlate with severe urticaria (87), it may be reason-
able to expect that Mrgpr polymorphisms will be associated
with, or protect from, acute or chronic itches.
Taken together, Mrgprs on mast cells and neurons provide
powerful links between itch, allergy, and neurogenic in-
flammation. The recent identification of a Mrgpr antagonist
that inhibits itch in mice (28) and the demonstration of
residues critical for activity via in silico modeling and in
vitro activity (157, 223) are consistent with the possibility
that drugs that target this class of receptors will be identified
and evaluated for therapeutic benefit.

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 FERDA CEVIKBAS AND ETHAN A. LERNER
B. NK1R
Tachykinins are a family of neuropeptides. They stimulate
rapid contraction of intestinal muscles as compared with
the slow effects mediated by bradykinins. The best-known
tachykinin with respect to itch is SP. Until recently, the
cognate receptor for SP in the periphery has been considered
the neurokinin-1 receptor, NK1R. It is now appreciated
that while NK1R may have a role in the spinal cord with
respect to itch, the relevant receptors for SP in the periphery
are members of the Mrgpr family, discussed above. This
shift in our understanding parallels the realization that the
role of the H1 receptor in clinical itch is remarkably limited.
SP is detected in primary sensory nerves that innervate the
epidermis, dermis, blood vessels, and various cell types. SP
exerts differentiated function on different cell types and
cutaneous structures. For example, it has been suggested
that SP upregulates NGF in keratinocytes which would af-
fect neuronal regeneration (44) or lead to sensitization. A
key role for SP in neurogenic inflammation is via close vi-
cinity to cutaneous blood vessels which is aggravated
through the additional feed-forward loop of NGF-depen-
dent upregulation and release of SP in endothelial cells
(185). Moreover, these tachykinin-marked sensory neurons
are classified as the unmyelinated C-fibers which mark the
C-nociceptors and the thinly myelinated A␦-fibers, both of
which conduct nociceptive stimuli and mediate the neuro-
genic inflammation. In addition to SP, CGRP is equally
present and released from perivascular nerve fibers and is
responsible for the flare in neurogenic inflammation (94,
211), although CGRP does not cause itch. NK1R⫹ neurons
in the spinal cord appear to mark projection neurons for
messaging itch and pain to supraspinal levels. The genera-
tion of knockin mouse with a Rosa 1s tdTomato reporter by
the Ross group is enlightening (117). Within the skin, the
authors detected Cre-mediated recombination in dermal fi-
broblasts but not in mast cells, endothelial cells, Merkel
cells, or Langerhans cells as elsewhere described. The lum-
bar spinal cord showed tdTomato labeling within lamina I
while deeper levels of the spinal cord stained for NK1R.
NK1R labeling was detected in most projection neurons,
important cross points for the transmission of pain and itch
(8). In this context, it was reported that ablation of the
NK1R⫹ cells in the spinal cord of the rat attenuated the
scratching responses elicited by 5-HT. The study revealed
that NK1R⫹ and GRPR⫹ neuron toxic ablation in an an-
imal model of chronic itch with ovalbumin (OVA) treat-
ment showed that SP-SAP resulted in reduction of sponta-
neous scratching and alloknesis scores. Toxic ablation of
GRPR⫹ interneurons did not affect either scratching re-
sponses or alloknesis (49). This finding suggests that the
spinal GRP-GRPR axis is not essential for itch sensitization.
Intriguingly, the lack of the GRPR neurons as well as the
NK1R⫹ resulted in significant reduction of enhanced re-
sponses to CQ. The segregation for this observed function
of the spinal GRPR neurons may be linked to peripheral
sensitization (hyperknesis) versus spinal action of sensitiza-
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tion (alloknesis). Nevertheless, spinal NK1R⫹ neurons
seem to play a role in both sensitized responses as well as the
itch of OVA– mice, possibly due to a selective central sen-
sitization of these spinal neurons and their polysynaptic
nature. However, there is contradictory data suggesting
functional NK1R in TRPV1⫹ rat DRG neurons popula-
tion, implying a peripheral role in nociception, particularly
in heat hyperalgesia (319).
In summary, most of the data described suggest an ascend-
ing spinothalamic role for NK1R⫹ neurons in itch. Overall,
these findings can explain the limited success of NK1R an-
tagonists in the treatment of itch.
C. PARS
PARs are encoded by four distinct genes, PAR-1 to PAR-4
(63). PAR-1 is the receptor for thrombin. Trypsin was
found to activate PAR-2 (202). PAR-3 and PAR-4 were
cloned by mRNA screening of rat platelets (310). PAR-1,
-3, and -4 are expressed on neuronal, epithelial, astrocytes,
and immune cells (204). Protease cleavage of PARs un-
masks a sequence which acts as a tethered ligand and binds
to conserved sequences to induce transmembrane signaling
(204). The sequence of the tethered ligand is characteristic
and distinct for each PAR, with SLIGRL derived from
mouse PAR-2 being the most studied. PAR-induced cellular
signaling engages either G proteins or arrestins. For exam-
ple, PAR-1, -2, and -4 interact with G proteins, which re-
sults in activation of different kinases such as mitogen-ac-
tivated protein kinase (MAPK) or phosphatidylinositol
3-kinase (PI3K) or protein kinases as well as tyrosine ki-
nases depending on the activating ligand and residual cell
type (266). The activation of PARs increases transcription
of cytokines, chemokines, and growth factors which regu-
late different cellular processes.
Proteases have long been recognized as mediators of non-
histaminergic itch. Itch induced by mucunain, the active
ingredient of cowhage, was first described by Arthur and
Shelley in 1955 (22). Mucunain induces long-lasting, hista-
mine-independent itch without pain. Arthur and Shelley
(22) speculated that mucunain might be a protease and
induce itch directly via action on sensory nerves or via an
indirect mechanism through the release of pruritic com-
pounds. Protease-induced non-histaminergic itch was in-
vestigated, identifying trypsin and chymotrypsin as prurito-
gens (140). Overexpression of proteases or PAR-2 in mice
results in a severe eczematous phenotype (86). Moreover, in
a severely itchy mouse strain overexpressing serine protease
channel activating protease-1 (CAP-1/Prss8), the phenotype
could be rescued by backcrossing into PAR-2 KO animals.
The concept of PAR-2-mediated itch was challenged by the
discovery that the synthetic peptide SLIGRL also activates
MrgprC11. It was found that SLIGRL-induced itch was lost
in Mrgpr cluster ⌬⫺/⫺ mice. MrgprC11 relies on the pres-
 ITCH
ence of the RL-NH2 sequence of the synthetic peptide. The
controversy has not been fully clarified, but the possibility
remains that the naturally occurring proteases might trigger
itch via PAR-2. Steinhoff and colleagues (140)suggested
that trypsin and tryptase activate PAR-2 on DRG neurons
to trigger histamine-independent itch and both proteases
induce neurogenic inflammation and activate PAR-1 and
PAR-4. PAR-2 is also involved in pain, which complicates
the picture. Effects were reduced in PAR-2-deficient mice,
suggesting that the major neuronal function of PAR-2 is to
induce hyperalgesia. Trypsin-mediated itch in mice did not
require the presence of either MrgprC11 or PAR-2, imply-
ing the involvement of an additional receptor, perhaps
PAR-4, which is expressed in rodent DRG neurons (23, 25).
Regarding signaling, Patricio et al. (209) employed the
PAR-4-specific activating hexapeptide AYPGKF-NH2
(AYP) to show that AYP activated the TRPV1⫹ neuron
population and that AYP-elicited itch was diminished in
TRPV1-deficient mice. The TRPA1 antagonist HC-
0300310 blocked AYP-elicited itch, suggesting the involve-
ment of this channel. However, TRPA1-deficient mice
showed augmented scratching to AYP that was mirrored in
calcium studies of TRPA1⫺/⫺ DRG neurons when stimu-
lated with AYP. A compensatory mechanism might play a
role in the heightened responses to AYP in TRPA⫺/⫺ mice
and neurons. Another controversial finding of the study is
the colocalization of PAR-4 with GRP in peripheral neu-
rons (209). The GRPR antagonist RC-3095 blocked itch
induced by AYP in mice, suggesting the involvement of
GRP-GRPR circuitry. Due to its ability to cross the blood-
brain barrier (9, 19), RC-3095 might exert its effect cen-
trally to block GRPR consistent with prior findings by
Mishra and Hoon (186). Future studies with more specific
genetic knockout animals will be needed to fully explain
this complex picture and its relevance to humans.
D. Histamine
Histamine is one of the most studied substances in preclin-
ical and clinical research. However, its importance in clini-
cal itch outside of urticaria and drug reactions is now con-
sidered limited, as that of histamine-independent itch has
gained favor. Histamine is a short-acting, endogenously
produced, widely distributed biogenic amine (253). Playing
a major role in allergic associated inflammation, histamine
regulates the maturation, activation, and chemotaxis of im-
mune cells (278) besides exerting immune regulatory func-
tions on monocytes, T cells, macrophages, and various
other immune cells (158). Histamine activates, with differ-
ent affinities, four distinct GPCRs, H1– 4, named chrono-
logically in order of their discovery (2). Histamine, the gold
standard for histaminergic itch mechanisms studies (FIG-
URES 1 AND 5), causes intense itch accompanied by vasodi-
lation, redness, flare, and swelling in human when applied
to the skin. In mice, histamine is often used as a positive
control in the context of investigations that involve other
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pruritogens. The major source of histamine is differential
granule release, together with other bioactive substances,
from mast cells, following IgE- or Mrgpr-dependent stimu-
lation. Histamine may be released from additional types of
cells, including neurons, basophils, and keratinocytes. H1
and H4 receptors are expressed on DRGs (FIGURE 5), al-
though the expression on the latter is low (293). H1R cou-
ples to G␣q/11 G protein and induces signaling via phospho-
lipases A2 (PLA2) and phospholipase C (PLC)-␤3 as well as
protein kinase C-␦ (124). H4R couples to G␣i/o proteins
and is also expressed on a variety of immune cells and other
cell types from the intestine and lungs (66a). Neuronal ac-
tivation of itch via histamine is linked to TRPV1 (124) as
well as TRPV4 (144).
The first antihistamine directed against the H1R, phenben-
zamine, was marketed in 1942. H1 antihistamines act to
downregulate constitutive receptor activity and are thus
inverse agonists rather than H1-receptor antagonists (164).
First-generation antihistamines are known for their seda-
tive side effects. It was not until three decades later that the
H2R antagonist cimetidine was put into clinical use for the
treatment of gastric acid disorders. The first H3 inverse
agonist is in use for narcolepsy (147). Cetirizine is a second-
generation H1R antagonist. It is a metabolite of hy-
droxyzine, a widely used first-generation antihistamine.
JNJ 7777120 is the first highly selective H4R antagonist,
but its development has been curtailed due to adverse ef-
fects. Other H4R antagonists are under clinical evaluation
for inflammatory disorders such as AD (300), while serli-
forant is a H4R antagonist undergoing evaluation for ves-
tibulopathy (24).
Urticaria or hives are recurrent, pruritic, and characterized
by central swelling with surrounding erythema in any body
region. In contrast to most itches, the urge to scratch may be
replaced with an urge to rub. What underlies the response
of rub versus scratch remains a mystery. Urticaria lasts less
than 6 wk in the acute form and may be associated with
medications (nonsteroidal anti-inflammatory drugs, opi-
ates, and narcotics), foods, viral infections, and contact al-
lergens. Fifteen percent of such patients also have angio-
edema. Chronic urticaria continues for more than 6 wk and
may be associated with autoimmune disorders such as sys-
temic lupus erythematous. H1R antagonists have been a
mainstay of treatment, although many are now treated with
biologics directed to IgE and additional targets. It is increas-
ingly appreciated that SP may be a major player in chronic
urticaria as well as chronic spontaneous urticaria (CSU)
which is characterized by spontaneous lesion reappearance.
High levels of SP have been detected in CSU patients.
Emerging concepts suggest that SP activates MRGPRX2, an
emerging therapeutic target on mast cells, and participates
in urticaria and the release of multiple allergens, including
histamine. Antihistamines have been widely used in the
treatment of allergic disorders for decades based on findings
961
 FERDA CEVIKBAS AND ETHAN A. LERNER
that histamine promotes inflammation and modulates im-
mune responses. Beyond itch, HR are associated with tu-
morigenesis, manifest as either promoting or inhibiting tu-
mor growth (181). Histamine was believed to promote neu-
roinflammation in diseases such as multiple sclerosis;
however, this finding has been questioned as blocking H4R
enhances inflammation (31). There have been discussions
about histamine in the role of airway inflammation based
on its activity on lung macrophages and the subsequent
induction of pro-inflammatory cytokines such as IL-6. In an
animal model of allergic airway inflammation, H4R KO
animals showed less pulmonary infiltration of eosinophils
and lymphocytes with a concomitant reduction of TH2 im-
mune activation (74). Blocking H4R in a model of pulmo-
nary fibrosis showed beneficial effects in reducing inflam-
mation (176, 177). Histamine activates also H1R on pul-
monary epithelial cells and induced TLR3 expression
leading to IL-8 secretion to accentuate inflammation. De-
pending on the cell population that is driving the disease
pathology, targeting either HR might be beneficial. In an
AD model, H4R blocking attenuated itch responses in mice,
presumably through reduction of IL-31 secretion from TH2
cells (230). Blocking H4R showed promising results in the
psoriasis-like model, induced with imiquimod, through re-
duction of TH1 responses. These findings underline the
pleiotropic effects of histamine. Of note, histamine exerts a
protective role in some other preclinical models such as in
the trinitrobenzene sulfonic acid model of colonic inflam-
mation in mice (309). In contrast, when colitis was induced
with dextran sodium sulfate, targeting H4R improved the
condition in this model (244).
E. Serotonin
5-HT is a monoamine neurotransmitter. Injection of sero-
tonin into skin causes itch in humans (34, 299) and scratch-
ing in mice (190). Despite much research, including data
linking serotonin to allergic skin disease and to pruritus
associated with both uremia and cholestasis (279), the im-
portance of serotonin as either a peripheral or central me-
diator of itch in humans is unknown. This uncertainly is
likely a reflection of the complexity of the serotonergic sys-
tem. This complexity is exemplified by the existence of 14
serotonin receptors from 7 receptor families (106). All are
GPCRs except for 5-HT3, which is a ligand-gated ion chan-
nel. The diversity of receptors makes it challenging to know
exactly which are important in itch. Most of these receptors
are expressed in spinal neurons involved in ascending trans-
mission. In the periphery, serotonin can be released from
mast cells, platelets, and endothelial cells during injury and
inflammation and acts on small- to large-diameter DRG
neurons (307). Serotonin is a component of the inflamma-
tory soup known to excite A␤- and C-fibers (156). Treat-
ment of pruritus by targeting serotonin receptors adds com-
plexity rather than clarification. SSRIs can help treat pruri-
tus, but they increase serotonin (centrally) by preventing
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reuptake. Ondansetron, an antagonist at the 5-HT3 chan-
nel, anecdotally can be of benefit in the treatment of chole-
static itch, uremic itch, and opioid itch. However, such
anecdotes provide limited useful information.
F. Additional GPCRs
Endothelin-1 (ET-1) is a 21-amino acid peptide and potent
vasoconstrictor implicated in pruritus (142). Produced by
endothelial, immune, and neuronal cells, ET-1 engages with
two GPCRs, endothelin-A receptor (ETAR) and endothe-
lin-B receptor (ETBR). In mice, ET-1 mediates itch behavior
via ETAR and ERK1/2. ETAR⫹ neurons are of peptidergic
origin and overlap with most of the itch receptors. ET-1
induces robust itch responses and is often used in rodent
research as a non-histaminergic itch agent and has also been
administered to humans via iontophoresis. Intriguingly, the
responses in humans seem to be partially linked to hista-
mine-induced itch, most likely via mast cell release based on
the findings that a H1R blocker partially blocked the itch
responses (142). It would be of interest to test other HR
blockers to delineate whether ET-1 is histamine-related itch
inducer in humans.
Prostanoids are derived from membrane lipids. Prostanoids
are formed via the cyclooxygenase (COX) pathway from
arachidonic acid (AA). Prostaglandins are the unstable
forms of prostanoids and have been implicated in itch. Pros-
taglandin E2 (PGE2) is itch-inducing in AD patients, but this
seems to rely on histaminergic itch (113). Despite increased
levels of prostanoids or other AA derivatives such as throm-
boxane in AD, it is not clear whether itch is induced directly
by these molecules or whether they function as inflamma-
tory sensitizers in itch. The transmembrane protein
TMEM79, which is expressed in keratinocytes and neu-
rons, was reported to be crucial in pathological responses to
oxidative stress (78), most likely in AD. TMEM79 loss in
keratinocytes triggers mast-cell degranulation and subse-
quently histaminergic itch with PGE2 and H4R/H1R inter-
dependency. Since histamine is not considered a major pru-
ritic contributor to AD, the relevance of this finding is not
clear.
Leukotrienes are derivatives of AA and have been long im-
plicated with itch. In particular, leukotriene (LT) B4, a lipid
chemoattractant and activator of granulocytes (238), has
gained attention as relevant to itch signaling when released
from keratinocytes upon itch stimulation by SP and SLI-
GRL (18, 139a). IL-31-mediated itch may employ keratin-
ocyte derived LTB4 (16). LTB4 inhibition was achieved ei-
ther by blocking the synthesis of the chemoattractant or by
blocking the chemoattractant with pharmacological antag-
onists. These data support the notion that itch is a complex
interplay of neuronal and immune components within the
skin and very likely other organs.
 ITCH
Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid
associated with a variety of inflammatory diseases. These
include not only AD and psoriasis (126), but also multiple
sclerosis, which is often accompanied by itch and pain (206)
that may be neuropathic in nature (267).The interaction of
S1P with the S1PR3 receptor leads to activation of TRPA1
pruriceptors and TRPV1 nociceptors (110). These data re-
veal that distinct molecular mechanisms may underpin the
discrimination of itch versus pain in the periphery.
That cannabinoids are used recreationally led to the identi-
fication of endogenous lipid-based compounds and recep-
tors. Use of cannabinoids to treat inflammatory skin disease
has been suggested and reported anecdotally (35). The in-
creased legalization of marijuana is likely to drive therapeu-
tic use, especially for itch and AD. Two cannabinoid
GPCRs have been identified (191, 214). In mice, both re-
ceptors have been detected in sensory neurons, whereas in
humans, only CB2R has been so localized (11, 263). Acti-
vation of CBR in sensory neurons may decrease neuronal
activity and modulate the axon-flare response. Tetrahydro-
cannabinol, a bioactive component of marijuana, blocked
scratching behavior elicited by compound 48/80 (245).
These antipruritic effects were CB1R dependent as revealed
by use of antagonists. Upon stimulation with hapten,
CB1R mutants were susceptible to the development of
features of AD (88). N-acetylethanolamines are benefi-
cial for the treatment of itch through activation of the
endocannabinoid system, and topical N-palmotoyletha-
nolamine (PEA) has been reported to decrease uremic
itch scores to baseline (273). Topical PEA cream also
reduced the itch in a cohort of mild to moderate AD
patients when applied twice daily for 4 – 6 wk (75).
XII. TRP CHANNELS
TRP channels constitute a family of ion channels expressed
widely across species. They have been strongly implicated in
itch, although their necessity has been questioned (234).
TRP channels were first identified in Drosophila in 1969
(62). Their importance in nociception came almost three
decades later, when it was determined that capsaicin acti-
vated a channel that became known as TRPV1. More than
25 distinct TRP channels have been described in mammals.
TRPs respond to various stimuli via an influx of cations.
TRPs are expressed in diverse cell types, including immune
cells, neurons, and keratinocytes, and participate as sensors
to maintain skin homeostasis. Based on their amino acid
sequences, TRP channels form six subfamilies. These in-
clude TRPA (ankyrin), TRPC (canonical), TRPM (melasta-
tin), TRPML (mucolipin), TRPP (polycystin), and TRPV
(vanilloid). TRP channels are gated by stimuli ranging from
small molecules and ions to thermal as well as mechanical
inputs, underlying their role in tissue homeostasis and sen-
sation. Their characteristic structure contains a central
channel pore and four subunits built around the pore. TRPs
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feature six transmembrane domains with short interconnec-
tions to each other and their long NH2-terminal domains
are paired with short COOH-terminal domains, both of
which extend into the cytoplasm. TRPs are generally non-
selective mono- or divalent cation-gated channels with no
anion permeability. Only a few TRPs have demonstrated
specific selectivity towards calcium or magnesium, while
most are nonspecific and gated by both cations. The asso-
ciation between TRPs and sensing has made them targets of
drug development, but side effects, such as altered thermo-
regulation with respect to antagonists of TRPV1, have con-
founded drug approval. Furthermore, polymorphisms in
TRP channels that manifest with alterations in pruritus, and
which could thus guide drug development, have not been
reported.
A. TRPV1
TRPV1 is gated by vanilloids, comprising compounds that
have a vanillyl group, of which capsaicin and its analog
resiniferatoxin, which is 1,000 times more potent, are mem-
bers. Additional TRPV1 activators include thermal stimu-
lus more than (50) 42°C (49), extracellular protons and
anandamide, a lipid derived from cannabinoids. TRPV1 is
found mostly on peptidergic nociceptor neurons and is a
marker for the sensory neurons mediating pain and itch (50,
196, 197). TRPV1 is also sensitized by molecules released
during inflammation, including bradykinin, prostaglandin,
and retinoids (52, 313). Activation via inflammatory medi-
ators results in the downstream signaling by protein kinases
C and A as well as phosphatidylinositol bisphosphate (PIP2)
(227). In inflammatory pain, TRPV1 expression is upregu-
lated, which may account for the increased heat perception
(121, 294, 295, 308). Targeting TRPV1 to treat inflamma-
tory pain seemed like a promising treatment strategy. Un-
fortunately, antagonizing TRPV1 has side effects such as
hyperthermia and loss of noxious heat perception (138).
The role of TRPV1 in the mediation of itch associated with
histamine, but not other tested pruritic mediators, was un-
covered when it was found that the injection of histamine
was attenuated in TRPV1-deficient mice. In contrast, itch
elicited from the injection of ET-1 and serotonergic itch
from ␣-Me-5-H were not altered. Seemingly, most prurito-
gens do not engage the TRPV1 channel for the transduction
of the itch signal. IL-31 is one of the pruritogens that me-
diates itch via both TRPV1 and TRPA1 (FIGURE 5).
Efforts are ongoing to tease apart, if possible, the relative
contributions of TRPV1 as compared with TRPA1 with
respect to itch versus inflammation. In the squaric acid
dibutylester (SADBE) model of allergic contact dermatitis,
both channels were required for scratching behavior while
genetic or pharmacological ablation of the TRPV1 popula-
tion promoted inflammation (84). In this model, C-fiber
neuronal activity precedes immune responses and regulates
963
 FERDA CEVIKBAS AND ETHAN A. LERNER
to some extent immune functions as suggested elsewhere
(33). In contrast, TRPV1 was necessary for inflammation in
the imiquimod-induced psoriasis mouse model of inflam-
mation (225).
B. TRPA1
The ankyrin family possesses multiple copies of the ankyrin
motif residing in the NH2-terminal domain and is required
for their assembly and gating of the channel (50, 51, 188,
221). TRPA1 was found initially to have a role in sensing
pain and cold and participating in inflammation, and was
activated by a range of noxious or pungent substances,
including mustard oil, garlic oil, allyl isothiocyanate, and
pollutants as well as ⌬(9)-tetrahydrocannabinol (THC) and
metabolites of acetaminophen (135, 210, 268). TRPA1 has
emerged as the channel most tightly associated with the
transduction of acute and chronic itch, although that role
has now been questioned (234). TRPA1 is expressed by a
subpopulation of small-diameter C-fiber polymodal affer-
ent in the dorsal root, trigeminal, and nodose ganglia
marked by the coexpression of the NGF receptor TrkA and
TRPV1 (135, 268). TRPA1⫹ fibers project to peripheral
tissues including the skin and the viscera. Their depolariza-
tion prompts the release of SP, neurokinins, and CGRP
which promote extravasation, vasodilation, and neurogenic
inflammation as well as hypersensitization to algesic stim-
uli. TRPA1 has been suggested to function as a gatekeeper
for the neuroinflammatory release of neuropeptides.
TRPA1 participates in non-histaminergic acute scratching
in mice from CQ and the endogenous enkephalin
BAM8 –22 (168, 302, 303). CQ directly activates MrgprA3
while BAM8 –22 activates MrgprC11, each of which cou-
ples to TRPA1 (FIGURE 5). With respect to dry skin induced
by acetone-ether-water (AEW), and considered by some to
recapitulate dry skin in humans and thus be a model of
chronic itch, TRPA1 was necessary as TRPA1 KO mice
genes scratched less as compared with their wild-type litter-
mates and phenotypic changes were less impressive (303).
TRPA1 was similarly necessary for the full manifestation of
the effects of oxazolone and urushiol allergic contact der-
matitis in mice (168). However, the requirement for TRPA1
in these processes has been questioned (234).
C. TRPV4
TRPV4 is expressed in keratinocytes, macrophages, and
nociceptive neurons (145, 178). It has been considered a
polymodal sensory modulator for thermal and chemical
stimuli as well as osmotic and mechanical sensory inputs. It
is also implicated in serotonin-induced itch (7). Serotonin
levels have been associated with different pruritic diseases
(141, 258), and there are many GPCRs in the serotonin
receptor family. In TRPV4 KO mice, scratching behavior is
attenuated in response to 5-HT, but not CQ, SLIGRL, or
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histamine (7). Single-cell calcium imaging was employed to
highlight serotonin activation of HTR2A and coupling to
TRPV4. The signals were extinguished in TRPV4 KO DRG
neurons but remained unaltered in DRG neurons isolated
from TRPV1 or TRPA1 KO mice. A link to the HTR7
receptor and TRPA1 has also been reported (190). By sen-
sory neuron gene expression studies across genetically dis-
tinct mouse strains, the authors connected expression levels
of HTR7 with non-histaminergic itch in the DBA mouse
line. HTR7 was labeled in sensory neurons and colocalized
with TRPA1 in hairy skin. Both receptors were required to
induce neuronal responses by the HTR7 agonist LP-44.
HTR7 was also implicated in persistent itch induced by
topical MC903. Integrating both serotonin receptors into
setting of allergic and nonallergic chronic itch, it has re-
ported that lineage specific ablation of TRPV4 in macro-
phages and keratinocytes reduces itch in the AEW-dry skin
or SADBE-induced ACD model.
D. TRPM8
The normal function of TRPM8 is to sense cold. In contrast
to other TRP channels, TRPM8 is activated by menthol or
icilin and inhibits or masks the sensation of itch due to the
cooling sensation (275). Menthol-containing emollients
provide an approach for temporary relief for itch. Skin cool-
ing attenuates spinal neuron responses to histamine injec-
tions (131a). Deficiency of TRPM8 in sensory neurons re-
sults in attenuated responses to its activators (59), whereas
more intense cold, ⬍10°C, was still detected, most likely by
other cold-sensitive channels. TRMP8 agonists have now
been evaluated in clinical studies. A pilot study tested two
TRPM8 agonists, (1R,2S,5R)-N-[2-(2-pyridinyl)ethyl]-2-
ispropyl-5-methylcyclohexancarboxamide and menthoxy-
propanediol, in a double-blind randomized study with dry
skin chronic itch patients (262), with promising reduction
of itch. In a study of pedal pruritus in atopic dogs, the
TRPM8 agonist 1-diisopropylphosphorylheptane was eval-
uated but did not improve pruritus (276). The effectiveness
of targeting TRPM8 remains to be clarified as do the mech-
anisms that connect TRPM8⫹ neurons to spinal itch cir-
cuitry.
E. TMEM16a Versus TRP Channels in Itch
The concept of TRP channels as major signal transducers
for itch has been challenged, as noted at the beginning of
this section. Undem’s group used preparations that in-
cluded skin with intact DRGs and spinal nerves and dem-
onstrated that the calcium-activated chloride channel
TMEM16a, rather than TRPs, are activated following stim-
ulation of histamine or CQ (234). It was suggested that
technical differences between the neurophysiology methods
and the site of nerve recordings could explain discrepancies
with prior findings. How this fascinating study impacts the
 ITCH
reported supportive role of TRPs in inflammation will be of
interest to the field.
XIII. VOLTAGE-GATED SODIUM CHANNELS
The contribution of voltage-gated sodium (Nav) channels
to itch is garnering attention (160, 240). Nav channels play
a central role in the transmission of sensory information.
Peripheral sensory neurons express Nav1.7, Nav1.8, and
Nav1.9 (154). Conventionally associated with transmitting
pain signals, it is increasingly recognized that Nav channels
contribute to itch (FIGURE 5). Loss-of-function mutations in
SCN9A, which encodes Nav1.7, results in a congenital de-
ficiency to pain, although itch has not been addressed (64,
198). Gain-of-function mutations cause painful neuropa-
thies (111, 118). Erythromelalgia is an autosomal dominant
condition caused by a gain-of-function alteration in Nav1.7
(65) that leads to burning pain and erythema in the extrem-
ities (293a) as well as a small fiber neuropathy (82). Gain-
of-function changes in Nav1.8 and Nav1.9 also result in
small fiber neuropathies (82) and familial episodic pain
(321). Impairment of Nav channels impacts depolarization,
inactivation, or recovery of neuronal firing and the net hy-
perexcitability of DRG neurons (280). Nav antagonists are
in preclinical and clinical studies (280). With respect to
Nav1.9, a woman with a gain-of-function mutation ex-
pressed in a heterozygous fashion presented with severe itch
and concomitant partial loss of pain sensation (240). To
better understand the impact on itch, Nav1.9 and the ho-
mologous mutation was studied in mice. Expression was
primarily detected in unmyelinated, nonpeptidergic small-
diameter DRG neurons, which expressed MrgprA3 or Mrg-
prC11, a subpopulation linked to non-histaminergic itch.
Loss of Nav1.9 led to reduction in histamine, BAM8 –22,
and CQ elicited scratching. Peak neuronal responses for
histamine and CQ were similar between KO and wild-type
mice, but the percentage of responding neurons was re-
duced. Like the human Nav1.9 mutation, heterozygous
Nav1.9L799p/wt mice scratched more frequently than their
wild-type littermates, thought to be due to deactivation or
hyperpolarization changes in the channel resulting in excess
Na⫹ influx (162). In line with these findings, a small popu-
lation of MrgprA3⫹ neurons from Nav1.9L799p/wt mice
was found to be hyperexcitable and may contribute to spon-
taneous itch activity (240). With respect to Nav1.7, a
monoclonal antibody directed against the paddle region of
the channel showed efficacy in mouse models of inflamma-
tory and neuropathic pain as well as models for acute and
chronic itch (160). Intrathecal injection suppressed itch in-
duced by peripheral administration of compound 48/80,
CQ, and GRP while systemic and intrathecal delivery sup-
pressed chronic itch in the dinitrofluorobenzene (DNFB)
hapten model of contact sensitivity. Like other Nav chan-
nels, Nav1.7 contributes to tetrodotoxin-sensitive sodium
channel-mediated excitatory synaptic transmission. The
primary afferents expressing Nav channels synapse with
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lamina IIo neurons and connect to lamina I neurons as part
of the circuitry involved in chronic itch and pain.
XIV. CYTOKINES AND ITCH
The immune system, nervous system, and epithelia have
evolved to balance homeostasis while protecting against
infections, injuries, and threats. The complex interactions
between these systems are multifactorial and multidirec-
tional. Danger signals can result in dysregulated responses
that are detrimental, with pathophysiological conse-
quences. Direct communication between cells and media-
tors was implied by the close vicinity of Langerhans cells
and mast cells to sensory neurons (21, 115, 265). The sim-
plified version of neuroimmune interaction has been mod-
ulated and has gained multiple layers of complexity in
which neurons participate actively in the recruitment of
immune cells. It is likely that each cell type in skin can
communicate directly or indirectly. Since Rothman’s re-
view, the view of a neuroimmune interplay has been wid-
ened by understanding the cross-communication between
the nervous system and the immune system via small mol-
ecules and cytokines. These messenger molecules are re-
leased by immune cells and activate receptors on sensory
neurons. Key cytokines involved in itch and nociception
include IL-2, IL-4, IL-13, and IL-31. While many cytokines
are involved in inflammation, none has been implicated
directly in pruritus, and they are not discussed further. A
variety of small molecules, including histamine and sero-
tonin, are released by controlled and differential granule
release from mast cells and interact with neuronal receptors
while sensory nerves release the neuropeptides SP and
CGRP to activate immune and non-neuronal cells. We fo-
cus on the cytokines that interact with cognate receptors on
neurons to drive itch and inflammation.
A. IL-31
IL-31 is the cytokine most directly implicated in mediating
itch (FIGURE 5). Blocking antibodies to IL-31 or its receptor
rapidly decrease itch in mice, canines, and humans (195,
237). The anti-inflammatory effect of such blockade is in
flux (200). IL-31 was discovered in 2004. It is a four-helix
bundle cytokine with minimal homology to IL-6 but classi-
fied as a member of the IL-6 family (109). IL-31 was found
initially to be produced by activated CD4⫹ T lymphocytes
but is also made by mast cells, macrophages, basophils,
eosinophils, keratinocytes, and dendritic cells (69, 125,
199, 235). Transgenic mice that overexpress IL-31, driven
by the Lck promoter in lymphocytes, developed eczematous
skin lesions and immune-triggered hair loss. The promoter
region includes binding sites for several transcription fac-
tors, including NFAT1, STAT6, JunB, AP-1, and NF␬B
which likely enhance IL-31 expression in TH2 lymphocytes
and mast cells (109, 320). IL-31 is not considered a classic
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 FERDA CEVIKBAS AND ETHAN A. LERNER
TH2 cytokine as the latter are associated with the induction
of allergy and eosinophilia, whereas IL-31 tends to be
downstream or separate from TH2 processes (109, 136,
207). IL-31 signals through a receptor heterodimer com-
plex consisting of IL-31R〈 and oncostatin-M receptor ␤
(OSMR␤). Both subunits are detected in the skin, brain,
lung, trachea, skeletal muscle, testis and ovary, prostate,
placenta, spleen, thymus, bone marrow, and blood leuko-
cytes with OSMR␤ being the more constitutively expressed
subunit (69, 70). Our research has detailed the cellular as
well as the molecular mechanism by which IL-31 exerts it
effects. IL-31RA has been localized on sensory neurons in mice
and humans (32, 55). We analyzed the receptor distribution
on sensory neurons and found expression in 3–5% of the total
neuron population. MrgprA3, another marker of itch sensory
neuron, is expressed in a similar percentage of DRGs. Neurons
that respond to histamine, SLIGKV/SLIGRL, and CQ par-
tially overlap with the IL-31RA⫹ neuron population. There
was also overlap of TRPV1 and TRPA1 expression. IL-31
directly induces itch when injected into the murine skin,
although questions remain as to whether IL-31 may have
nociceptive effects. The expression and distribution of
IL-31 receptors on sensory neurons indicate a direct mes-
senger function in sensory aspects of inflammation includ-
ing itch and possibly pain.
1. IL-31 receptors and downstream signaling
In contrast to other IL-6 cytokines, IL-31 does not interact
with the gp130 receptor subunit but binds with low affinity
first to IL-31R␣. Following receptor engagement, a pleth-
ora of downstream signaling pathways are activated, in-
cluding Janus activated kinase (JAK)-Stat, Ras/Erk, and the
PI3K/AKT (60). Activated TH2 cells are the primary but
not exclusive source of IL-31 secretion. Typical AD triggers
including Staphylococcus aureus and OVA induce the se-
cretion of IL-31 from TH2 cells (55) while human beta
defensin (hBDN) and the antimicrobial peptide cathelici-
din-37 (LL-37) induce release from mast cells (199), now
recognized to be mediated via Mrgprs. IL-31 is thus ideally
suited for the neuroimmune interplay in innate immunity
and cutaneous inflammation. Human basophils, which are
effectors of allergy, produce IL-31 and are also activated by
IL-31 (217). Activation of IL-31RA on basophils provokes
the release of IL-4 and IL-13, key cytokine drivers of AD,
suggesting a multicellular role for IL-31 to coordinate in-
flammation and drive itch. Additional insights into the
downstream effects of IL-31 have been gained by in vitro
studies in which recombinant cytokine is injected into
mouse skin. IL-31 influences differentiation and expression
of the structural protein filaggrin (61). In AD, impairment
of filaggrin results in skin barrier dysfunction (76, 77).
These data imply that IL-31 is involved in structural pro-
cesses in addition to inflammatory ones. The injection of
IL-31 daily for 2 wk resulted in keratinocyte proliferation,
skin thickening, associated impaired barrier function man-
ifest by increased transepidermal water loss (TEWL), which
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is a feature of AD, and increased transcription of TRPV2, a
signal transducer channel localized on sensory neurons, but
not other TRP channels.
2. IL-31 and itch
IL-31 is one of the first cytokines that has been described to
directly act on sensory neurons to trigger itch. The initial
itch studies were done with osmotic pumps that release
IL-31 into wild-type and c-Kit mast cell-deficient mice (69)
and transgenic mice overexpressed IL-31. The overexpres-
sion resulted in these mice in acanthosis, parakeratosis, and
hyperplasia, and an intense immune phenotype infiltrate
was present in all and resembled the human disease. In-
creased numbers of mast cells were noted in the skin of
IL-31 transgenic animals, a finding also in human AD. The
most direct explanation that accounts for these observa-
tions is that while mast cells are not necessary for aspects of
the inflammation associated with IL-31, by interacting with
its receptor on various cell types, including sensory neurons,
this cytokine influences feedback and feed-forward net-
works between the nervous and immune systems and kera-
tinocytes. In addition, the differential granule release from
mast cells, together with pruritogens, exacerbates the itch-
scratch cycle. Single injections of IL-31 caused dose-depen-
dent itch in mice that was reduced in mice lacking TRPV1
and TRPA1. These data are consistent with IL-31 acting as
a direct pruritogen (55).
It has been suggested that IL-31 elicits acute itch, whereas
IL-4 and IL-13 are drivers of some cases of chronic itch.
However, due to a constant inflammatory release of IL-31,
this cytokine is suitable to target for both acute and chronic
itch (FIGURE 6).
The IL-31 responsive neuron population comprises 3–5%
of DRG neurons, reflecting transmission via a specific pop-
ulation. The IL-31 population is comprised in the NP3–
inflammatory itch sensing neurons which are also activated
by histamine (FIGURE 2). The highest overlap of IL-31 re-
sponsive neurons was found to be with TRPA1⫹, consis-
tent with the reduced itch in responses TRPA1 KO mice.
IL-31 mediated itch signals through an ERK1/2-dependent
mechanism rather than the JAK-STAT pathway. Since ab-
lation of JAK1 in sensory neurons inhibited IL-31 itch
(203), the details of signaling in acute versus chronic itch
associated with IL-4 and IL-13 require additional clarity.
Targeting IL-31 in AD results in significant reduction of itch
with no improvement of the inflammation, which raises
questions about the connection between itch and inflamma-
tion (137). A possible explanation for the missing efficacy in
the inflammatory axis might be that a complete depletion of
IL-31 is required to block itch and inflammation simultane-
ously as seen with phototoxic ablation of sensory itch (200)
Another neuroimmune-regulatory role of IL-31 is the neu-
ropoietic stimulation on sensory neurons similar to NGF
(83) which is consistent with increased nerve fiber density in
 ITCH

ACUTE CHRONIC
IL-4RD IL-13RD1
OsmRE OsmRE

Histamine
IL-31RD
IL-31RD

PERSISTENT
Histamine ITCH
Receptor
(Inflammation)

FIGURE 6. Acute and chronic itch in humans. In acute itch, histaminergic itch is induced by histamine via
activation of its receptors on sensory neurons. Non-histaminergic itch can be induced by a plethora of
molecules, of which some are identified. One such molecule is interleukin (IL)-31 which is released from
immune cells including CD4⫹ TH2 cells and mast cells. Upon release, IL-31 activates a heterodimeric receptor
complex consisting of IL-31R␣ and oncostatin M receptor ␤ (OSMR␤) on sensory neurons to elicit itch directly.
It is possible that this process induces the release of neuropeptides such as substance P (SP) from sensory
neurons. SP activates MRGPRX2 on mast cells and may be induced on sensory neurons. Itch triggers
degranulation of mast cells and the differential and controlled liberation of various neuropeptides, proteases,
and cytokines. A continuous inflammatory milieu may result in chronic itch, which is debilitating in many
diseases. IL-31 has been linked to chronic itch skin conditions. During inflammation, immune cells release
other cytokines including IL-4 and IL-13 which signal via the heterodimer IL-4R␣ and IL-13R␣1 and are reported
to function as neuronal enhancers for different itch pathways. Bile acids have recently been reported to activate
MRGPRX4 and may thus contribute to cholestatic itch.

lesional skin of IL-31 transgenic mice and human AD. Tran-
scriptional profiling of mouse DRGs revealed overlap but
also differences between stimulation with IL-31 as com-
pared with NGF. These data should be interpreted with care
as NGF is added to the cultured DRG neurons that are
stimulated with IL-31. IL-31 stimulation resulted in en-
hanced expression of neuropoietic genes as compared with
NGF (83). Intriguing findings were that the neuropoietic
functions exerted by IL-31 were linked to STAT-3 and were
TRPV1 independent, which contrasts with the ERK1/2
phosphorylation and presence of TRPV1 associated with
itch. IL-31, like other representatives of the IL-6 cytokine
family, employs multiple signaling pathways during inflam-
mation, neuropoiesis, and itch.
skin had higher expression of these components and corre-
lated with visual analogue scale ratings for pruritus. It is
possible that IL-31 is the mediator of itch in CTCL patients.
The relevance of IL-31 in chronic spontaneous urticaria has
been examined (219). IL-31 levels were higher than in neg-
ative controls but less than in patients with AD. It has been
suggested that in addition to mast cells, IL-31 induces ba-
sophil migration and release of IL-4 and IL-13 to contribute
to the pathophysiology (218). Overall, the relationship of
levels of IL-31, OSMR␤, and IL-31RA in pruritic states, as
determined by immunological and molecular approaches, is
an active area of investigation. Current observations em-
phasize the pleiotropic effects of IL-31 and its receptors in
inflammatory diseases associated with pruritus.

3. IL-31 in human pruritic diseases

IL-31 levels correlate with the severity of pruritus in AD,
prurigo nodularis, and CTCL but not in nonpruritic psori-
asis patient samples, consistent with transcriptional up-
regulation in pruritic AD (53, 194, 256). Expression was
induced in human peripheral blood mononuclear cells by
staphylococcal superantigen, which is associated with
atopy, but not influenced by either influenza or HSV. IL-31
is produced by CTCL T cells, leading to increased IL-31
levels in serum and peripheral blood mononuclear cells, and
is correlated with pruritus severity (256). Localization stud-
ies with immunofluorescence labeling for IL-31, OSMR␤,
and IL-31RA revealed that moderately and severely CTCL
B. IL-4 and IL-13
The TH2 cytokines IL-4 and IL-13 are major drivers in the
proinflammatory orchestration in AD. Both cytokines have
been detected at elevated levels in the skin and serum of AD
patients. IL-4 is apparent at the onset of AD, whereas IL-13
is associated with chronicity (FIGURE 6). A role for IL-4 and
IL-13 in chronic itch, not just AD, has been reported (203).
These cytokines activate cultured DRG neurons in mice but
do not elicit itch behavior. Rather, IL-4 increases the re-
sponsiveness of sensory neurons to other itch mediators,
whereas IL-31 activates such neurons and evokes scratching
behavior (55). It remains unclear whether IL-13 exerts sim-

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 FERDA CEVIKBAS AND ETHAN A. LERNER
ilar sensitization effects to IL-4. IL-4R␣ appears fundamen-
tal to chronic itch as conditional knockout mice, lacking
IL-4R␣ gene in nociceptive neurons, do not develop either
chronic itch or histopathological features in the MC903
model of AD-like model. Neither IL-5 nor its receptor had a
role in this model. These findings support the cellular and
molecular basis for the therapeutic effects of dupilumab, an
antibody directed towards the IL-4R␣ subunit and the first
biologic to treat moderate to severe AD (FIGURES 6 AND 7).
XV. OTHER CYTOKINES AND THEIR
RELATIONSHIP TO ITCH
IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) are
cytokines that function upstream of IL-4, IL-13, and IL-31.
They are released from keratinocytes as well as from epi-
thelial cells from other tissues and contribute to the initia-
tion of type 2 inflammation. IL-33 and TSLP evoke scratch-
ing behavior in mice and activate mouse sensory neurons
(169, 304). None of these cytokines has been shown to
evoke itch directly in humans. However, their pleiotropic
effects and complex signaling are consistent with at least an
indirect impact on itch.
The proinflammatory type 1 cytokine tumor necrosis factor
(TNF)-␣ and its receptor TNFR1 are implicated in acute
and chronic itch via peripheral and central sensitization
mechanisms in mice (184). Known for its role in chronic
pain, cancer, and neuropathy, TNF-␣ excites and sensitizes
primary afferents (130, 233), eventually via TRPV1 up-
regulation. To evaluate the role of TNF-␣ in acute itch, the
authors employed compound 48/80 and CQ and demon-
strated that TNFR1 KO mice showed fewer scratching re-
sponses from these itch-inducing agents. Additionally, the
dry skin model revealed that TNF-␣ expression is upregu-
lated in the skin; DRG and the cognate receptor expression
is elevated in spinal cord tissue. The findings in mice may
correspond to observations in human itch. Thus thalido-
mide has been effective in many dermatologic disorders,
including inflammatory and noninflammatory itches (249).
These broad effects likely follow from the impact that tha-
lidomide has on protein ubiquitination (85) and its capacity
to decrease TNF-␣ production (189). Similarly, by regulat-
ing neuronal plasticity in pain, TNF-␣ increases N-methyl-
D-aspartate currents in lamina II neurons in the spinal cord
and sensitizes spinal cord neurons in chronic itch (180).
A different class of cytokines, namely, chemokines, are reg-
ulators of multiple cellular processes (56). Chemokines are
expressed in different tissue types, including the central ner-
vous system, and have chemotactic function with implica-
tions in neuroinflammation and chronic pain (89 –91).
CXCL10 signals via CXCR3, a GPCR, both of which have
been associated with maintenance of chronic pain post pe-
ripheral nerve and chronic constriction injury (57). CXCR3
was recently reported to mediate itch induced by an allergic
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contact dermatitis mouse model (216). Neuronal responses
to CXCL10 were intensified in cultured DRG neurons dis-
sected from mice treated with SADBE as compared with
vehicle-treated ones. In a recent study, CXCR3 and its li-
gand CXCL10 were reported to modulate chronic itch and
alloknesis phenomenon induced by the dry skin model and
48/80 injections (131). CXCR3 KO mice exhibited less
signs of alloknesis with lower signs of astrocyte activation.
A. JAK Inhibitors
Oclacitinib is a JAK inhibitor (JAKi) approved by the
United States Food and Drug Administration in 2013 for
the treatment of itch and allergic diseases in canines. The
drug was launched in early 2014. The supply was exhausted
within 2 mo. This situation exemplified the pent-up demand
for effective therapeutics for itch. It raised the profile of the
unmet need for both dogs and humans (167). JAKi are
emerging as treatments for inflammation in general, includ-
ing allergic and autoimmune disorders. JAKs were known
to be expressed in sensory neurons, which led to the evalu-
ation of a JAKi as a potential therapy for chronic itch (203).
The canonical cytokines IL-4 and IL-13 signal via JAKs as
do upstream cytokines IL-33 and TSLP. IL-31 transmits
itch via MAPK but utilizes JAK signaling to stimulate
growth of small fiber neurons. JAK1-JAK3 are also acti-
vated by IL-2, IL-7, IL-9, IL-15, and IL-21, whereas IL-6,
the prototypic proinflammatory cytokine, signals through
JAK1, JAK2, and TYK2 (248).
In the clinic, topical application of tofacitinib, a JAK1/3i,
led to itch improvement starting at day 2. Baricitinib, an
oral JAK1/2 selective inhibitor, reduced chronic itch and
skin inflammation in a phase 2 clinical trial with moderate
to severe AD. Genetic depletion of JAK1 in sensory neurons
resulted in diminished itch in mice treated with the inflam-
mation inducing vitamin D analogue MC903 (203). Con-
sistent with this finding, a JAK1 gain-of-function point mu-
tation in mice resulted in a pruritic dermatitis phenotype with
scratching and stepwise progression into immunological ab-
normalities (312). The application of petrolatum to the ears
masked the damage to the barrier and delayed the immune
dysregulation of elevated TH2 cytokines and increased ex-
pression of serine proteases, particularly kalikrein-6 and
marapsin which are skin barrier regulators. A JAK1 gain-
of-function mutation in humans caused severe pruritic der-
matitis (67). The JAK inhibitor ruxolitinib led to improve-
ment. Collectively, these data emphasize the role of JAKs in
inflammatory conditions and chronic itch. There is a grow-
ing interest in developing JAKi as topical treatments for
mild-moderate AD to circumvent systemic adverse side ef-
fects. Tofacitinib, the first commercially available JAKi,
was approved originally for the treatment of rheumatoid
arthritis. The ointment formulation of tofacitinib tested in
AD patients successfully improved the Eczema Area and
Severity Index (EASI) scores to 80% after 4 wk of treatment
 ITCH

MAST CELL
MrgprX 2

IL-4Ra
IL-13RD1
MrgprX 2
OsmRβ
?
MrgprX
MrgprX
X44
IL-31RD

FIGURE 7. Peripheral and central targets of

itch. Peripheral itch targets are receptors and
mediators of chronic itch including the interleu-
kin (IL)-31 pathway. Targeting IL-4 and IL-13
with dupilumab has been successful in atopic
dermatitis. Antagonists of MRGPRX2 might be
beneficial in the treatment of inflammation,
itch, and urticaria. Antagonism of MRGPX4
has the potential to benefit the treatment of
cholestatic itch when driven by bile acids. In
SKIN THALAMUS neuropathic pain, targeting peripheral GABA-R
DORSAL has proven analgesic properties, which could
HORN be translated to itch. Central targets of itch act
DRG in the central nervous system and include the
use of ␬-opioid receptor (KOR) agonists and
␮-opioid receptor (MOR) antagonists. Target-
ing spinal serotonin-pathways via 5-hydroxy-
tryptamine (5-HT) 3 and 7 receptors may
achieve clinical success in chronic itch man-
agement. Antagonists directed against the
NK1R most likely work spinally. Targeting itch-
specific circuits such as gastrin releasing pep-
tide receptor (GRPR) might represent a thera-
peutic avenue. Increasing inhibitory tone via re-
plenishing GABA reduces acute and chronic
itch in mice. Gabapentin and pregabalin, widely
used to treat neuropathic pain, are prescribed
GRP
SP in the clinic to treat chronic itch patients. DRG,
H1/H4-R
MOR 5HT 3/7-R
dorsal root ganglion; GRP, gastrin releasing
KOR peptide; SP, substance P.
GRPR

NK1-R

PRURICEPTIVE
PROCESSING
Inhibition
Ca2+-influx
Gabapentin
Pregabalin
GABA-R

Glutamate

while showing antipruritic action as early as 24 – 48 h (36). XVI. MODELS AND TECHNIQUES
Similarly, JTE-052 provided itch relief in moderate-to-se-
vere AD patients (192). The relative contributions of neu- Histamine-induced itch is the most studied and well-under-
ronal versus immune JAKs in pruritus are being clarified. stood acute itch despite the findings that most chronic itch

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 FERDA CEVIKBAS AND ETHAN A. LERNER
forms are of non-histaminergic nature. Preclinical models
of non-histaminergic itch are the chemically as well as me-
chanically induced itch forms broadened with models of dry
skin, allergic, atopic, cholestatic, and genetic. Moreover,
there has been growing effort to assess itch and the associ-
ated dysesthesia in humans with surrogate models. The re-
alization that scratching in animals occurs after algesic and
pruritic agents has led to the search for different technical
assessments of itch.
A. Measuring Itch in Mice
Behavioral assessment of itch in mice was initially studied
by few researchers and was overshadowed by pain research.
Behavioral testing to measure itch was undertaken in different
ways. Until 2008, pruritogens were assayed by injection into
the nape followed by recording and analysis of scratching by
bouts over time (149). This approach could not necessarily
distinguish pruritic from nociceptive behaviors. An important
advance was introduced by Shimada and LaMotte (250).
Their cheek model discriminates between itch- and pain-
associated behavior (250). Algogens such as capsaicin trig-
ger wiping of the injected ipsilateral cheek with the fore-
limbs, whereas pruritogens such as histamine evoke
scratching via the hindlimbs. This approach is now the stan-
dard. Akiyama et al. (4) reported that when mice are in-
jected with algogens such as capsaicin, the mice behavioral
responses of wiping were reduced by morphine. In contrast,
histamine-evoked scratching was diminished by naltrexone,
a ␮-opioid antagonist. The authors additionally tested
whether spicules, native with cowhage or inactivated, when
loaded with histamine or capsaicin would result in wiping
or scratching. Cowhage-evoked itch is accompanied by no-
ciceptive sensations such as a stinging, burning sensation
(152). Cowhage-evoked scratching peaked between 10 and
15 min while wiping behavior remained through the record-
ing time of 30 min. Even inactivated spicules loaded with
histamine elicited more scratch and wiping behavior as
compared with the cowhage-loaded ones. Similarly, capsa-
icin-induced behavior post spicule application was more
enhanced than cowhage-elicited responses with more
prominent wiping behavior suggesting that the behavioral
assessment is more objective than the classical assay. Of
note, while cowhage spicules are excellent tools for evalu-
ating itch in humans, mice rapidly remove the spicules, and
they are not generally used in mice. By means of the cheek
model, the authors uncovered that formalin-induced behav-
ior is more reflective of itch rather than pain or in addition
to dose-dependent nociception. Most of the other classical
algogens, such as mustard oil and bradykinin, evoked pre-
dominantly wiping behavior. LaMotte et al. (153) also in-
troduced another model that provides behavioral differen-
tiation between itch and pain, namely, the calf assay for
itch. Processing of somatosensory information for the calf
model happens in the lumbar spinal cord region which has
been more extensively studied as compared with the trigem-
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inal processing when signals are conveyed from the cheek.
An advantage is the better characterized neuronal popula-
tion in the lumbar spinal cord responding to chemical and
mechanical stimuli. Injections of capsaicin evoke licking
behavior, whereas histamine injections result in biting re-
sponses like paw injections, a behavioral assessment widely
used in pain research (316). Profiling neurons from different
dermatomes may contribute to more fully understanding
similarities and differences between the inputs and the pro-
cessing of itch and pain.
B. Genetic Models
Another axis through which to study itch is via genetically
modified strains of mice in which the mediation, transmis-
sion, or coding of itch has been modified (271, 272). Ge-
netic manipulation of the molecules involved in the trans-
mission of itch either heightens or reduces itch or protects
from itch. A variety of models have been introduced in
preceding sections. Examples include overexpression of the
cytokine IL-31, which results in excessive scratching and
self-inflicted lesions and transcription factor bhlhb5 KO
animals which have a severe neuropathic itch phenotype.
One of the early mouse models for itch is the NC/Nga
mouse (129, 251). Spontaneous signs and symptoms in-
clude itching, erythema, scaling, dryness, and alopecia at 8
wk of age. However, the NC/Nga mice pathophysiology is
not exactly predictable and hence bears a poor rate of re-
producibility. Models that have been considered to be prox-
ies for AD and chronic itch include the overexpression of
cytokines IL-4, and TSLP, separate from IL-31 (314). A
mouse model of CTCL was developed by inoculation of
human Myla cells in which levels of microRNA (miRNA)
were increased in mouse serum (104). This study uncovered
an unusual role for miRNA in chronic itch triggered by the
pathology of CTCL. Patients with CTCL suffer from
chronic itch for which no treatment paradigms have been
established. This model provides a molecular basis to un-
derstand the origin of chronic itch in CTCL which was
linked to levels of circulating miRNA that were also in-
duced in human patients (220).
C. Itch with Sensitization Models
Most commonly used models for itch are sensitization of
the skin by application of either haptens or allergens such as
ozaxolone, vitamin D analogues, or OVA (179, 289). In
correlation with human AD, the oxazolone model presents
an epidermal serine protease signature and a concomitant
decrease of antimicrobial peptides such as the ␤-defensin-3.
This model, as well as that using the hapten trinitrochloro-
benzene applied to the skin of the hairless mouse strain,
shifts the TH1 responses towards TH2 as seen in AD (179).
Vitamin D [1␣,25-(OH)2D3] or MC903 can be used to
induce AD-like skin inflammation (165) MC903 sensitiza-
 ITCH
tion was linked to the overexpression of TSLP. Epicutane-
ous sensitization with OVA on shaved skin (102) of differ-
ent strains of mice induces an eruption that mimics the
features of human AD (261). Erotic or dry skin itch can be
achieved through repeated application of an AEW solution
at any skin location with any mouse strain (201). For pso-
riatic itch, the topical application of imiquimod, a topical
anti-cancer drug, results in spontaneous scratching bouts
accompanied by alloknesis (239).
D. Human Itch and Surrogate Models
In humans, itch is often accompanied by nociceptive sensa-
tions of burning, pricking, and stinging. Psychophysics is
used to measure these sensations using the visual analogue
scale while the numerical rating scale is used in the setting of
clinical trials to measure itch. Latency, peak, and duration
can be incorporated into the itch measurements (254, 255).
Cowhage is an ideal tool for evaluating itch in humans.
Native cowhage elicits itch, burning, pricking, and stinging.
In addition, spicules can be readily inactivated in an auto-
clave and then “reconstituted” with other test agents. The
spicules function as microneedles and do not generate no-
ciceptive responses when inactivated. Like murine itch
models, pruritogens such as histamine, BAM8-22, and se-
rotonin can be tested in humans via injection, but alterna-
tively by reconstituting spicules. Histaminergic itch is con-
veyed by the mechanoinsensitive C-fiber population,
whereas non-histaminergic itch such as cowhage-elicited
itch employs polymodal C-fibers (193). Histamine and mast
cell degranulators cause the typical wheal, a manifestation
of acute protein extravasation, and flare reaction, caused by
neuropeptides.
XVII. CONTAGIOUS ITCH
Contagious or social itch is triggered by visual or other cues
in the absence of a conventional pruritogen. In contrast to
itch from exposure and infection from a contagious organ-
ism, such as the scabies mite, contagious itch is triggered by
visual exposure to somebody else scratching or the auditory
cues, as in a lecture about pruritic dermatological skin con-
ditions (112). Contagious itch via audiovisual transmission
is experienced by humans and non-human primates and has
been reported in rodents (112, 247), although the signifi-
cance of this itch is not clear. The initial description was of
a human audience exposed to presentations with pictures of
insects, scratch marks, and allergic reactions followed by a
presentation with soothing cues with pictures of babies. A
significant number of scratching movements was measured
during the “itchy” presentation, with increased itch percep-
tion reported by the audience, which contrasted with the
relaxing portion of the presentation. Mirror neurons were
identified initially within the ventral premotor area when
monkeys conducted a certain movement or in observation
of this movement (122).
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An effort has been made to associate the cellular and mo-
lecular mechanism of contagious itch with the GRP-GRPR
axis (315). Here, naive mice were reported to exhibit con-
tagious itch when observing videos of BRAFNaV1.8 mice,
which exhibit exaggerated scratching behavior (324), in the
absence of olfactory or auditory stimulation. Dependence
on SCN was suggested as this area receives direct visual
input; contagious itch was absent in GRP and GRPR mu-
tant mice and mice in which GRPR was conditionally de-
pleted in the SCN, yet was restored by delivery of GRP or by
optogenetic stimulation (315). The importance of these
findings has been questioned, given that contagious itch was
not observed in wild-type mice injected with histamine
(166).
XVIII. CLINICAL ITCHES
Itch can arise anywhere along the pathways between the
skin and brain. This anatomy encouraged itch to be classi-
fied as pruritoceptive when arising in the skin, neuropathic
when associated with neuronal pathology, and psychogenic
when associated with a psychological condition (291). This
approach frames a brief discussion, for which multi-au-
thored reviews are available. A recent report that suggests a
descriptive classification of chronic itch (264) has the ben-
efit of additional detail incorporating skin findings together
with underlying systemic conditions to assist in establishing
itch as a disease while potentially being less informative
with respect to mechanism and pathophysiology.
Most itches are pruritoceptive. They arise either from ex-
ogenous environmental substances or from the persistent
presence of endogenous mediators that are produced in or
make their way to the skin. Itches associated with insect
bites or poison ivy are examples of acute itches, resulting
from allergic responses in each case. Chronic itches are
often associated with inflammatory skin disease, such as
AD. The co-dependency of these itches and connection with
neurogenic inflammation are exemplified by the observa-
tion that neural lesions that impact the areas of inflamma-
tory skin disease eliminate the sensation of itch while result-
ing in resolution of the inflammation (26). Chronic itch can
also be a part of noninflammatory systemic diseases, includ-
ing cholestasis, chronic kidney disease, or even pregnancy.
These should be viewed as chronic acute itches as the itch
rapidly resolves in most instances shortly after organ trans-
plant or birth. The mediators driving these itches are being
determined. With respect to cholestatic itch, bile acids in-
teract with MRGPRX4, while lysophosphatidic acid (LPA)
produced by autotaxin (148) interacts with LPA receptors
on sensory neurons. With respect to the itch of chronic
kidney disease, we have hints that there may be parallels
with that of cholestatic itch. As an extension, it is tempting
to speculate that the severe itches of primary biliary cirrho-
sis and polycythemia vera may relate to heme metabolism.
971
 FERDA CEVIKBAS AND ETHAN A. LERNER

There is no shortage of other challenging itches. The advent influenced by hormonal differences (260). It is thus possible
of targeted anticancer immunotherapies is frequently asso- that therapeutic approaches could be targeted to patient
ciated with therapy-limiting pruritus, for which the mecha- physiology.
nism is unknown and no animal models are available (306).
Neuropathic and psychogenic itches are chronic and fre-
quently intense. Examples of the former include post-her- XIX. TARGETING ITCH
petic itch, notalgia paresthetica, and brachioradial pruritus
which can be associated with nerve compression. A number Just as clinical itches can arise anywhere along the pathways
of severe itches, including genital itch, which likely include between the skin and brain, interruption of a pathway has
degrees of central sensitization, are not readily categorized. the potential to modulate itch (FIGURE 7).
Ocular itch, thought to be of an allergic nature, calls for a
topical approach for treatment. Itch from parasites, partic- Approaches to treating itch are represented in FIGURES 7
ularly helminths, including nematodes of the genus AND 8. FIGURE 8 is an acknowledgment of the style of Dr.
Strongyloides, causes misery worldwide, regardless of eco- Seuss.
nomic background, and often presents as a diagnostic di-
lemma and marked delay in diagnosis (274). Again, the The skin is viewed as a funnel topped with its barrier and
mediators are not known. filled with keratinocytes that support a web of sensory fi-
bers. Side chambers topped by inflammatory cells feed into
Not only is the treatment of chronic itch a challenge, but the funnel. The neck of the funnel consists of neuronal fibers
also careful evaluation leads to the determination of an that coalesce into the spinal cord. These axons continue to
underlying etiology in a fraction of patients (306). When a the brain where the signals are interpreted as itch followed
cause cannot be determined, these patients are considered by generation of the motor response of scratching which
to have chronic pruritus of unexplained origin or CPUO impacts the skin barrier to drive the itch-scratch cycle.
(143), an acknowledgment of the classic description of fever
Therapy can thus be directed to protecting or repairing the
of unexplained origin or FUO by Petersdorf and Beeson
barrier with topical approaches; blocking sensory neuronal
(212). While patients with chronic itch frequently note that
activity or neuropeptide release, immune cell activity, or
they would prefer to commit suicide than continue to suffer
mediators; or modulating spinal or brain activation or in-
(101), documented reports of suicide are rare.
hibitory pathways. Approaches directed to each of these
We are often asked if itch differs between the sexes. This
question, as well as potential differences in itch that could
be associated with mental health, economic differences, or
race, which assumes that races can be distinguished, has
been considered (66). There are no objective data to support
any such differences based on physiology or pathophysiol-
ogy. There are data to suggest that the processing of itch
and pain-related sensations can differ between men and
women exposed to native cowhage spicules or cowhage
spicules prepared with histamine or capsaicin (107). Differ-
ences in the presentation of pruritus based on race and sex
have been suggested (133). No difference in the prevalence
of itch between sexes has been identified when each has the
same disease, in this case, chronic kidney disease (47, 116).
In our itch clinic, we sometimes have the impression that on
average, woman tolerate severe itch better than men do, but
we recognize the subjective nature of this comment. Inter-
pretation of any data that suggest differences must take into
account potential differences in interview style. For exam-
ple, asking if a patient itches or has other nociceptive con-
cerns versus whether a patient spontaneously reports itch
can impact findings.

Identical questions have been raised with respect to pain
with similar findings. In mice, it has been suggested that
male mice utilize microglia in the spinal cord to mediate
pain, whereas female mice use T cells, a finding that may be
FIGURE 8. Itch-scratch cycle. The many areas where therapeutic
approaches can be directed are depicted. These areas range from
the skin barrier, depicted as a funnel with associated immune cells
together with afferent fibers that flow into the spinal circuitry and on
to the brain.

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 ITCH
areas are in clinical use. The combination of fundamental
research together with recognition of genetic polymor-
phisms that impact itch and inflammation may lead to tar-
geted therapeutic approaches with limited off-target effects.
XX. FUTURE DIRECTIONS
Remarkable progress is being made in understanding the
physiology of itch. At the same time, we are at the prover-
bial end of the beginning with respect to having a deep
understanding of itch. Questions related to details of mech-
anisms remain at every level of the itch-scratch cycle, and
addressing these questions will provide ongoing opportuni-
ties for investigators. The development of humanized mice
has the potential to partially overcome the translational gap
between preclinical and clinical findings. Why is there so
much redundancy with respect to itch signaling pathways?
Further to this question, with the recent implication of neu-
trophils in innervation and itch (297), essentially all cells
that populate the skin can contribute to itch. Does itch
relate to tickle and touch? Is there communication between
free nerve endings, the glial network at the epidermal-der-
mal junction, Meissner corpuscles, Ruffini endings, and
Merkel cells or are these structures independent one from
the other? What are the relative and specific contributions
of the various receptor and channels involved in itch, in-
cluding the Piezo channels that are important in touch? It is
likely that polymorphisms in receptors and channels, be-
yond that found already for Nav1.9, will be identified in
genetic databases that lead to increased itch. The possibility
of finding variants that protect from itch may be elusive as
it involves proving a negative.
Imaging techniques are always advancing. The generation
of mice in which neurons are functionally labeled with ge-
netically encoded calcium indicators, together with the ca-
pacity of genetically labeling cell types in the skin, will allow
for detailed visualization of neuroimmune interactions and
potentially their bidirectional communication. Can imaging
techniques be developed that allow for the visualization of
C-fibers in humans in vivo? Will brain and spinal cord im-
aging in mice and humans eventually lead to resolution on a
cellular level and contribute to understanding details of cen-
tral itch processing and differences with pain?
With respect to itch therapy, as with pain, the placebo effect
for drugs or vehicles can exceed 50%. The psychological
and psychosomatic factors that contribute in a positive way
to the placebo effect are thus important. The inverse, man-
ifest as a negative expectation, or nocebo effect, can be
detrimental to therapy (305). How might the learning pro-
cesses associated with these effects be harnessed to enhance
therapeutic benefit? Can we take advantage of inhibitory
circuitry to modulate itch? What is the mechanism of action
of natural products that may help itch, such as flavonoids?
Why are current therapies that target the IL-31 pathway so
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effective at treating itch but not concurrent inflammation?
Besides drugs, physical modalities, such as therapeutic ap-
proaches using lasers, already help to relieve itch associated
with burn wounds and scars, although the mechanism of
efficacy is uncertain. Is such monochromatic light targeting
mast cells or something else? Heat and cold can impact
neuronal function. Can they be applied to the skin or by
point sources in the DRG to target itch? Can objective mea-
sures of itch, or other senses, be developed so as to improve
upon psychophysical measures and the numerical and vi-
sual analog rating scales? Whether itch can be alleviated
completely while maintaining other sensory modalities re-
mains to be determined, but we are entering an age in which
the suffering from itch may be replaced by the pleasure of
scratching.
ACKNOWLEDGMENTS
Figures 1–7 were designed by Dani Guralnick, DGD LLC.
We are most grateful to Jimmy Xia for the whimsical illus-
tration. We thank Anaia Davidson, Lydie Yang, and
Malena Ramos for formatting.
Present address of F. Cevikbas: Dermira, Inc., 275 Middle-
field Rd., Suite 150, Menlo Park, CA 94025.
Address for reprint requests and other correspondence: E.
Lerner, Cutaneous Biology Research Center, Massachusetts
General Hospital, 149 13th St., Charlestown, MA 02129
(e-mail: elerner@mgh.harvard.edu).
GRANTS
This work was supported by Pfizer Aspire Program Grant
233429, Dermira, Inc. Grant 231828, and National Insti-
tutes of Health Grant 1R21AR067399.
DISCLOSURES
F. Cevikbas holds equity in Dermira, Inc. E. Lerner is on the
Scientific Advisory Board of Escient Pharmaceuticals.
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