Chapter 1
Pathophysiology of Pain in the Peripheral
Nervous System
Rachel Milner1,* and Cahir Doherty2
1
University of Warwick, Coventry, UK. 2 University of Nottingham, Nottingham, UK.
*
Corresponding author: e-mail: rachelannmilner@hotmail.com
PAIN
Pain and Nociception Are Distinct Concepts
The International Association for the Study of Pain (IASP)
defines pain in humans as “an unpleasant sensory and emo-
tional experience associated with the actual or potential
tissue damage, or described in terms of such damage”
(IASP Task Force on Taxonomy, 1979). It is important that
we define pain, and other terms used in the discussion of the
pathophysiology of pain, before moving on.
Within this chapter the term pain will always be used to
refer to the unpleasant subjective phenomenon, which is
usually, but not always, perceived in association with tissue
damage. Its subjective nature is highlighted by the vocab-
ulary that we use to describe pain varying between indi-
viduals and cultures. I might describe my headache as
sharp and splitting, while yours might be pounding or tight.
Is what we experience really very different?
Pain has multiple components including:
l Location.
l Intensity.
l Character or quality; that is, whether it is sharp, dull,
stinging, or burning.
l Affective component such as fear and unpleasantness.
l Attention—the ability of pain to interrupt other activ-
ities and capture our attention.
Pain is also closely linked to memory. This facilitates the
development of protective behaviors for the future, but also
means that our current experiences of pain are shaped by
influences from the past. Our current emotional state will also
affect how pain is perceived; thus, our experiences of pain
not only vary from person to person but also within any
one individual over time, dependent upon influences from
that individual’s internal and external environment. Mem-
ories, emotions, and genetic factors amalgamate to make each
time we experience the sensation of pain a unique event.
Nerves and Nerve Injuries, Vol. 2. http://dx.doi.org/10.1016/B978-0-12-802653-3.00050-6
© 2015 Elsevier Ltd. All rights reserved.
Pain is almost invariably an unpleasant sensation; its
ability to persuade us from pursuing potentially damaging
behaviors means that pain has evolved with us from the ben-
efits bestowed to our early ancestors. Acute pain serves a
clear evolutionary advantage; it draws attention to tissue
damage occurring and then prevents further injury by
sending out reflexive withdrawal responses to stop the
harmful activity. Pain lasting beyond the time of initial
injury modifies our behavior to protect or rest the damaged
tissues, giving time for inflammation to stimulate the pro-
cesses of healing and repair. Modification of behavior by
pain helps individuals to prevent tissue damage and pro-
motes their survival and consequent ability to reproduce.
Rarely are individuals born with a congenital inability to
feel pain, a trait that may seem envious; these individuals
rarely survive into late adulthood. Their tissues accumulate
the effects of multiple small insults, particularly the sur-
faces of joints and ligaments subject to the rough and
tumble of childhood. Unable to fully recover, their tissues
become prone to infection of the damaged tissue and they
become susceptible to conditions such as osteomyelitis.
Conditions like appendicitis, which are rarely fatal in
others, can go unnoticed until they generate a significant
fever or symptoms such as nausea and vomiting. Delayed
intervention leads to complications, and individuals who
cannot sense pain frequently die young. So, as unpleasant
as it is, pain serves us with an unrivaled drive to protect our-
selves and to survive. Within this chapter, we will discuss
what peripheral events occur to generate these painful
perceptions.
Pain is not a peripheral event; our nerves sense cellular
damage in the tissues, which we then perceive as pain. This
perception is generated by the cortex of the brain. There is
no single “pain center” in the cortex; the unpleasant feelings
we experience are, therefore, a summative expression of
several areas of cortical processing. Many areas of the brain
are involved in processing painful stimuli. These include
3
4 PART I Pain Involving the Peripheral Nerves
the primary and secondary somatosensory cortices that
process the sensory-discriminative aspects of pain (location
and intensity) and the prefrontal, anterior cingulate, insula
and parietal opercular cortices that process the affective-
motivational (unpleasant, aversive) aspects of pain and
behavior. Multiple areas of cortical processing reflect the
multifactorial nature of pain (Figure 1.1). Our intelligent
brain integrates the neuronal information encoded by each
of these areas and expresses it as one coherent experience
(Tracey & Mantyh, 2007; Treede, Kenshalo, Gracely, &
Jones, 1999).
Some of the terms that are used to describe painful phe-
nomena throughout this chapter will be defined here.
Algesia is the sensation of pain, while hyperalgesia is the
feeling of increased sensitivity to painful stimuli. This
means that a lower intensity of damaging stimulus is
required to generate pain than normal. Allodynia refers to
painful sensations generated by normally innocuous
stimuli, and suggests there has been a deviation in neuronal
function from the normal status quo. The physiological
events that lead to hyperalgesia and allodynia will be eluci-
dated within the relevant sections of this chapter.
r us
gy
te
la
u g
nt eri r c i n
o
A
Prefrontal
cortex
FIGURE 1.1 Cortical areas involved in pain processing.
NOCICEPTION
In contrast to pain, nociception refers to the neurological
events, both central and peripheral, that encode information
about noxious stimuli. Nociception has the potential to
cause the perception of pain, but pain does not always result
from nociception. Nociception also influences physio-
logical events; it can cause raised blood pressure and heart
rate through autonomic regulation and promotes cortisol
release via modulating effects on the hypothalamic-
pituitary-adrenal axis. Nociceptive events causing pain also
modify behavior; for example, withdrawal of a limb from a
heating element. These aversive actions are called noci-
fensive behaviors. Nocifensive behavior in animals is often
observed as a proxy measure of pain perception and noci-
ceptive events; for example, mice with modified genes
for nerve receptors may be observed to see how quickly
they withdraw from a pressure or heat stimulus.
Nociception was first described by Sherrington in 1906.
He used the term to describe the detection of noxious events
and proposed the existence of a type of primary sensory
neuron, the nociceptor (Sherrington, 1906). These sensory
ex
cort
ory
ens
atos
som
ary
Prim
ary
ond y
Sec sensor
mato
so cortex
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1
neurons that encode noxious stimuli in the peripheries are
termed primary afferent nociceptors (PANs). The term
PAN refers to a group of afferent neurons of multiple types
that will be described in greater detail later.
NOCICEPTORS
Primary afferent neurons convey nociceptive information
from the peripheries to the spinal cord, where it is relayed
to the thalamus and cortex. Ion channels are essential for
generating action potentials.
Nociceptive neurons form part of our primary afferent
system; these neurons convey information from our periph-
eries toward the CNS. They are the first neuron in a
sequence of relayed signals to the CNS. They are differen-
tiated from other sensory neurons by the high threshold of
activation that is required in order to initiate depolarization
and by their unencapsulated, free nerve endings (FNEs).
PANs lack the specialized receptor organs found in other
primary afferent neurons, such as muscle spindles. FNEs
of PANs are located throughout most anatomical structures
of the body including skin, musculoskeletal tissues, and the
viscera. Notably, the brain is devoid of innervation by
PANs and, while damage to the brain parenchyma generates
an inflammatory response, it does not generate feelings of
pain. This makes it possible to conduct brain surgery on a
conscious patient without the need for analgesic agents in
the brain tissue. We tend to describe pain as somatic if it
is derived from the skin or musculoskeletal tissues and as
visceral pain if it is derived from damage to the organs.
Each PAN consists of its receptor region (the FNEs), an
axon that projects between the target structure and the
spinal cord, a cell body located within the dorsal root gan-
glion (DRG) of the spinal dorsal root, and central processes
that project to lamina I and II of the dorsal horn (see
Figure 1.2, which shows the basic anatomy of a PAN).
These processes form a presynaptic terminal that is usually
excitatory in nature, releasing glutamate onto postsynaptic
neurons. Nociceptive information from the body is
FIGURE 1.2 Functional anatomy of a typical primary
A E
afferent nociceptor.
5
transmitted up the spinal cord in the anterolateral system/
spinothalamic tract, to the brain stem and VPL nucleus
of the thalamus. At the brain stem, nociceptive signals
can directly influence physiological function, while the
thalamus relays information about tissue damage to several
cortical areas. Not until this point in the pathway is pain per-
ceived. With the head the trigeminal nerve is anatomically
analogous to the somatosensory nerves of the rest of the
body. Its cell bodies lie within the trigeminal ganglion and
its central projections terminate on postsynaptic neurons
that ascend to the thalamus in the spinal trigeminal tract of
the medulla (Willard & Holt, 2007).
The function of PANs is to transmit information about
tissue damage to higher order neurons. In order to do this
they must convert a mechanical, thermal, or chemical
stimulus into an action potential, and subsequently release
a chemical neurotransmitter at the dorsal horn. Nociceptors
are generally excitatory neurons that release glutamate as
their neurotransmitter at the dorsal horn. FNEs provide
the sensory transduction region of the nociceptor, con-
verting the stimulus into a receptor membrane potential
through the activation of ion channels. Na+, K+, and Ca2+
channels are involved in maintenance of, and fluctuations
in, the charge across the receptor membrane. Opening of
these cation channels, leading to the depolarization of the
sensory area of the PAN membrane, will be referred to
throughout this chapter as the generation of a “receptor
potential.” It is analogous to the “action potential” gen-
erated along the axon. If the threshold is reached, the
resultant receptor potential is then converted into a series
of propagating action potentials, transmitting a signal
along the length of the axon to the synaptic terminal. Axon
depolarization is generated by voltage-gated Na+ and K+
channels. At the dorsal horn, release of neurotransmitter
must occur in order to convey signals to postsynaptic
afferent neurons. This is largely mediated by voltage-gated
Ca2+ channels. Any stage in this process is subject to mod-
ulation by a number of factors that will be discussed later in
the chapter (Schaible, Ebersberger, & Natura, 2011).
F
D
A. Sensory receptor terminals
(free nerve endings)
B. Axon
B C. Schwann cell: variable myelination
D. Cell body
C
E. Central dendritic processes
F. Presynaptic central terminals
6 PART I Pain Involving the Peripheral Nerves
CLASSIFYING NOCICEPTORS
Nociceptors are the smallest unmyelinated and lightly
myelinated primary afferent nerve fibers. They conduct
impulses more slowly that afferent fibers conveying touch
signals. Nociceptors release peripheral neuropeptides at
their sensory receptor terminals, as well as neurotrans-
mitters at the spinal cord.
Afferent nerves can be classified by their conduction
velocity. Conduction velocity is governed by the mor-
phology of the neuron axon; the larger the diameter the
faster the conduction speed, while thicker myelin sheaths
also increase conduction rates. We find four groups of
afferent neurons, classified by their conduction speeds
from fastest to slowest: Aα, Aβ, Aδ, C.
Traditionally, it was thought that only the slowest con-
ducting Aδ and C fibers carried signals from noxious
stimuli which could be perceived as pain. However, it is
increasingly understood that there is greater functional
overlap between fiber groups. Aβ fibers may also conduct
signals for noxious stimuli, while C and Aδ fibers can
conduct signals from nonnoxious mechanical and thermal
stimuli. Within this chapter we will focus on the Aδ and
C fibers. Nociceptor thresholds also vary according to their
location. Cutaneous PANs and those supplying muscle have
a high threshold of activation that clearly differentiates
them from low-threshold, large-caliber nonnociceptive
afferents. Visceral PANs are less well differentiated by
threshold of activation, having lower thresholds that are
closer to those of other afferent neurons (Djouhri &
Lawson, 2004; Julius & Basbaum, 2001; Lawson, 2002;
Schaible et al., 2011).
C FIBERS
The most numerous group of nociceptors are the small-
caliber, unmyelinated C fibers. They are reported by exper-
imental participants as giving rise to unpleasant, poorly
localized, and burning sensations. C fibers are the slowest
conducting of nociceptors; they have both discrete and
polymodal receptors. Polymodal C fibers transduce
mechanical, noxious thermal stimuli and algesic com-
pounds, while discrete C fiber mechanoreceptors, cold ther-
moreceptors, and chemoreceptors also exist. Up to 15-20%
of cutaneous C fibers are thought to be of the “silent noci-
ceptor” type. These silent nociceptors have an unusually
high threshold for mechanical and thermal stimuli, and
are not activated under normal conditions. However, in
the presence of inflammation they can become active due
to a lowering of their threshold as the chemicals of inflam-
mation sensitize the receptor membrane to thermal and
mechanical stimuli. Notably, silent nociceptors are now
more commonly being referred to as mechanically
insensitive afferents (MIAs), as it is their mechanical sensi-
tivity that is most significantly enhanced by inflammation.
C fibers can be broadly divided into two subclasses,
depending on the peptides they secrete and the neurotrophic
factors they respond to. The functional ramifications of this
classification are not yet fully understood, but their role in
chronic pain states is under investigation.
Peptidergic C fibers:
l Synthesise, store and release neuropeptides such as sub-
stance P, neurokinin A, and calcitonin gene-related
peptide (CGRP).
l Express the TrkA neurotrophin receptor, a high-affinity
tyrosine kinase receptor for nerve growth factor (NGF).
Nonpeptidergic C fibers:
l Express fewer peptides.
l Express the purinergic receptor P2X3, a subtype of the
ATP-gated ion channel.
l Express the c-ret growth factor receptor that is sensitive
to glial-derived neurotrophic factors (GDNF).
These two types of C fibers with distinct trophic require-
ments become most distinct in adulthood. During the
embryonic period, development and survival of afferent
neurons is reliant on the presence of specific neurotrophic
factors. There appears to be a shift from a predominance
of peptidergic/NGF-sensitive fibers in embryonic life to a
more equal balance between the two types once adulthood
is reached. Approximately 55-60% of C fibers in adulthood
are of the nonpeptidergic/GDNF-sensitive type.
The two types of C fibers show a subtle distinction in the
way they project to the laminae of the dorsal horn. Pepti-
dergic fibers project mostly to lamina I and outer lamina II,
while the nonpeptidergic nociceptors project to inner lamina
II. Inner lamina II houses the receptors for a group of second
order afferent neurons expressing a specific type of protein
kinase C (PKC) that are local to this lamina only. If the inner
lamina II PKC is ablated by gene targeting, it is possible
to almost remove hyperalgesic responses to nerve injury.
The nonpeptidergic/GDNF-sensitive nociceptors are conse-
quently thought to play a role in the evolution of neuropathic
pain states in nerve injury. Peptidergic/NGF-sensitive noci-
ceptors are thought to be critical to inducing hyperalgesic
responses in the presence of inflammation. Differences in
function between the two classifications of C fiber manifest
predominantly at the dorsal horn and, therefore, will not be
discussed further in this chapter.
There are regional differences in the distribution of
nerve phenotypes that correspond to their local functional
requirements. The skin is supplied with two large popula-
tions of nociceptors, both peptidergic and nonpeptidergic,
while in musculoskeletal tissues the majority of PANs are
peptidergic. Peptidergic fibers have the potential to generate
neurogenic inflammation through peripheral release of

neuropeptides. Perhaps this afferent distribution, in part,
underlies why musculoskeletal injuries are more prone to
chronicity than those of the skin (Bennett, Koltzenburg,
Priestley, Shelton, & McMahon, 1998; Julius & Basbaum,
2001; Silos-Santiago et al., 1995; Snider & McMahon,
1998; Zhang, Cavanaugh, Nemenov, & Basbaum, 2013).
Aδ FIBERS
The Aδ fibers are a group of faster conducting PANs,
slightly larger than the small-caliber C fibers, and have a thin
covering of myelin to speed conduction velocity. Conse-
quently, the subjective nature of pain described when Aδ
fibers are stimulated is often described as immediate and
well-localized pain. Aδ fibers typically respond to a discrete
type of stimulus, such as mechanical stimuli or damaging
hot or cold temperatures. They are less likely to be polymodal
receptors than are C fibers (Gold & Gebhart, 2010; Julius &
Basbaum, 2001; Schmidt et al., 1995; Woolf & Ma, 2007).
GENERATING A RECEPTOR POTENTIAL
Electrical potentials are generated and maintained by ion
channels within the plasma membrane of nociceptors. Flow
of ions through these channels generates currents that pass
along the neuron.
In this section we review the fundamental mechanisms
that allow nociceptors to maintain a membrane potential and
to generate action potentials that propagate along the axon.
Neurons maintain their cytoplasm at a negative
potential, relative to the outside of the cell, generated by
movement of ions across the plasma membrane between
the outside and inside. Ions must cross the plasma mem-
brane through channels because they are charged and
cannot diffuse through the phospholipid membrane
directly. Ions will flow through channels according to
Na+ D F 3Na+
Na+/Ca2+
B 2K+ ATP
A GPCR
cAMP
Na+/Ca2+
K+
K+
B K+
TK
C E
D
FIGURE 1.3 Ion channels and receptors expressed at the sensory receptor terminals of PANs.
Pathophysiology of Pain in the Peripheral Nervous System Chapter 1 7
two forces: first, the electrical charge across the membrane,
which is generated by the electrical charges accorded to all
ions; and second, according to the concentration gradient of
that specific ion. Ion channels can be leakage channels,
which allow the free movement of ions according to elec-
trical and concentration gradients, or they may be subject
to conformational changes, which mean they take on an
open or closed state. Sodium (Na+) and potassium (K+)
are the most significant ions in maintaining receptor
potential. At resting state, leakage channels allow Na + to
leak in and K + to leak out. K2P channels that allow K+ to
leak out through two-pore domains are important in neuro-
muscular function, as they allow the cell to hyperpolarize
and, thus, maintain a stable resting potential. Unopposed
leakage of ions would quickly lead to a loss of potential
across the membrane; therefore, pumps, which use ATP,
drive 3Na+ out of the cell for every 2K+ in, maintaining a
negative membrane potential. Depolarizing of the receptor
membrane allows a sudden flow of positive cations into the
cell; this is mediated by gated ion channels that can be in an
open or closed state. Two types of ion channel are expressed
at the PAN sensory terminal: (1) ligand-gated ion channels
(also called ionotropic receptors) that open (or close) in
response to binding of an external ligand, such as the mole-
cule capsaicin; and (2) indirectly gated by a metabotropic
receptor. Metabotropic receptors are either G protein-
coupled receptors (GPCRs) that activate second messengers
such as cAMP and cGMP indirectly gating the ion channel,
or receptor tyrosine kinases that gate channels directly or
indirectly by phosphorylation. GPCRs can also trigger
intracellular activation cascades in response to binding of
an external ligand. This can modify intracellular events
such as releasing Ca2+ stores and activating enzymes that
may also influence ion channel function. Figure 1.3 repre-
sents the array of channels and receptors found at the
sensory terminals of PANs.
Na+ Na+
G
A. GPCR, e.g., B2 receptor for bradykinin
B. Ligand-gated ion channel, e.g., TRPV1, 5-HT receptor
C. Receptor tyrosine kinase, e.g., TrkA receptor for NGF
D. Cation leakage channels
E. K2P K+ leakage channel
F. Na+/K+ ATPase
G. Voltage-gated Na+ channel
Na+
8 PART I Pain Involving the Peripheral Nerves
PROPAGATION OF ACTION POTENTIALS
ALONG THE AXON
Voltage-gated ion channels propagate action potentials
along the nerve axon. The functions of these channels are
influenced by noxious stimuli, including cold and chemical
inflammatory mediators.
Generation of a receptor potential is down to ion
channels in the receptor membrane; however, propagation
of that signal in the form of spreading action potentials
along the axon requires a different group of channels. These
channels are the voltage-gated Na+, K+, and Ca2+ channels
and the hyperpolarization-activated, cation nonselective
(HCN) channels. These fast acting voltage-gated channels
are highly expressed by nociceptors. They are responsible
for propagating the currents generated at the receptor
membrane of the sensory terminal and can modify PAN
conduction such that they influence the nociceptive infor-
mation that eventually reaches the spinal cord. This has
implications in disease states and in developing targets
for analgesia. We will consider the voltage-gated Na+
channels, as their role in some disease states has been iden-
tified. Voltage-gated Na+ channels are made up of two sub-
units: an α-subunit that is the pore domain of the channel
through which Na+ flows, and a β-subunit that has a number
of functions, including regulating channel expression and
interacting with the extracellular matrix and the cyto-
skeleton. There are nine known types of α-subunit that form
the pores for Na+ movement, they are named NaV1.1-
NaV1.9, some of which are expressed by PANs. The family
of NaV channels are divided into two functional groups
according to their sensitivity to tetrodoxin (TTX), a neuro-
toxin that can block action potentials by binding to the pore
of NaV α-subunits. TTX-S channels are sensitive to tetro-
doxin and TTX-R channels are resistant to it; PANs express
both types of channel.
NaV channels that are found expressed predominantly
by small-caliber nociceptors include NaV1.7, NaV1.8,
and NaV1.9. NaV1.8 is thought to have an essential role
in conduction of PANs that are sensitive to mechanical
stimuli and noxious cold, contributing to the mediation of
mechanical and thermal hyperalgesia in inflammatory
states. NaV1.8 is the only voltage-gated Na+ channel that
continues to function at very low temperatures and,
therefore, has a role in conduction signals about noxious
cold stimuli. Mutations in the gene for NaV1.8 are thought
to contribute to the pathogenesis of painful neuropathies,
causing enhanced channel responsiveness to depolarization
and producing hyperexcitability of afferent neurons.
NaV1.9 is expressed by nociceptors that also express
NaV1.8. A few nociceptors have also been identified that
express one or the other, but these are a minority. NaV1.9
is thought to influence hypersensitivity of PANs caused by
inflammatory mediators. Inflammatory chemicals such as
bradykinin, prostaglandin E2, and serotonin may target
NaV1.9 channels through GPCR signaling pathways leading
to facilitated conduction in the presence of inflammation.
NaV1.7 presents an interesting target for pain relief, as
mutations in the SCN9A gene that codes for the NaV1.7
α-subunit result in congenitally altered pain states. Con-
genital indifference to pain (CIP) is a condition that causes
individuals to experience severely impaired perception to
pain when they are otherwise normal. A loss of function
mutation of the SCN9A gene coding for NaV1.7 has been
identified in these individuals, suggesting that NaV1.7
has an essential role in mediating conduction of pain signals
in humans. Gain of function mutations of the same genes
have been identified in patients suffering with congenital
pain states, including paroxysmal extreme pain disorder
and inherited erythromelalgia. Erythromelalgia causes
pain, edema, and skin changes in response to heat and
movement in the limb. A mutation in the NaV1.7 channel
is thought to lower the threshold to single action potentials
and to high frequency firing in afferent neurons, resulting in
the disproportionate feelings of pain that are generated in
the condition. NaV channels provide us with an encour-
aging target for analgesic therapy, particularly for those
genetic conditions that impart significant suffering. Agents
that partially ameliorate pain sensations are emerging and
the aim to improve the selectivity of NaV channel blocking
agents is underway (Chowdhury et al., 2011; Dib-Hajj,
Black, & Waxman, 2009; Faber et al., 2012; Goldberg
et al., 2007; Jukič, Kikelj, & Anderluh, 2013).
TYPES OF NOXIOUS STIMULI AND THEIR
RECEPTORS
Noxious stimuli, including heat, cold, mechanical stretch,
and chemical stimuli, have the potential to generate feelings
of pain. Nociceptors express receptors for these stimuli that
can be discrete to one type of stimulus or polymodal. These
receptors are targets for analgesic compounds.
Noxious stimuli with the potential to cause pain come in
several modalities; namely, mechanical, thermal (hot and
cold), and chemical. Innocuous mechanical, thermal, and
chemical stimuli also exist, but it is the ability to activate
PANs that will be discussed in this chapter.
Noxious mechanical stimuli activate nociceptors in the
form of direct pressure or tissue deformation. This allows us
to perceive damaging events such as excessive pressure,
organ distension, edema, and bone destruction.
Thermal stimuli are either noxious heat or noxious cold.
Extreme high and low temperatures cause cellular damage
via destruction of the structural elements of the cell or via
functional alterations of its enzymes. A heat pain threshold
is reported at 47  C and a cold threshold at 9  C (Morin &
Bushnell, 1998).
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1
Noxious chemical stimuli consist of a wide range of sub-
stances that activate both Aδ and C fiber types. Noxious
substances can both directly activate PANs via opening
of ion channels, or may sensitize the nociceptor to depolar-
ization by other stimuli.
NOXIOUS STIMULI RECEPTORS
In order to begin conveying a signal of tissue damage to the
CNS, a receptor potential must be generated at the sensory
terminal of the PAN. FNEs have a plasma membrane with a
multitude of receptors and ion channels embedded within it.
When noxious stimuli activate these receptors, ion channels
open allowing the flow of ions across the sensory terminal
membrane, generating a receptor potential. The various
receptor molecules embedded in the sensory terminal mem-
brane allow PANs to act as transducers; changing
mechanical, thermal, or chemical information into an elec-
trical signal that can be conducted along the neuron. The
presence of specific types of receptor ultimately dictates
a PAN’s ability to conduct each type of noxious stimulus;
thus, the receptors expressed by a neuron decide if its
function is unimodal or polymodal. As receptors are
becoming better understood, their potential as therapeutic
targets for analgesia is under investigation.
Here, we consider the types of receptors that have been
identified for specific modalities of noxious stimuli and
how they lead to nociceptor activation.
RECEPTORS FOR NOXIOUS HEAT
Transient receptor potential (TRP) channels are a group of
ion channels identified in a variety of organisms. They are
known to mediate sensory transduction for a range of
modalities including taste, olfaction, vision, and thermal
and mechanical sensation. TRP channels are permeable to
cations such as Na+, Ca2+, and Mg2+ when activated by spe-
cific stimuli. Being permeable to cations gives them the
potential to modify receptor potential. Several families of
TRP channels exist, including TRPV (vanilloid), TRPA
(ankyrin), and TRPM (melastatin). The TRPV (vanilloid)
family are expressed in primary afferent neurons and have
a role in noxious heat detection.
TRPV1 channels are expressed by both C and Aδ noci-
ceptors at their sensory terminal.
They are activated at a temperature threshold of 43  C,
and also by the chemical capsaicin. Capsaicin is the active
component of chilli peppers that gives them their hot and
spicy nature. Capsaicin is known to elicit a sensation of
burning pain via activation of nociceptors; therefore, it is
widely used in experimental situations to study the neuro-
physiology of PANs (Caterina et al., 1997).
Another heat sensitive TRPV channel, the TRPV2
channel, is expressed in Aδ fibers, but not significantly in
9
C fibers. It is also activated by noxious heat, but only by
a higher threshold of 52  C. TRPV2 is not activated by
capsaicin.
Nonnoxious heat is also detected by the TRPV family of
channels. TRPV3 is activated by temperatures around
33  C, while TRPV4 detects in the range of 27-42  C.
TRP channels are involved in cold detection, too; conse-
quently, this group has been termed the thermoTRP
channels.
The thermoTRP channels probably contribute to sensa-
tions of hyperalgesia and allodynia in the presence of
inflammation. Inflammatory mediator chemicals cause
functional modification of thermoTRP channels, altering
a person’s sensitivity to heat. This will be further discussed
under the topic of noxious chemicals and inflammation.
Outside of the TRP family of channels, the calcium-
gated chloride channel ANO1 (Anoctamin 1) is also impli-
cated in noxious heat sensation, becoming functional at
temperatures over 44  C. It acts as a heat sensor and may
also have a role in mediating nociception (Cho et al.,
2012; Julius & Basbaum, 2001; Story, 2006).
RECEPTORS FOR NOXIOUS COLD
People begin to report pain in response to cold temperatures
at around 15  C when C and Aδ fibers with cold responsive
receptors are activated.
Receptors for noxious cold are not as well defined as
those receptive to noxious heat. ThermoTRP channels
appear to have a role in both noxious and innocuous cold
sensations. Two specific channels we will consider are
TRPM8 and TRPA1.
The TRPM8 (TRP melastatin 8) channel is expressed by
all primary afferent neurons, with approximately 10% of C
fibers expressing the thermoTRP channel. TRPM8 is per-
meable to Ca2+ and transduces both innocuous and noxious
pain sensations. Becoming active around 25-28  C, TRPM8
allows Ca2+ entry to the sensory terminal of the nociceptor,
creating a receptor potential. This is perceived as an
innocuous sensation of cold, which may even be plea-
surable, such as the cool breeze from an open window.
As temperatures fall, TRPM8 channels continue to function
into a painful range below 15  C. TRPM8 is also activated
by menthol, explaining the cool sensation felt when
menthol is applied to the skin. Eucalyptol and spearmint
also activate the TRPM8 channel, giving similar cool sen-
sations. Further evidence for TRPM8 as a noxious stimulus
receptor is its increased expression in tissues of the prostate
and urothelium that generate cancer pain; however, it is not
yet clear if it generates painful sensations outside of patho-
logical states.
A second thermoTRP channel, TRPA1, is likely to have
a role in noxious cold sensation. It is expressed by a small
subset of PANs; notably, the parent population of PANs are
10 PART I Pain Involving the Peripheral Nerves
those that express TRPV1, the noxious heat receptor. This
subset of PANs expressing both TRPV1 and TRPA1 are
polymodal nociceptors for both noxious heat and noxious
cold. TRPA1 is activated at temperatures of and below
17  C, and is found to be insensitive to menthol. It is,
however, activated by some irritant chemicals derived from
mustard oil, cinnamon oil, and garlic. Activation of TRPA1
by mustard oil, for example, produces a burning sensation of
pain. It is likely that TRPA1 is a poymodal receptor for
noxious stimuli, capable of generating painful sensations
in response to both cold and chemical stimuli. Patients can
develop increased sensitivity to cold, as well as to heat. This
cold hyperasthesia and cold allodynia is probably mediated
through the TRPA1 channel, whose mRNA is upregulated
in the presence of inflammation and nerve injury (Bautista
et al., 2007; Knowlton, Bifolck-Fisher, Bautista, &
McKemy, 2010; Kwan et al., 2006; Story, 2006).
It is probably not just activation of channels sensitive to
temperature change that causes the painful sensations of
noxious cold. Below temperatures of 15  C, noxious cold
stimuli also activate nociceptors indirectly through tissue
injury and altered vascular tone. A reduction of the depolar-
ization of warm-sensing primary afferent neurons may also
contribute to unpleasant sensations. It is notable that the
threshold for activation of nociceptors in response to
noxious cold is not as discrete as noxious heat. Around
50% of C fibers are activated at hot temperatures of
47  C, suggesting widespread receptor activation. This
compares to only 10-15% of C fiber activity when temper-
atures drop to 4  C. It is only when temperatures drop below
0  C that a far greater proportion of both C and Aδ noci-
ceptors are activated. This widespread and diverse acti-
vation of PANs at 0  C is likely to be due to tissue
damage caused by the extremely low temperatures
(Bautista et al., 2007; Julius & Basbaum, 2001; Knowlton
et al., 2010; Zimmermann et al., 2007).
RECEPTORS FOR NOXIOUS MECHANICAL
STIMULI
Mechanical stimuli are perceived as sensations of touch,
pressure, and vibration throughout a nonpainful range.
These sensations are frequently associated with pleasurable
feelings, such as during receipt of a relaxing massage.
Mechanical forces that have the potential to cause tissue
damage quickly generate feelings of pain and are
unpleasant to experience. Examples of noxious mechanical
stimuli include excess pressure, for example, on catching a
finger in a closed door or tissue stretch caused by edema of
underlying tissues. Visceral organs generate sensations of
pain when they are stretched; trapped wind distending the
bowel is a benign example. Here we consider the receptors
at the sensory terminals of PANs that transduce these dam-
aging mechanical events.
Noxious mechanical stimuli activate populations of
both C and Aδ nociceptors via their FNEs embedded in
somatic and visceral tissues; suggesting both types of
PAN express receptors with the capability to transduce a
mechanical stimulus into the opening of cation channels
in the receptor membrane, leading to rapid depolarization.
We refer to these receptors as mechanoreceptors.
Specific receptors for noxious mechanical stimuli have
been difficult to identify. Several channel types are cur-
rently under investigation. The TRP family of channels
are implicated in transduction of mechanical stimuli. The
Ca2+-permeable TRPV4 channel, which we met as a trans-
ducer of innocuous warmth in the range of 27-42  C,
appears to also act as a mechanoreceptor for noxious stimuli.
TRPV4 demonstrates sensitivity to changes in osmolarity.
In the presence of hypotonic solutions, the channel is acti-
vated; thus, in conditions of edema TRPV4 channels
activate PANs, notifying the CNS of tissue stretch. Using
animal models, a reduction in aversive behavior in response
to pressure on the tail occurs in individuals with the TRPV4
gene inactivated; suggesting a decrease in awareness of a
noxious mechanical stimulus when compared to individuals
with the TRPV4 gene functioning normally. TRPV4 also
contributes specifically to mechanically evoked visceral
pain, and may have a role in generating painful feelings
in conditions such as inflammatory bowel disease. Afferent
neurons supplying the colon wall show enhanced activation
in the presence of a TRPV4 agonist and, conversely, a
reduced activation with deletion of the TRPV4 channels.
Using animal models, it is possible to demonstrate reduced
behavioral responses to bowel distension in creatures
lacking TRPV4 channels. These findings give evidence
for TRPV4’s ability to transduce mechanical events into
nociceptive signals and feelings of pain. The TRPA1
channel, a proposed receptor for noxious cold, may also
have a role in mechanosensory transduction, but its specific
function as a mechanoreceptor has not yet been clarified
(Brierley et al., 2008; Fein, 2012; Kwan et al., 2006).
Other types of channels implicated in mechanosensi-
tivity include K+ channels and acid-sensing channels. The
TREK-1 channel (encoded by the KCNK2 gene) is a two-
pore K+ channel with polymodal properties. It demonstrates
sensitivity to noxious mechanical, thermal, and chemical
stimuli, and is also thought to have a role in mediating
mechanical hypersensitivity in the presence of inflammation.
Rather than direct activation of ion channels, one pro-
posed mechanism for mechanical activation of PANs is via
the release of chemical messengers. Extracellular ATP is
thought to be a likely candidate due to small (and large)
diameter afferent fibers expressing both G protein-coupled
ATP receptors and ATP-gated ion channels, thus giving
ATP the potential to trigger alterations in membrane potential
through multiple molecular mechanisms (Alloui et al., 2006;
Honoré, 2007; Julius & Basbaum, 2001; Patel et al., 1998).
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1
In summary, the receptors for noxious mechanical
stimuli are not yet identified as clearly as other noxious
stimuli receptors, making it harder to develop targeted ther-
apeutic interventions that target mechanically generated
nociceptive events.
CHEMORECEPTORS
A diverse range of receptors to chemical stimuli are
expressed at the sensory terminals of PANs, meaning that
many molecules have the potential to alter the receptor
potential and contribute to depolarization. Extracellular
molecules affect nociceptor membrane potential, directly
by interacting with ion channels or indirectly through inter-
actions with GPCR within the plasma membrane.
We will consider chemoreceptors in two groups: first,
those involved in acute pain responses to noxious sub-
stances and, second, we will consider the role of endog-
enous inflammatory mediators released during tissue
damage.
NOXIOUS CHEMICAL DETECTORS
Some inherently noxious molecules directly activate PANs,
leading to painful sensations. Most frequently, these sub-
stances come into contact with the skin, the mucous mem-
branes of the respiratory and gastrointestinal tract, and the
conjunctiva of the eye. They cause pain and irritation, for
example, when you accidentally rub chilli in your eye, or
breathe in too much bonfire smoke. Historically, some of
these molecules have been used during conflicts with dev-
astating consequences, for example, mustard oil forms the
irritant substance in tear gas. However, with controlled
experimental use, these noxious substances can provide
useful information about the function of PANs and our
sensory nervous system.
TRPV1 AND CAPSAICIN
Some of the TRP channels we have already met also act as
noxious chemical transducers, generating painful responses
to irritant chemicals. TRPV1, the noxious heat receptor, is
also known to be sensitive to the exogenous chemical cap-
saicin and to cutaneous applications of ethanol. Capsaicin
generates unpleasant burning feelings when applied to the
skin, so it is a curious fact that capsaicin is employed in a
therapeutic modality as topical creams and patches to treat
neuropathic and musculoskeletal pain. Traditionally, the
effects of capsaicin are described as desensitization of
PANs; however, recent physiological findings suggest that
defunctionalization is a better descriptive term. Continued
exposure to capsaicin will cause reduced responsiveness
11
of TRPV1 channels to activation. This specific phe-
nomenon is desensitization; it requires the persistent
presence of capsaicin to occur. However, exposure of the
skin to repeated low concentrations of capsaicin, or short-
term exposure to high concentrations, causes reduced
feelings of pain that persist beyond the short-term effects
of desensitization and persist when there is no longer cap-
saicin present in the tissues. These lasting effects are
referred to as defunctionalization.
TRPV1 is expressed by most C and some Aδ fibers and
is the only receptor for capsaicin, making it a very specific
therapeutic target. Receptors for capsaicin cause TRPV1
channels to open, allowing the influx of Na+ and Ca2+ with
a significant preference for Ca2+. Activation of TRPV1
channels by capsaicin also releases Ca2+ from intracellular
stores, giving a massive increase in intracellular Ca2+ con-
centration that soon overwhelms the cell’s ability to
sequester the excess. A sustained high intracellular Ca2+
concentration activates cellular enzymes, including pro-
teases that disassemble elements of the microtubule cyto-
skeleton. There is also osmotic swelling of the cell
caused by Cl accumulation accompanying the influx of
Ca2+. Enzymatic activation, altered cytoskeletal structure,
and osmotic changes to the PAN cause impaired nociceptor
function for extended periods. Capsaicin also interrupts the
metabolic activities of PANs; however, this is not mediated
through TRPV1 receptors. Via an independent pathway,
capsaicin prevents respiration at the mitochondrial mem-
brane of the organelles that are abundant in nerve terminals.
The interruption of metabolism is thought to cause failed
maintenance of the integrity of the PAN membrane and a
structural collapse of the nerve terminal. Consequently,
repeated application of topical capsaicin reduces the func-
tionality of local PANs causing localized regression of PAN
sensory terminals with resultant analgesic effects. If cap-
saicin treatments are withheld for a period of time, the noci-
ceptor terminal’s structure and function return to normal,
making treatment a temporary solution. In the early stages
of treatment, capsaicin can generate burning sensations via
TRPV1 receptors; unfortunately, patients may find this
intolerable and subsequently fail to adhere to the recom-
mended treatment protocol (Anand & Bley, 2011;
Trevisani et al., 2002).
A second TRP channel is recognized as being receptive
to a range of noxious stimuli. TRPA1, already discussed as
a potential transducer of noxious cold, shows sensitivity to
mustard oil, cinnamon, wasabi, horseradish, and garlic.
TRPA1 is expressed by all sizes of primary afferent
neurons, not just nociceptors. Less familiar irritant sub-
stances include formaldehyde, used in tissue preservation;
acrolein, the irritant component of cigarette smoke and
burning vegetation; and isocyanates, an irritant to the eyes
and respiratory tract that is found, among other substances,
in pesticides. TRPA1 channels demonstrate activation upon
12 PART I Pain Involving the Peripheral Nerves
exposure to all of these noxious chemicals, resulting in
depolarization of PANs and unpleasant sensations.
Interestingly, the sensitivity of TRPA1 to noxious sub-
stances is thought to play a role in the pathogenesis of
airway inflammation and hypersensitivity in asthma.
Exposure of the respiratory tract to irritants, such as ciga-
rette smoke, activates TRPA1 channels in primary afferent
neurons, allowing ion influx and depolarization. Genetic
ablation of TRPA1 genes reduces allergen-induced leu-
kocyte infiltration and cytokine and mucus production in
the airways. This integration of neurological, immune,
and inflammatory function is a concept that we will return
to when we consider neurogenic inflammation and the sen-
sitization of sensory nociceptor terminals.
TRP CHANNELS AS POLYMODAL
RECEPTORS
Experimental and in vivo studies have identified the TRP
channels as important receptors for noxious stimuli in
PANs. Their expression at the sensory terminals of noci-
ceptors, in part, determines the types of noxious stimulus
to which that particular nociceptor is sensitive. For
example, populations of C fibers expressing TRPV1,
TRPM8, TRPA1, and TRPV4 channels will demonstrate
sensitivity to noxious heat, noxious cold, a range of irritant
chemicals, and to noxious mechanical stimuli. These
channels do not just open or close in direct response to their
specific stimulus, but also affect how the nociceptor
responds to other types of stimuli. For example, activation
of TRPV1 channels by heat causes painful hot sensations,
while simultaneously reducing the threshold of the cell to
activation. These channels are critical to the polymodal
function of some nociceptors, integrating sensitivity to
noxious stimuli and propagating encoded information about
tissue damage to the CNS that may then be interpreted as
pain. TRP channels are not the whole story; other types
of channels and GPCR are also implicated in the activation
of PANs through sensitivity to noxious stimuli. Our under-
standing of TRP channel function is increasing in speci-
ficity. With this knowledge, new targets for drug
therapies in the prevention of pain are likely to emerge.
GENES THAT ENCODE FOR TRP CHANNELS
Mutations in the genes that encode for TRP channels are
under investigation as to their role in genetically determined
pain states. Autosomal-dominant familial episodic pain
syndrome (FEPS) is characterized by debilitating upper
body pain that is triggered by fasting and physical stress.
A gain of function mutation in the TRPA1 gene was found
to be linked to the syndrome, causing the channel to exhibit
a fivefold increase in activation by cold or chemical stimuli.
This defect in the TRPA1 channel of nociceptors is thought
to be an underlying mechanism for the pain that sufferers of
this condition experience. TRPA1 antagonists were able to
inhibit the mutant channel, reducing pain experiences
(Basbaum, Bautista, Scherrer, & Julius, 2009; Bessac
et al., 2009; Caceres et al., 2009; Kremeyer et al., 2010;
McNamara et al., 2007; Story, 2006).
TISSUE INJURY AND INFLAMMATION
Chemical inflammatory mediators sensitize PANs and
induce peripheral release of proinflammatory neuropep-
tides by the nociceptor. There are complex interactions
between nociceptors and the immune system that are
mediated by peripheral and central events.
We have discussed the role of exogenous chemical stim-
ulants of PANs. Perhaps more clinically important is a con-
sideration of the events surrounding tissue damage, the
release of endogenous inflammatory mediators, and how
they activate and sensitise PANs leading to acute and
chronic sensations of pain.
Tissue injury results in cellular damage releasing an
“inflammatory soup” of substances that are both proinflam-
matory and proalgesic; macrophages, mast cells, immune
cells, and platelets also contribute to the soup, adding che-
mokines, cytokines, and neurotrophic factors to the mix.
Some of these substances will directly alter the excitability
of the nociceptor membrane via ion channels at the receptor
membrane. Others do not directly activate the receptor
membrane, but lower its threshold via metabotrophic
receptors.
SEROTONIN
The neuropeptide serotonin (5-HT) is known to be a pro-
inflammatory mediator. It is taken up and then released
by platelets, mast cells, and immune cells in response to
tissue damage in peripheral tissues. It contributes to inflam-
mation and healing by altering vascular tone, inducing
platelet aggregation, and activating nociceptors. Injecting
serotonin under the skin causes local inflammation and
hyperalgesia, leading to itching sensations if greater doses
are applied. Conversely, inflammation caused by tissue
damage increases levels of peripheral endogenous sero-
tonin. Raised endogenous serotonin levels have also been
found in people with painful joint movements and in muscle
tissue samples in association with allodynia. These findings
suggest a role for serotonin in inflammation and peripheral
pain states. Across the human body there are at least 12 sub-
types of serotonin receptor conveying different activities. In
the central nervous system, serotonin regulates functions
including cognition, mood, and sleep through its receptors.
Within the peripheral nervous system, primary afferent
neurons express multiple serotonin receptors that include
both a ligand-gated cation ion channel (5-HT3 receptor)
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1
and a GPCR (5-HT2A receptor). Multiple receptor types
mean that serotonin activates several molecular pathways
through binding to its receptors. Consequently, serotonin
modulates PAN activation directly through cation influx
and indirectly through second messenger pathways, which
modulate activity of other channels and peptide expression
within the cell. This includes modulation of TRPV1
channels and increased secretion of the proinflammatory
peptide CGRP by nociceptors.
Serotonin receptors are predominantly expressed by
PANs that show sensitivity to capsaicin; that is, PANs that
also express TRPV1 channels. As levels of serotonin
decrease, activation of TRPV1 channels falls with correlate
decreases in pain sensation; thus, serotonin is thought to
regulate the stimulus threshold of PANs by altering the
properties of TRPV1 receptors. Activation of TRPV1
channels caused PANs to depolarize at lower temperatures,
perceived as heat hyperalgesia, a phenomenon also gen-
erated by injecting serotonin.
In summary, peripheral endogenous serotonin enhances
nociceptor activity through several mechanisms including
increased Ca2+ influx through cation channels, enhanced
proinflammatory peptide release by neurons, and by modu-
lating TRPV1 channels to promote hyperalgesia. Reducing
the presence of peripheral serotonin, or its ability to bind
to its receptors, decreases the above phenomena and, conse-
quently, the likelihood of PAN activation and the perception
of pain. Localized therapeutic agents that target peripheral
serotonin receptors are currently being studied for their
potential to relieve peripheral pain conditions (Hung et al.,
2011; Loyd, Henry, & Hargreaves, 2013; Van
Steenwinckel et al., 2009; Zeitz et al., 2002).
BRADYKININ
Bradykinin (BK) is a small endogenous proinflammatory
peptide known to be an effective inducer of acute pain.
Its other inflammatory functions include potent vasodi-
lation and increased vascular permeability of some vessels,
as well as causing contraction of nonvascular smooth
muscle. Bradykinin’s precursor molecule is present in
plasma and is enzymatically cleaved to form the active
peptide in the presence of tissue injury. Bradykinin is
rapidly deactivated by kininases and by angiotensin con-
verting enzyme (ACE), making its effects restricted to
the local area of damage.
Bradykinin activates PANs directly to cause acute sen-
sations of pain; it also sensitizes PANs to thermal stimuli,
causing heat hyperalgesia. The functions of BK appear to
be mediated through two main receptors: the B1 and B2
receptors, which are both G protein-coupled receptors that
activate second messenger pathways within the cell.
The B2 receptor is routinely expressed by primary
afferent neurons and mediates responses to BK that induce
13
acute pain sensations. Activation of B2 releases a Gq
subunit that initiates an activation cascade through PIP2
and IP3 to ultimately cause intracellular Ca2+ release. This
rise in intracellular Ca2+ causes immediate depolarization
via closure of M-type K+ channels and Cl channel
opening. At resting, membrane potential chemical gradients
mean that Cl ions leave the cell rather than entering it,
pushing the PAN to threshold at its sensory terminal. Acti-
vation of secondary messenger cascades via the B2 receptor
targets another key ion channel, the TRPV1 channel. This
means that BK probably induces hyperalgesia to heat
through increasing sensitivity of the TRPV1 channel to
thermal stimuli. TRPV1 is normally activated at 43  C;
in the presence of bradykinin, PANs may depolarize at
lower ambient temperatures.
The B1 receptor is thought to have a different role to the
B2 receptor; it probably mediates prolonged sensitization to
heat stimuli in chronic inflammatory conditions, rather than
causing acute pain sensations. B1 is not routinely expressed
by PANs; its expression is upregulated in the presence of
chronic inflammation. Tissue damage causes increased
expression of the neurotrophic factor, glial-derived neuro-
trophic factor (GDNF). It is GDNF that upregulates B1
expression in a subset of small-caliber B2-expressing
neurons; notably, 60% of these neurons also express
TRPV1 channels. After prolonged tissue injury, activation
of B1 channels sensitizes TRPV1 channels for a more pro-
longed period than pathways that sensitize TRPV1 via the
B2 receptor; thus, B1 receptors probably have a more
important role in mediating long-term inflammatory pain
induced by bradykinin.
In summary, bradykinin causes acute and chronic pain
and thermal hyperalgesia in the presence of inflammation
through second messenger cascades mediated via B2 and
B1 receptors, respectively. Therapeutic targets should focus
on the B1 pathways as well as the B2 receptor in order to
have meaningful analgesic effects (Brown & Passmore,
2010; Regoli, Rizzi, Perron, & Gobeil, 2001; Schaible &
Richter, 2004; Vellani, Zachrisson, & McNaughton, 2004).
ATP
ATP, the coenzyme essential for metabolism, is abundant
within cells. Injecting ATP into skin is known to cause
dose-dependent pain responses. Because the plasma mem-
brane of cells are impermeable to ATP, the sensory ter-
minals of PANs must express receptors for ATP that
mediate receptor membrane potential. During tissue injury,
ATP is released into the extracellular space and comes into
contact with the sensory terminals of PANs, evoking acute
pain responses via their activation. There are two subtypes
of purinergic receptor for ATP, P2X and P2Y, which are
then divided into many further subtypes.
14 PART I Pain Involving the Peripheral Nerves
P2X receptors are ligand-gated ion channels, small-
caliber PANs expressing P2X2 and P2X3 channels, individ-
ually and bound together as the P2X2/3 receptor. PANs
expressing P2X3 are distributed through most tissue and
organ systems including skin, hollow organs, and joints.
They are expressed peripherally at sensory terminals, but
also centrally where ATP is thought to sensitize the trans-
mission of pain signals to second order afferents. In the
presence of extracellular ATP, activated P2X channels
allow Na+ and Ca2+ to enter the neuron causing depolari-
zation and inducing sensations of acute pain. The P2Y
receptors for ATP are metabotropic GPCRs that are thought
to have a role in mediating heat sensitization in the presence
of inflammation in polymodal cutaneous nociceptors (Ford,
2012; Hamilton, Warburton, Bhattacharjee, Ward, &
McMahon, 2000; Jankowski & Koerber, 2010).
PROSTAGLANDINS AND THROMBOXANES
Prostaglandins and thromboxanes are derivatives of arachi-
donic acid synthesized in the presence of cyclo-oxygenase
(COX) enzymes. These prostanoids are short-lived com-
pounds that require ongoing formation for sustained effects.
Their diverse physiological effects include modifying vas-
cular smooth muscle tone, promoting platelet aggregation,
and sensitizing PANs in the presence of inflammation.
These effects are mediated through a multitude of different
GPCRs for prostanoids thoroughout the body.
Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2)
are probably the most significant prostaglandins in PAN
sensitization. The EP family of GPCRs are receptive to
PGE2 and PGI2, with EP2 and EP4 receptors being
expressed by PANs. Activation of EP receptors activates
second messenger pathways with several outcomes,
including promoting antidromic release of substance P
and CGRP by sensory nerves and sensitizing PANs to
thermal, mechanical, and chemical stimuli. PGE2 probably
induces heat sensitivity via modification of TRPV1
channels; molecular pathways for sensitization of PANs
to mechanical and chemical stimuli are less well under-
stood. Prostaglandins, therefore, promote polymodal hyper-
sensitivity and also perpetuate PAN activation through
antidromic release of neurogenic inflammatory mediators.
This explains why COX inhibitors make effective thera-
peutic agents for a range of inflammatory diseases.
Interestingly, the EP3 receptor may have an opposite
role to EP2 and EP4. EP3 has been found highly localized
to primary afferent neurons and the spinal cord, and been
identified in the afferent nerves supplying the joints of
patients with painful osteoarthritis. PGE2 activates the
EP3 receptors of PANs; rather than increasing intracellular
levels of cAMP, EP3 inhibits the production of cAMP via
activation of inhibitory G proteins and, therefore, inhibits
the sensitizing effects of EP3 and EP4 activation. Selective
activation of the EP3 receptor could provide a novel
approach to treating inflammatory pain conditions
(Natura et al., 2013; Petho & Reeh, 2012).
PROTONS
The acidic nature of the inflammatory soup also contributes
to PAN activation by increasing the local concentration of
protons. Depolarization of PANs is elicited by TRPV1
cation channels and through a family of acid-sensing ion
channels (ASICs).
The TRPV1 channel is subject to allosteric modification
by protons, making it increasingly sensitive to moderate
heat. In very acidotic conditions of less than pH 6, TRPV1
channels have an increased sensitivity to heat and can be
activated at room temperature. At pH range 6-8 the
presence of protons potentiates the response of TRPV1
channels to heat and capsaicin, causing heat hyperalgesia
at normal temperatures. Notably, pH 6-8 is the typical pH
created by the local acidosis of tissue injury.
The TRPV1 channel is not the only channel sensitive to
pH changes. Mice lacking TRPV1 continue to show with-
drawal responses to protons, suggesting nociceptive acti-
vation is occurring through different channels; of
particular interest is the ASIC family. ASICs are a family
of channels that are permeable to cations and activated
by extracellular acidosis. Their activation leads to changes
in neuron membrane potential through the movement of
cations. They are also subject to modulation by other
endogenous substances, including some neuropeptides
and polyamines, as well as arachidonic acid, lactate,
ATP, serotonin, and nitric oxide. The effects of exogenous
substances have also been studied, including derivatives of
venom toxins and NSAIDs. ASICs have been identified in
both peripheral afferents and in CNS neurons in locations
that are important in pain processing. It is thought that they
play a role in both peripheral and central pain processing.
Peripherally, they contribute to nociceptor activation, while
centrally they may alter neuron excitability or neuron
plasticity.
Many subtypes of ASICs are expressed by PANs with
slight functional variances. ASIC3 appears to be important
in the modulation of inflammatory pain, as its expression
and activity are potentiated in the presence of inflammatory
mediators such as bradykinin and serotonin. An upregu-
lation of the expression of ASIC3 in the presence of
ongoing inflammation is likely to contribute to peripheral
sensitization.
It seems ASIC3 has a role in generating the pain felt
during myocardial ischemia and infarction. ASIC3
channels expressed on myocardial PANs are activated by
mild changes in pH caused by damage to myocardial cells
during ischemia. Within the first few minutes of a heart
attack, the local area becomes mildly acidotic due to
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1
protons leaching from cells; pH 7 is quickly reached. While
ASIC3 channels rapidly desensitize to a sustained drop in
pH in the peripheries, in myocardial PANs, ASIC3 channels
maintained a sustained current at pH 7.3-6.7, not adapting
to the continued presence of protons. Lactic acid generated
by myocardial ischemia also stimulates the channels, giving
a dramatic increase in ASIC3 current in its presence. It
appears that these highly sensitive ASIC3 channels in the
heart are specialized to generate PAN depolarization in
response to minor cellular damage, giving us an early
warning system for damage to a most precious organ.
ASICs are currently under investigation as targets for
analgesic agents. Malgabalin-1 is a peptide derived from
the venom of the black mamba snake with the ability to
block ASIC currents and consequent analgesic potential.
Amiloride, too, acts as an ASIC inhibitor and evidence is
emerging for its potential to reduce cutaneous and migraine
pain (Deval et al., 2010; Diochot et al., 2012; Holland et al.,
2012; Story, 2006; Ugawa et al., 2002; Yagi, Wenk, Naves, &
McCleskey, 2006).
SENSITIZATION OF PANs BY
INFLAMMATORY MEDIATORS
Peripheral sensitization is the phenomenon of increased
activity of PANs due to an increased sensitivity to stimu-
lation. This increased sensitivity results in the phenomena
of hyperalgesia, a heightened perception of pain in response
to a noxious stimulus, and allodynia, perception of pain in
response to a normally innocuous stimulus. Peripheral sen-
sitization has the potential to result in increased levels of
pain for the individual concerned, both in response to
usually painful stimuli, but also in circumstances that would
not normally cause pain. This sensitization of PANs occurs
in response to persistent and repeated noxious stimuli or to a
particularly intense noxious event. Its perpetuation nor-
mally requires an ongoing state of tissue injury; once
inflammatory events have resolved, the sensitivity of local
PANs returns to normal.
In peripheral sensitization the nocieptor threshold of
activation is lowered, meaning that it depolarizes more
readily than normal and even spontaneously. Lowering
the threshold for activation is achieved by shifting the
balance of ions across the receptor membrane through mod-
ification of ion channels and receptors. Interestingly, PANs
demonstrate differences in the modality of noxious stimulus
they are most sensitized to, dependent upon their somatic
location. PANs supplying the muscles and joints are most
strongly sensitized to mechanical stimuli, while cutaneous
PANs become most sensitized to thermal stimuli. Consider
the aching you feel walking around in the days after an
uncharacteristic bout of exercise, or the pain caused by
warm shower water on sunburned skin; both are examples
15
of lowered threshold PANs generating noxious sensations
in response to normally innocuous activities. Thankfully,
peripheral sensitization usually requires persistent tissue
injury to be maintained, so unless you decide to compete
in another triathlon or forgo the sunscreen again, these
activities will return to the same nonpainful status they
had before your tissues were injured.
Many of the inflammatory mediators that are released
into the extracellular space during tissue injury have the
ability to sensitize the receptor membrane of PANs. Inflam-
matory mediators influence function of receptors and
channels to increase the propensity of the nociceptor to
depolarize propagating a signal centrally. Inflammatory
mediators are not the only endogenous substances that
can sensitize nociceptors; sex hormones, such as estrodiol,
have also been demonstrated to induce activation of PANs
through peripheral sensitization, while neurotrophic factors
including NGF upregulate the expression of TRPA1
channels. Under normal circumstances PANs can adapt to
a prolonged stimulus; however, in the presence of inflam-
mation, once the nociceptor is sensitized it will no longer
adapt and continues to convey nociceptive signals to the
spinal cord in the presence of the noxious stimulus.
In addition to receptor and channel modulation,
increased sensitivity is also achieved through recruiting
additional neurons to convey nociceptive signals. A signif-
icant proportion of C fibers are the MIAs. These are a pop-
ulation of silent nociceptors that only respond to very high
intensity stimuli under normal conditions. In the presence of
inflammation, MIAs become sensitized and begin to
conduct nociceptive signals to the spinal cord. This
increases the barrage of information reaching the spinal
cord from PANs with a corresponding increase in pain per-
ception and sensitivity to noxious stimuli. As their name
suggests, MIAs demonstrate a more significant change in
their sensitivity to mechanical stimuli than other modalities
in the presence of inflammation.
In summary, the presence of persistent inflammation
causes increased flow of information from PANs to the
dorsal horn of the spinal cord through three mechanisms:
modification of ion channels and receptors to noxious
stimuli, upregulating the expression of noxious stimuli
receptors, and by recruiting populations of normally silent
nociceptors. These combined events are known collectively
as peripheral sensitization of nocieptors and increase pain in
the form of both hyperalgesia and allodynia (Gangadharan &
Kuner, 2013; Gold & Gebhart, 2010; Hucho & Levine, 2007;
Schaible & Richter, 2004; Svensson, Wang, Dong, Kumar, &
Cairns, 2010).
CENTRAL SENSITIZATION
Peripheral neurological events influence central neurological
events. Afferent neurons within the spinal cord can become
16 PART I Pain Involving the Peripheral Nerves
increasingly sensitive to activation when subject to con-
tinuous or high-intensity input from peripheral nociceptors.
Peripheral events are not the end of the story when it
comes to sensitizing events causing pain. As discussed
within the introductory parts of this chapter, pain is not a
mechanical event, but a neurological one manifested by
the central nervous system and not perceived until neuro-
logical signals reach the cortex. Therefore, nociceptive
signals can be modified at any part of their pathway toward
the cortex. Just as sensitization of PANs occurs in the
peripheries, it also happens centrally. Central sensitization
refers to events that occur in the dorsal horn of the spinal
cord and is not analogous to peripheral sensitization; while
peripheral sensitization normally requires continued
presence of the pathological stimulus to be maintained,
central sensitization lasts for longer periods of time and per-
sists in the absence of pathology.
A detailed discussion of the events of central sensiti-
zation is beyond the scope of this chapter; however, an
introduction to the topic is appropriate in the context of
the contribution of peripheral events to pain conditions.
Central sensitization occurs in the dorsal horn of the
spinal cord, where the central terminals of PANs synapse
with subsequent afferent neurons in the pathways that ulti-
mately deliver information about noxious peripheral events
to the cortex. The responses of CNS neurons to PANs are
modified so that peripheral noxious events are no longer
coupled to pain signal generation in the spinal cord. The
dorsal horn becomes increasingly sensitive to input and
can generate spontaneous activity.
Central sensitization can only occur in the presence of
sustained and intense noxious stimulation. Tissue injury
is not necessary to cause central sensitization, but the gen-
eration of signals significant enough to cause central
changes is usually associated with tissue damage. When a
sustained and intense input from PANs to the dorsal horn
is generated, central neuropeptides, neurotrophic factors,
and inflammatory mediators trigger cellular events that
modulate the structure and function of dorsal horn neurons.
This structural and functional alteration causes a
decrease in the threshold of activation of ascending
neurons; consequently, their responsiveness to normal
levels of activation is increased. There is also loss of the
normal inhibitory mechanisms that modulate ascending
signals, and spontaneous neuronal activity at the dorsal horn
can occur.
These phenomena cause an increased propensity for
ascending pain signals to be generated and painful feelings
to be perceived.
The persistent presence of peripheral inflammation can
also result in a functional, or phenotypic, switch of primary
afferent neurons that do not normally convey nociceptive
information contributing to centrally sensitizing phe-
nomena. When peripheral terminals of large-caliber,
myelinated Aβ fibers are exposed to inflammatory medi-
ators and NGF, they begin to express SP and brain-derived
neurotrophic factor (BDNF). Subsequently, these large-
caliber fibers release SP and BDNF at the spinal cord in
response to innocuous stimuli, and SP and BDNF within
the spinal cord induce local events that further contribute
to sensitization of central pain processing circuits.
Both peripheral and central sensitization are examples
of the remarkable plasticity of the nervous system, demon-
strating how functional change can occur in the face of con-
tinued or intense noxious stimulation. These events only
just touch on the complexity of pain generation and per-
ception by the peripheral and central nervous system.
Further local and descending modulatory events are gen-
erated by the brain stem, thalamic, and cortical pathways
that can ramp-up or reduce the degree and nature of pain
experienced by an individual. This, in some way, goes
toward explaining why pain management is a complex
process largely determined by a trial and error approach
to interventions. An emerging trend toward a biopsycho-
social approach to pain management is necessitated as
pharmacological interventions alone prove unsatisfactory
(Latremoliere & Woolf, 2009).
NEUROGENIC INFLAMMATION
PANs can generate inflammatory events at their peripheral
receptor terminals by releasing proinflammatory neuropep-
tides into the tissues.
It has long been established that PANs do not just prop-
agate action potentials centrally, releasing neuropeptides at
the spinal cord, but that they also release neuropeptides
peripherally, at their sensory terminals.
Peripheral release of peptides by PANs is stimulated
when the sensory terminal is depolarized. This can be
due to local activation by noxious stimuli contacting their
relevant receptor molecules and altering the receptor mem-
brane potential, or by antidromic activation. Antidromic
flow of depolarizing currents occurs when the neuron is
stimulated along the length of its axon. This generates a
bidirectional current flowing both centrally and periph-
erally, stimulating the increased expression of and central
and peripheral release of neuropeptides. Substance P
(SP), CGRP and, to a lesser extent, neurokinin A are iden-
tified as being released at the peripheral terminal of PANs
(Figure 1.4).
The population of DRG neurons that demonstrate
peripheral peptide release are the polymodal C fibers that
express the TRPV1 receptor for moderate heat and
capsaicin.
Peripheral release of SP, neurokinin A, and CGRP
induce local tissue effects that promote inflammation. Sub-
stance P and neurokinin A increase vascular permeability in
capillary beds, while CGRP induces vasodilation in
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1 17

C
D
A

C
FIGURE 1.4 Antidromic flow of axon depolarization causes neurogenic inflammation to spread to adjacent tissues. A: Tissue damage causes release of
inflammatory mediator molecules. B: Receptor potentials generated, leading to axon depolarization. C: Antidromic flow toward collateral sensory ter-
minals causes peripheral release of SP and CGRP. D: PAN activation causes release of neuropeptides at the dorsal horn.

precapillary arterioles. This results in local hyperemia and
edema. SP and CGRP are also thought to influence acti-
vation of immune cells. Substance P increases proliferation
of peripheral leukocytes, stimulates cell movement and
activation, and induces cytokine release from neutrophils,
macrophages, and mononuclear cells. CGRP has an
influence on the immune system by promoting chemotaxis
of peripheral leukocytes toward it. Neuropeptides also
induce inflammatory effects through interactions with
inflammatory cells such as mast cells. During tissue injury,
mast cells release NGF that activates and sensitizes PANs,
releasing SP. Mast cells have receptors for SP that, when
activated, cause increased histamine and TNF-α expression.
Histamine activates PANs while TNF-α sensitizes them,
increasing their likelihood of depolarizing and releasing
SP, further enhancing mast cell activity. Thus, a self-
perpetuating cycle of activation is established unless
inhibited by coexisiting anti-inflammatory mechanisms
(Figure 1.5).
The hyperemia and edema caused locally by the release
of these vasoactive peptides is termed neurogenic inflam-
mation, that is, inflammation that is induced directly by
the sensory nerves. It leads to the wheal-and-flare reactions
that are seen in response to skin damage.
Neurogenic inflammation is not confined to the sensory
nerve terminal that was originally activated; it has the
potential to spread to other sensory branches of that same
nerve. Once the receptor terminal is depolarized, an action
potential propagates centrally along the neuron. This elec-
trical current also spreads along the axon membrane in a
peripheral direction along any collateral branches of the
neuron. This spreading wave of depolarization causes release
of vasoactive peptides at distal terminals, creating an
extending area of neurogenically mediated inflammation.

Mast cell Histamine

release
Increased
histamine
expression &
TNF-α
release NGF
release

PAN
PAN
sensitization
PAN
TNF-α activation
release

SP
release
FIGURE 1.5 Immune cells and nociceptors interact via messenger molecules to promote a proinflammatory state.
18 PART I Pain Involving the Peripheral Nerves
Spreading of inflammation through the nervous system
is recognized as a possible modality for the symmetrical
distribution of joint inflammation in rheumatoid arthritis.
The joint that is initially inflamed activates PANs supplying
it. With persistent stimulation, these PANs undergo
peripheral sensitization and relay high-volume nociceptive
input to the dorsal horn. Analogous afferent neurons sup-
plying the contralateral joint demonstrate antidromic acti-
vation, while the opposite joint is inflamed. This
antidromic activity causes peripheral release of substance
P and CGRP, leading to neurogenic inflammation in the
contralateral joint and is thought to account for the symmet-
rical distribution of rheumatoid arthritis (Kelly, Dunham, &
Donaldson, 2007; Kidd et al., 1989).
Neurogenic inflammation has the unfortunate property
of being able to propagate a self-sustaining cycle of tissue
inflammation. Tissue injury leads to release of inflam-
matory mediators including bradykinin and serotonin, as
we have already discussed. These chemicals have vascular
effects that induce local inflammation, but also can cause
activation of PANs by interacting with receptors at the noci-
ceptor sensory terminal. Activation of the PAN causes
peripheral release of neuropeptides SP, NK, and CGRP.
These peptides contribute to promoting the existing inflam-
matory events in the damaged tissues by attracting further
immune cells and inflammatory mediators that continue
to activate the nociceptor. A cycle of tissue injury and neu-
rogenic inflammation may result, which has the potential to
spread from the original site of injury through collateral
nociceptor terminals. The phenomenon provides a potential
model of pathophysiology for some chronic inflammatory
diseases and is consequently a therapeutic target (Herbert
& Holzer, 2002; Jancsó, Katona, Horváth, Sántha, &
Nagy, 2009; Richardson & Vasko, 2002).
Neurogenic inflammation is not an unopposed
phenomenon. As a theme that is consistent through all
physiological pathways, there also exists contrary
anti-inflammatory effects of neuropeptides. While SP, neu-
rokinin A, and CGRP act on GPCRs to stimulate inflam-
matory events, there is an array of neuropeptides that
reduce inflammation and inhibit the function of inflam-
matory cells. Many of these neuropeptides are not produced
exclusively by neurons, but are also secreted by some inflam-
matory cells. Over 10 anti-inflammatory neuropeptides have
been identified. They predominantly act on immune cell
GPCRs coupled to adenylate cyclase and mediate inflam-
matory responses through downregulating release of inflam-
matory mediators and upregulating anti-inflammatory
mediators. Neurogenic inflammation is subject to inherent
peripheral control mechanisms that, in the absence of
pathology, prevent spreading of inflammation and excessive
tissue damage. If agonists for these anti-inflammatory
receptors could be identified, it could provide a generation
of novel anti-inflammatory agents (Jancsó et al., 2009;
Pintér, Pozsgai, Hajna, Helyes, & Szolcsányi, 2014).
NOCICEPTOR INTERACTIONS WITH
THE IMMUNE SYSTEM
Nociceptors and immune cells interact to modulate
responses to tissue injury and inflammation. The full extent
and nature of these interactions is not yet understood. A
better understanding of these interactions could provide
new therapeutic avenues for pain control and treating
inflammatory disease.
Immune cells release factors that modulate inflam-
matory responses and activate and sensitize PANs. Mast
cells and macrophages can be found localized to PANs,
and they are activated in tissue injury to release proinflam-
matory cytokines, chemokines, and factors that stimulate
the complement cascade. Inflammation also promotes
extravasation and accumulation of neutrophils, monocytes,
and T lymphocytes at the site of injury. These accumulated
immune cells can all contribute to peripheral sensitization
of nociceptors as the chemical factors they release interact
with PAN receptor molecules. This is a two-way interaction
because while immune cells can activate PANs, PANs
reciprocally attract and activate immune cells. For example,
if a nociceptor axon is damaged, TNF-α is released by
Schwann cells recruiting macrophages to the area, and mac-
rophages release mediators including IL-1 that bind to
nerve terminals and induce SP release. Substance P and
CGRP facilitate mast cell degranulation and attract neutro-
phils. These bidirectional neuroimmune interactions
promote an amplification of recruitment of immune cells
and inflammatory tissue changes and may underpin some
of the complex interactions between pain and disease.
Immune cells can also mediate inhibitory effects on
nociceptors, suppressing inflammation and reducing pain.
Immune cells, including leukocytes and keratinocytes,
contain opioid peptides such as β-endorphin, met-
enkephalin, and dynophin-A. These opioids are released
by immune cells in inflamed tissue, creating targeted anal-
gesia. PANs express opioid GPCRs that, when stimulated,
activate biochemical cascades stimulating K+ rectifier
channels, inhibiting voltage-gated Ca2+ channels, and inhi-
biting andenylate cyclase. The functional consequences of
opioids binding to PANs are decreased neuronal excit-
ability, decreased firing rate, and inhibition of neurotrans-
mitter release. The presence of inflammation increases the
expression of opioid receptors in the afferent nerves sup-
plying the inflamed tissue, giving a targeted effect of antino-
ciceptive opioids release at inflamed sites by immune cells.
Interactions between the immune system and pain per-
ception are not limited to peripheral events. Infiltration of
 Pathophysiology of Pain in the Peripheral Nervous System Chapter 1
the CNS by immune cells is thought to contribute to chronic
pain states, while circulating cytokines may interact with
central nervous pathways involved in modulating physio-
logical responses to, and the perception of, pain. Local
inflammatory events are thought to create a degree of sys-
temic cytokine circulation. Systemic cytokines interact with
the hypothalamus to trigger thermogenesis and to stimulate
the hypothalamic-pituitary-adrenal axis. This has the
potential to increase output of “stress” hormones CRH,
ACTH, and cortisol into general circulation. Stress hor-
mones influence how the CNS modulates hyperalgesia
and arousal. All of us have probably experienced the ten-
dency to be more susceptible to pain, or to be more upset
by pain, when we are under stressful circumstances. An
in-depth discussion of these systemic and centrally
mediated effects of nociceptor and immune interaction is
beyond the scope of this chapter (Chiu et al., 2013;
Kapitzke, Vetter, & Cabot, 2005; Ren & Dubner, 2010;
Stein & Machelska, 2011; Willard, 2003).
NEUROGENIC INFLAMMATION AND
PERIPHERAL SENSITIZATION IN DISEASE
Arthritis
Neurogenic inflammation is thought to play an important
role in arthritis. Our joints are densely innervated by pepti-
dergic afferent neurons. For example, animal models
suggest that 80% of all primary afferent neurons supplying
the knee are nociceptive. This may explain why inflam-
matory conditions of the joints are associated with a notable
pain component, often causing significant impact upon
quality of life.
Joints also have an abundant supply of autonomic nerve
fibers. Interestingly, autonomic fibers are known to also
secrete peripheral vasodilatory neuropeptides at their
peripheral terminals in a similar fashion to PANs. Auto-
nomic fibers secrete vasoactive peptide (VIP) and neuro-
peptide Y (NPY) peripherally, both of which are found in
the synovial fluid of inflamed joints.
PANs and autonomic fibers innervate most articular
structures including the connective tissues, the joint capsule
and synovial membrane, bone and periosteum, and liga-
ments and tendons. Innervation of the cartilage structures
has been historically debated, but it is currently thought that
the superficial layers of the knee menisci and the hyaline
cartilage are innervated. Studies of the distribution of PANs
in joints finds that they are closely apposed to the blood
vessels, with fibers that secrete CGRP lying close to arterioles
in the synovium and autonomic fibers supplying blood vessels
of the synovium, connective tissues, and joint capsule.
A dense supply of neuropeptide secreting neurons is
thought to have significant contributing and maintaining
19
effects in arthritic joints. In experimentally induced disease
states, the PANs supplying inflamed joints show upregu-
lated expression of SP and CGRP. Sustained joint inflam-
mation leads to peripheral sensitization of joint PANs,
while recruiting the MIAs to convey additional nociceptive
signals to the spinal cord. These phenomena are thought to
contribute to the pain of arthritis, giving hyperalgesia to
mechanical stimuli. This explains why even small or non-
weight-bearing movements, that are pain free in healthy
joints, can cause pain in the chronically inflamed or arthritic
joint (Donaldson, 2009; McDougall, 2006; Niissalo,
Hukkanen, Imai, T€ornwall, & Konttinen, 2002).
COMPLEX REGIONAL PAIN SYNDROME
Complex regional pain syndrome (CRPS) is a debilitating
condition in which the patient experiences severe pain,
swelling, and skin changes in a limb secondary to a degree
of trauma. CRPS is diagnosed in the presence of the
following criteria:
– There has been a preceding noxious event, with or
without obvious nerve injury.
– There is spontaneous pain or hyperalgesia that is not
limited to one nerve territory and is disproportionate
to the inciting event.
– There are edema, skin blood flow, and sudomotor
abnormalities, motor symptoms, and trophic changes
in the effected limb.
– Other diagnoses have been excluded.
In CRPS type I there is no demonstrable nerve lesion
present. This is the most prevalent type, while CRPS type
II is classified by evidence of nerve damage.
Pain and hyperalgesia are the strongest features of
CRPS, with 75% of patients having pain at rest and nearly
100% reporting hyperalgesia to mechanical stimuli.
Movement is consequently painful, and patients develop
aversive behaviors that contribute to the motor symptoms.
The pathophysiology of CRPS has not been fully eluci-
dated, but peripheral sensitization and neurogenic inflam-
mation are thought to underpin some of the processes that
lead to symptoms in the early stages of disease. Tissue
injury (e.g., long bone fracture) activates and sensitizes
PANs, causing peripheral release of the neuropeptides SP
and CGRP; this may account for the initial skin changes
in CRPS. Substance P and CGRP induce vasodilation and
plasma protein extravasation, leading to increases in skin
temperature and edema. CRPS patients have high levels
of plasma protein extravasation and show greater responses
to SP than normal patients in whom the amount of SP
released by PANs is not sufficient to affect movement of
plasma proteins. The early stages of CRPS show increased
hair and nail growth of the affected limb, which may be
20 PART I Pain Involving the Peripheral Nerves
promoted by increased levels of CGRP. X-rays of affected
limbs show patchy areas of osteoporotic change in the
bones of the affected limb. TNF-α and SP are known to
activate osteoclasts, and one proposed mechanism for
increased reabsorption of bone is because of the presence
of these neuropeptides. The persisting and spreading effects
of CRPS are probably due to processing in the central
nervous system, including cortical reorganization. Central
sensitization may mediate the spreading of pain sensations
from the site of initial injury and allodynia (Birklein, 2005;
Birklein & Schmelz, 2008; K€ ock, Borisch, Koester, &
Grifka, 2003).
CONCLUSION
Activating peripheral nociceptors involves a complex and
multifaceted series of physiological events that are crucial
to our survival as a species. Many modalities of stimulus
exist that activate both highly specific and polymodal
receptors on our peripheral afferent nerves. This allows us
to encode multiple modalities of damaging and potentially
damaging information into electrical nervous impulses that
are propagated to the spinal cord for further processing. As
we better understand the structural and functional properties
of these receptor molecules, and how they transduce one
form of energy into another, the possibilities for modulating
their function grow. We are perhaps far from the advent of
the magic bullet that can selectively block peripheral noci-
ceptor activation, while maintaining the functional activity
of other afferent neurons, but we are moving closer to tar-
geted treatments for peripherally generated pain. Of course,
understanding peripheral nociceptive mechanisms is only
the tip of the iceberg. Pain is a far more complex and dif-
fusely generated phenomenon, a truly biopsychosocial entity
that each individual manifests according to their own per-
sonal milieu of biological and environmental factors. Fully
understanding and then treating this phenomenon requires
continuing study and multidisciplinary cooperation by scien-
tists and health professionals. Attacking pain at the level of
peripheral nociceptive events is just one doorway into the
human battle with pain.
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