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PAIN xxx (2011) xxx–xxx
Commentary
Dissecting itch and pain sensations in human skin
Although pruritus is one of the most common symptoms in
cutaneous as well as systemic diseases [6], our understanding of
itch-coding neural mechanisms is still unsatisfactory. For example,
it is commonly believed that histamine injection produces only
itch and capsaicin injection only pain. In an intriguing article in this
issue of Pain, however, Sikand et al. [10] demonstrate that hista-
mine injections not only produce itch, but also nociceptive sensa-
tions, such as pricking/stinging or burning. These sensations do
not necessarily ‘‘hurt’’ or are painful. Furthermore, this article sub-
stantiates the dual contribution of capsaicin-expressing, TRPV1+
positive neurons to both itch and pain. Capsaicin injection or treat-
ment of patients with capsaicin cream usually produces nocicep-
tive sensations with little or no transient itch. However, under
certain conditions, capsaicin can also produce an itch sensation
[2]. In other words, itch and nociceptive qualities can coexist. This
finding may be relevant to the clinical situation where patients suf-
fering from various dermatological conditions may not report
experiencing a ‘‘pure’’ sensation of itch or pain, but rather a com-
bination of these sensations. An example of this phenomenon is
illustrated in patients with contact dermatitis, rosacea or herpes.
Similarly, BAM8-22, an adrenal gland-derived proenkephalin
derivative, activates the Mas-related G protein-coupled receptor
C11 and X1 in mice [4] and in humans can produce histamine-
independent itch, as well as a nociceptive sensation [8].
The Sikand et al. finding brings to mind the important debate as
to how sensory sensations, including itch, pain and touch, are en-
coded in the peripheral and central nervous system. Major compet-
ing views are the specificity (population coding of ‘‘labeled lines’’)
theory and the pattern theories [5]. Strictly speaking, the new find-
ings do not necessarily favor one or the other theory, but stresses
the fact that if labeled lines for itch and pain exist, then (1) a com-
munication between itch- and pain-associated nerves must occur
and (2) that certain nerve fibers (in the periphery or CNS) react
to pruritogens but not algogens (eg gastrin-releasing peptide/gas-
trin-releasing peptide receptor (GRP/GRPR) [12]). The reality is –
as shown by LaMotte and coworkers – that most mediators (eg his-
tamine, capsaicin, endothelin, serine proteases, SP, BAM, etc.) are
promiscuous, ie they can produce itch and/or pain, depending on
the mode of application (superficial vs deep, large area vs small
area, peripheral vs central), and concentration. The critical ques-
tion that remains is: under what circumstances does a histamine
receptor-expressing unmyelinated afferent fiber transmit (mostly)
itch, but sometimes pain, and: under what condition does a capsa-
icin receptor-positive, unmyelinated afferent fiber transmit
(mostly) pain, but sometimes itch? Here, additional molecular
and cellular studies of itch and pain pathways in humans are nec-
DOI of original article: 10.1016/j.pain.2011.06.001.
0304-3959/$36.00 Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
doi:10.1016/j.pain.2011.07.013
www.elsevier.com/locate/pain
essary and these should include correlated psychophysical and
neurophysiological analyses.
Another important question in sensory neurobiology is whether
hyperalgesia and allodynia can co-exist with hyperknesis in human
skin. Brull et al. [1] observed that histamine injected in an area of
mechanical allodynia produced by capsaicin injection produces
neither itch nor pruritic dysesthesia (alloknesis = pruritus by
non-pruritic stimulus, and hyperknesis = extraordinarily enhanced
itch by pruritic stimuli). The authors concluded that the allodynia
blocked both the itch and the pruritic dysesthesia elicited by hista-
mine. However, in the present study Sikand et al. [10] found that a
capsaicin injection that evoked nociceptive sensations (without
itch) can also produce allodynia (and hyperalgesia) accompanied
by hyperknesis (enhanced mechanically-evoked itch). Thus, hyper-
algesia and allodynia can co-exist with hyperknesis in human skin,
just as itch can co-exist with pricking/stinging, burning and hyper-
algesia [3,9].
Sikand and coworkers [10] also assessed whether histamine,
when applied by injection or spicules, evokes similar types of dys-
esthesia: alloknesis, hyperknesis and hyperalgesia. Of note, capsa-
icin when delivered by spicules predominantly produced itch,
whereas its injection typically produced nociceptive sensations,
without itch. Thus, capsaicin spicules produced alloknesis, whereas
capsaicin injection produced allodynia in addition to hyperknesis
and hyperalgesia. Based on these observations, it is reasonable to
hypothesize that histamine activates the same subset of sensory fi-
bers when applied either by spicules or by injection and can pro-
duce the same sensory quality and dysesthesias as can capsaicin.
However, capsaicin – when injected – activates an additional
subset of sensory fibers, which are hypothesized to be ‘‘nocicep-
tive-specific’’. The latter fibers may act centrally to mask itch and
replace alloknesis with allodynia, but without affecting hyperkne-
sis. Understanding these complex circuits in humans is hampered
by our limited abilities to study neural and interneural communi-
cation in humans. This is the elegance of the LaMotte and cowork-
ers contribution, which significantly increases our knowledge
about the complex pathophysiology of itch in humans.
Another interesting observation in the Sikand et al. [10] study is
that local application of very small amounts of histamine via a sin-
gle spicule, which most likely activates only a small number of
peripheral nerve fibers, produces sensations comparable to those
evoked by large volumes and amounts of injected histamine. This
finding suggests that abnormal activity in a small number of pru-
riceptive afferents might be sufficient to produce significant itch
and dysesthesias in a patient who suffers from chronic itch. This
observation, in fact, is reminiscent of our experience with patients
suffering from chronic pruritic diseases and has an important clin-
ical implication. The finding may help to destigmatize chronic itch
sufferers, who have hypersensitive itchy skin in response to mini-
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2 Commentary / PAIN xxx (2011) xxx–xxx
mal stimuli, such as sweating or wool fibers. The assumption that
the problem that these patients suffer is ‘‘psychological’’ may dis-
appear [11].
Sikand et al. [10] also observed a dose-dependent histamine-in-
duced flare, depending on the mode of histamine administration
(ie, via spicules or by injection). The area of flare in response to a
single spicule was smaller than the area evoked by multiple spic-
ules, and this was smaller than the area evoked by injection. How-
ever, comparable intensities of itch were observed in all three
conditions. The authors hypothesize that sensory nerve fibers
responsible for the production of flare (possibly mechano-insensi-
tive afferents, MIAs) [7] and itch (either mechano-sensitive fibers,
MSAs or a combination of MSA and mechano-insensitive fibers,
MIAs) may be different. This hypothesis needs to be verified by
demonstrating that histamine-induced axon-reflex flare can exist
without itch, and, vice versa. Another explanation could be that
the same fiber can be responsible for axon-reflex flare and itch,
but that the itch intensity will be determined not only by periph-
eral neural activation but also by central processing in the brain.
In summary, this new report from the LaMotte laboratory con-
tributes greatly to our understanding of the complexity of itch and
pain sensations (including pain/itch-sensitization) evoked in hu-
man skin, and provides a valuable basis for designing future stud-
ies into the molecular mechanisms that connect itch and pain
circuitry.
1. Conflict of interest
No conflict of interest to declare.
References
[1] Brull SJ, Atanassoff PG, Silverman DG, Zhang J-M, LaMotte RH. Attenuation of
experimental pruritus and mechanically evoked dysesthesias in an area of
cutaneous allodynia. Somatosen Mot Res 1999;16:291–8.
[2] Klein AH, Iodi Carstens M, Carstens E. Facial injection of pruritogens or
algogens elicit distinct behavior responses in rats and excite overlapping
populations of trigeminal neurons. J Neurophysiol 2011; Jun 8. [Epub ahead of
print].
[3] LaMotte RH, Shimada SG, Green BG, Zelterman D. Pruritic and nociceptive
sensations and dysesthesias from a spicule of cowhage. J Neurophysiol
2009;101:1430–43.
[4] Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ,
Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X. Sensory neuron-
specific GPCR Mrgprs are itch receptors mediating chloroquine-induced
pruritus. Cell 2009;139:1353–65.
[5] Ma Q. Labeled lines meet and talk: population coding of somatic sensations. J
Clin Invest 2010;120:3773–8.
[6] Paus R, Schmelz M, Biro T, Steinhoff M. Frontiers in pruritus research:
scratching the brain for more effective itch therapy. J Clin Invest
2006;116:1174–86.
[7] Schmelz M, Michael K, Weidner C, Schmidt R, Torebjork HE, Handwerker HO.
Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport
2000;11:645–8.
[8] Sikand P, Dong X, LaMotte RH. BAM8-22 peptide produces itch and nociceptive
sensations in humans independent of histamine release. J Neurosci
2011;31:7563–7.
[9] Sikand P, Shimada SG, Green BG, LaMotte RH. Similar itch and nociceptive
sensations evoked by punctate cutaneous application of capsaicin, histamine
and cowhage. Pain 2009;144:66–75.
[10] Sikand P, Shimada SG, Green BG, LaMotte RH. Sensory responses to injection
and punctate application of capsaicin and histamine to the skin. Pain, 2011.
doi:10.1016/j.pain.2011.06.001.
[11] Steinhoff M, Bienenstock J, Schmelz M, Maurer M, Wei E, Bíró T.
Neurophysiological, neuroimmunological, and neuroendocrine basis of
pruritus. J Invest Dermatol 2006;126:1705–18.
[12] Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch
sensation in the spinal cord. Nature 2007;448:700–3.
⇑
Martin Steinhoff
Akihiko Ikoma
Departments of Dermatology and Surgery,
University of California, San Francisco (UCSF),
513 Parnassus Ave.,
Room S-1268,
94143 San Francisco,
CA, USA
⇑ Corresponding author.
E-mail address: SteinhoffM@derm.ucsf.edu (M. Steinhoff).