COMMENTARY

See related article on pg 2042

The Pruritus Receptor Unit: A Target

for Novel Therapies
Gil Yosipovitch1
Although the role of prostanoids in itch was actively studied a decade ago,
interest in this area has waned in recent years. Andoh et al. (2007, this issue)
demonstrate that the prostanoid thromboxane A2 elicits scratching through its
TP receptor. Identification of new itch mediators and their respective receptors
within the skin will undoubtedly be the focus of future drug development for
this distressing symptom.
Journal of Investigative Dermatology (2007) 127, 18571859. doi:10.1038/sj.jid.5700818

A unique feature of itch is that it is

restricted to the skin and occasionally the adjoining mucosa, such as the
conjuctiva. Itch sensation emanates
from the activity of nerve fibers in the
epidermis and upper layers of dermis. Although a specific receptor for
itch has not yet been identified within
these layers, the following data support
this notion: (i) removal of the epidermis abolishes perception of pruritus,
(ii) inflammation in the reticular dermis
and subcutaneous fat, such as that seen
in panniculitis and cellulites, frequently
causes pain but not itch (it is assumed
that nerve fibers located in deeper layers of the reticular dermis and subcutaneous fat do not transmit pruritus,
(iii) light microscopy using specific
markers for nerve fibers such as protein
gene product 9.5 and ultrastructural
studies of human skin have demonstrated the existence of intraepidermal nerve
fibers with free nonspecialized nerve
endings extending into the stratum
granulosum, and these fibers are overexpressed in itchy dermatoses. Many of
these fibers stain positively for neuropeptides believed to be itch mediators,
such as substance P, somatostatin, vasoactive intestinal polypeptide, and neuropeptide Y, suggesting that pruritus is
transmitted in the epidermis by C fibers.
C fibers are primary afferent nociceptors.
Moreover,
keratinocytes
express a variety of neural mediators

and receptors, all of which appear to

be involved in itch sensation. These
include opioids, proteases, substance
P, nerve growth factor, neurotrophin
4, and endocannabinoids, and their
respective receptors, including - and
-opioid receptors, PAR-2, vanilloid
receptors, TRPV ion channels, TrkA,
TrkB, and cannabinoid receptors 1 and
2. Keratinocytes also have voltage-gated
ATP channels and adenosine similar to
C nerve fibers (Steinhoff et al., 2006).
Because these channels have a role in
pain, it is possible that keratinocytes
may act as itch receptors in specific
skin inflammatory conditions.
Histamine has been considered the
archetypal itch mediator in inflammatory skin disease for decades. However,
the mechanism by which histamine
induces itch transmission via nerve
fibers was unclear until recently. Han
et al. (2006) demonstrated that phospholipase C3, a molecule that links
G proteincoupled receptors to an
intracellular signaling network, mediates the scratching response activated
by the histamine H1 receptor on C
nerve fibers. However, the role of histamine in most types of chronic itch is
minimal, as attested by the lack of efficacy of antihistamines in alleviating
pruritus. A recent study suggests that
histamine H4 agonists and histamine
H3 antagonists induce itch by a G proteincoupled receptor that mobilizes

Departments of Dermatology, Neurobiology & Anatomy, and Regenerative Medicine, Wake Forest
University School of Medicine, Winston-Salem, North Carolina, USA
Correspondence: Dr Gil Yosipovitch, Department of Dermatology, Wake Forest University Medical Center,
Medical Center Boulevard, Winston Salem, North Carolina 27157, USA. E-mail: gyosipov@wfubmc.edu

Ca2+ in eosinophils. In addition, the histamine H4 receptor is found in human

skin mast cells (Lippert et al., 2004).
Moreover, histamine and a selective
histamine H4 receptor agonist caused
a scratching response in mice, which
was almost completely attenuated in
histamine H4 receptor knockout mice
or by pretreatment with a selective
histamine H4 receptor antagonist. The
inhibitory effect of the histamine H4
receptor antagonist was greater than
that observed with histamine H1 receptor antagonists (Dunford et al., 2007).
Histamine H4 receptor-mediated pruritus has been shown to be independent
of mast cells or other hematopoietic
cells, suggesting that this itch may be
mediated by peripheral nerve fibers in
the skin.
The role of proteases in the pruritus
of atopic eczema has been clearly demonstrated. Proteases, such as tryptase,
activate proteinase activated receptor-2
(PAR2) localized in C nerve fiber terminals in the skin (Steinhoff et al., 2006).
The importance of epidermal serine
proteases in eliciting itch has been further demonstrated in a mouse model,
which showed that overexpression of
serine protease caused severe itch and
scratching. Proteinase activity can also
be found in common allergens and

The scratching response

was abolished by
deficiency of TP
receptor and TP
receptor antagonist.

staphylococcal skin infections, both of

which aggravate atopic dermatitis and
itch. Recent studies demonstrated that
serine proteases also impair the stratum corneum barrier function; this may
further explain why impaired stratum
corneum barrier function in dry skin
induces itch (Nakamura et al., 2006).
For more than a decade, the perception of pruritus has been known to
be modified by endogenous opiates
via central opioid receptors. A recent
study illustrated that - and -opioid
receptors are expressed in keratinocytes and in peripheral nerve endings
in the skin. In particular, induction of
dry skin dermatitis in -opioid-receptor
www.jidonline.org 1857

COMMENTARY

knockout mice had a significant impact

on increasing density of epidermal
nerve fibers and resulted in significantly
less scratching behavior in comparison
with wild-type mice. The inflammatory
infiltrate composed of mast cells and Tcell lymphocytes did not correlate with
the alterations in opioid receptors, suggesting that opioid can exert itch without inflammation or mast cell activation,
as was previously thought (Bigliardi-Qi
et al., 2005). Nociceptin, the endogenous peptide ligand for opioid receptor-like-1 (ORL1) receptor, is another
opioid receptor involved in itch. Recent
data using a mouse model suggest that
nociceptin acts on the ORL1 receptor
expressed on keratinocytes to produce
leukotriene B4, which induces scratching (Andoh et al., 2004).
Although the role of prostanoids in
itch was actively studied a decade ago,
it has become somewhat neglected
over recent years. Prostaglandins were
initially found to enhance histamineinduced itch in the skin (Hagermark et
al., 1977). Prostaglandins are the products of transformation of the essential
fatty acid arachidonic acid by cyclooxygenase 1 or cyclo-oxygenase-2. It
appears that only pruritic neurons that
display lasting activation following histamine are excited by PGE2, and mechanosensitive fibers are unresponsive
to both histamine and PGE2. PGE2 has
also been shown to have a direct lowlevel pruritogenic effect without inducing protein extravasation in healthy and
atopic dermatitis patients; this suggests
that prostanoids peripheral action is
not solely via histamine and that prostanoids may potentiate pruritus via a
nonspecific effect on nerve fibers.
In this issue, Andoh et al. (2007)
add significantly to our knowledge of
the involvement of thromboxane A2
(TXA2), a prostanoid synthesized from
prostanoid H2 via cyclo-oxygenase and
TXA synthetase, in cutaneous itch. They
beautifully demonstrate that TXA2 elicits scratching through its TP receptora
G proteincoupled receptor located
in both keratinocytes and skin nerve
fibers. The scratching response was
abolished by deficiency of TP receptor
and TP receptor antagonist. The TXA2
agonist caused membrane-cell depolarization, which was short lived in pri-

mary sensory neurons, but the scratching response lasted around 50 minutes,
which coincided with depolarization in
keratinocytes. TXA2 may be produced
by keratinocytes and acts on keratinocytes as an autocrine factor, releasing
other itch mediators such as leukotriene B4 and nociceptin, as well as itch
enhancers, such as nitric oxide.
Oral administration of aspirin, a
cyclo-oxygenase inhibitor, does not
ameliorate pruritus except in polycythemia vera; however, topical salicylates
and topical aspirin have been demonstrated to significantly reduce pruritus
in patients with chronic localized itch
(Yosipovitch et al., 2001). Do other
prostanoids have a role in pruritus? A
recent study illustrated that prostaglandin D2 (PGD2) is a mediator that inhibits
itching in NC/NG mice with atopic-like
dermatitis and that repeated scratching
in this model further reduced levels of
PGD2, suggesting that the vicious itch
scratch cycle is associated with low
levels of PGD2 (Sugimoto et al., 2007).
The role of other prostanoids and eicosanoids, including leukotrienes and
12-hydroxyeicosatetraenoic acid (12HETE), in the pathogenesis of pruritus is
unclear. We previously demonstrated in
rats that prostanoids secreted from the
bone marrow have a diurnal rhythm.
This could possibly explain why the
bone pain of metastatic cancer, as well
as pruritus, irrespective of underlying
cause, is frequently exacerbated during
the night (Yosipovitch et al., 1995).
Multiple other neuromediators are
involved in both itch and pain, such
as neurotrophins and transient receptor potential activators. The prototype
neurotrophic factor is NGF, which was
found to be elevated in atopic eczema
(Toyoda et al., 2002). The prototype
transient receptor potential activator
is TRPV1, a vanilloid receptor located
both on C nerve fibers and on keratinocytes. This receptor is activated
by capsaicin as well as endogenous
substances, such as cannabinoids,
prostaglandins, and various neurotrophins. Cannabinoid receptors CB1
and CB2 are located in the epidermis;
recently, a cannabinoid agonist was
shown to inhibit histamine-induced
itch (Rukweid et al., 2004). In addition,
topical agonists of cannabinoid recep-

1858 Journal of Investigative Dermatology (2007), Volume 127

tors were shown to have an antipruritic

effect in atopic eczema and uremic
pruritus (Stander et al., 2006).
The role of cytokines, such as interleukin (IL)-2, in pruritus is well documented. This has been the basis for
the use of immunomodulators, such
as tacrolimus and pimecrolimus. These
topical calcineurin inhibitors inhibit
the production of IL-2 and have been
shown to inhibit itch. IL-31 is a newly
discovered cytokine produced by
T helper 2 cells. Keratinocytes express
the IL-31 receptor, and, in a recent
study using a transgenic mouse model,
overexpression of this cytokine led
to severe scratching and dermatitis
(Sonkoly et al., 2006).
The identification of new neuropeptides and their respective receptors in
the skin that are specific to itch transmission will eventually form targets
for novel topical and systemic therapies. This in turn will provide needed
therapeutic options for the millions of
patients who suffer from chronic itch.
CONFLICT OF INTEREST
The author states no conflict of interest.

REFERENCES
Andoh T, Nishikawa Y, Yamaguchi-Miyamoto
T, Nojima H, Narumiya S, Kuraishi Y (2007)
Thromboxane A2 induces itch-associated
responses through TP receptors in the skin in
mice. J Invest Dermatol 127:20422047
Andoh T, Yageta Y, Takeshima H, Kuraishi Y (2004)
Intradermal nociceptin elicits itch-associated
responses through leukotriene B(4) in mice.
J Invest Dermatol 123:196201
Bigliardi-Qi M, Lipp B., Sumanovski LT, Buechner
SA, Bigliardi PL (2005) Changes of epidermal
mu-opiate receptor expression and nerve
endings in chronic atopic dermatitis.
Dermatology 210:919
Dunford PJ, Williams KN, Desai PJ, Karlsson L,
McQueen D, Thurmond RL (2007) Histamine
H4 receptor antagonists are superior to
traditional antihistamines in the attenuation of
experimental pruritus. J Allergy Clin Immunol
119:17683
Hagermark O, Strandberg K, Hamberg M (1977)
Potentiation of itch and flare responses in
human skin by prostaglandins E2 and H2 and
a prostaglandin endoperoxide analog. J Invest
Dermatol 69:52730
Han SK, Mancino V, Simon MI (2006)
Phospholipase Cbeta 3 mediates the
scratching response activated by the histamine
H1 receptor on C-fiber nociceptive neurons.
Neuron 52:691703
Lippert U, Artuc M, Grutzkau A, Babina M, Guhl
S, Haase I et al. (2004) Human skin mast cells
express H2 and H4, but not H3 receptors.

COMMENTARY

J Invest Dermatol 123:11623

Nakamura T, Hirasawa Y, Takai T, Mitsuishi K,
Okuda M, Kato T et al. (2006) Reduction of
skin barrier function by proteolytic activity of
a recombinant house dust mite major allergen
Der f 1. J Invest Dermatol 126:271923
Rukweid R, Dvorak M, Watkinson A, McGlone
F (2004) Putative role of cannabinoids in
experimentally induced itch and inflammation
in human skin. In: Itch: Basic Mechanisms
and Therapy (Yosipovitch G, Greaves MW,
Fleischer Jr AB, McGlone F, eds), Marcel
Dekker: New York, 11530
Sonkoly E, Muller A, Lauerma AI, Pivarcsi A,
Soto H, Kemeny L et al. (2006) IL-31: a new
link between T cells and pruritus in atopic

skin inflammation. J Allergy Clin Immunol

117:4117

Prostaglandins Leukot Essent Fatty Acids 76:

93101

Stander S, Reinhardt HW, Luger TA (2006)

[Topical cannabinoid agonists. An effective
new possibility for treating chronic pruritus].
Hautarzt 57:8017

Toyoda M, Nakamura M, Makino, T, Hino T,

Kagoura M, Morohashi M (2002) Nerve growth
factor and substance P are useful plasma
markers of disease activity in atopic dermatitis.
Br J Dermatol 147:719

Steinhoff M, Bienenstock J, Schmelz M, Maurer

M, Wei E, Biro T (2006) Neurophysiological,
neuroimmunological, and neuroendocrine
basis of pruritus. J Invest Dermatol 126:1705
18
Sugimoto M, Arai I, Futaki N, Honma Y, Sakurai T,
Hashimoto Y et al. (2007) Putative mechanism
of the itch-scratch circle: repeated scratching
decreases the cutaneous level of prostaglandin
D(2), a mediator that inhibits itching.

Yosipovitch G, Sugeng MW, Chan YH, Goon A,

Ngim S, Goh CL (2001) The effect of topically
applied aspirin on localized circumscribed
neurodermatitis. J Am Acad Dermatol
45:9103
Yosipovitch G, Yosipovitch Z, Harell D, Ashkenazi
I, Erman A (1995) Diurnal rhythm of prostanoid
secretion from bone/marrow organ in the rat.
Bone 17:7983

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