For a long time, itch appeared to be a neglected symptom - not
because of a lack of interest from researchers, but perhaps owing
to a misguided concept that somehow itch was the 'little brother of
pain' and, therefore, relatively less important. In fact, this
particularly disturbing sensation was more like an orphan, equally
neglected by funding agencies and medical authorities.
The initial lack of clues into the mechanisms of itch
transmission made this oversight rather understandable. However,
this situation is now changing, and itch is increasingly receiving
attention from many research groups. Notable progress has been made
in recent years to better understand itch generation, transmission,
signaling and processing within the higher structures of the
central nervous system (CNS). However, with a few exceptions, itch
still cannot be easily or fully suppressed using any pharmacologic
means currently available, owing to the simple fact that we are
still missing an effective itch-specific approach. Itch therapy is
complicated because its causes can be multiple, and can differ
depending on the particularities of the specific etiology
involved.
Table 1. List of abbreviations used throughout the
article.
Novel Molecular Receptors for Itch
The first receptors implicated in itch were the H1 histamine
receptors. However, most chronic itches of various etiologies, with
the exception of urticaria, remained refractory to antihistamines
directed at H1 receptors. Recent advances in the field have
uncovered that the novel H4 receptor plays an important role in
inflammatory and allergic responses, as well as in pruritus, which
might explain, at least in part, the limited ability of H1
antihistamines to relieve chronic itch. Furthermore, it is now
known that itch can be transmitted via several non-histaminergic
pathways (Figure 1) and thus this is the most likely explanation as
to why antihistamines fail to relieve itch.
Therefore, attention has turned in recent years to 'alternative'
receptors for itch. Although it has been known for many decades,
thanks to the pioneering work of Shelley and Arthur, that the
spicules of the tropical plant cowhage (Mucuna pruriens,
velvet bean) can induce an itch that is unquenchable by
antihistamines, it was only revealed a few years ago that the
mechanism involved a protease called mucunain, which acted on
proteinase-activated receptor 2 (PAR2).1 Corroborating
evidence indicates that PAR2 is an important mediator of itch in
atopic dermatitis, where it is also overexpressed.2 PAR2
can be activated by a variety of proteases such as trypsin,
tryptase and kallikreins, and its activation by a cysteine protease
gave more traction to the idea that endogenous proteases such as
cathepsin S could be important factors in itch
induction.3
Since the identification of the transient receptor potential
cation channel subfamily V member 1 (TRPV1) receptor as the
molecular target of the powerful irritant capsaicin,4 an
avalanche of discoveries in the field of pain research has impacted
itch transmission. Capsaicin - mainly used as an analgesic in
arthritis and post-herpetic neuralgia, etc. - is an unconventional
antipruritic agent, producing a powerful and lasting
desensitization of nerve fibers.5 This molecule elicits
itch sensation upon topical application, which suggests a role for
TRPV1 in itch mediation. Subsequent findings about the larger
family of TRPV3,6 TRPV4 and melastatin receptors (e.g.
TRPM8 which, when stimulated by menthol, produces a cooling,
itch-relieving effect) have cemented their clear role in itch
modulation.7,8 TRPV1 has been reported to be required
for the transmission of histaminergic itch. Conversely, TRPV1 is
co-expressed in the small population of neurons expressing PAR2,
suggesting cross-talk and/or a dual-gating mechanism required for
the transmission of itch via non-histaminergic routes (Figure
1).
One of the most significant developments in the field occurred
when a specific itch G-protein-coupled receptor (GPCR) called
gastrin-release peptide receptor (GRPR), from the bombesin receptor
family, was reported in the superficial dorsal horn in
mice.9 GRPR-positive neurons were also found in the
dorsal root ganglion (DRG), and act as interneurons in the spinal
cord. Ablation of GRPR-positive neurons with bombesin-saporin
(which induces selective neuronal cell death) significantly
diminished scratching behavior in response to non-histamine
pruritogens in mice (e.g. chloroquine and the PAR2 agonist peptide
SLIGHR-NH2 ), but did not affect pain responses. Genetic
knockout of the GRPR also led to a reduced response to itch stimuli
but did not affect pain transmission.
In a related development, the discovery of Mas-related gene
product receptors (Mrgprs) as the molecular relays of chloroquine
itch is particularly interesting, as Mrgrps are reportedly
co-expressed with GRPR in small- and medium-diameter neurons, which
suggests a potential interaction between specific itch afferents
and specialized itch neurons in the spinal cord.10 Both
are G-protein-coupled receptors. The antimalarial drug chloroquine
is a powerful itch inducer in rodents, and also induces severe itch
in humans, selectively in the Black African population. Chloroquine
acts specifically on a subset of Mrgprs - MrgprA3 and C11 - in
mice, whereas the corresponding receptor that it acts upon in
humans, MrgprX1, is present in DRG neurons. Recently, the topical
application of a specific agonist peptide of MrgprX1, BAM8-22, has
been tested in humans and has produced itch and nociceptive
sensations that could not be inhibited by pre-administration of the
potent antihistamine doxepin.11 This is a significant
finding, as it shows that some important itch discoveries in animal
models are translatable to humans. In addition, the ankyrin TRPA1
receptor is required for the induction of itch evoked by
chloroquine.12
Quite a stir in the field has been produced by findings
suggesting that Toll7, the target of the immunomodulator drug
imiquimod, may be directly involved in itch signaling.13
However, the exact mechanism of action currently remains
controversial, as a newer report using transgenic models has
concluded that, ultimately, TRPV1 is responsible for the itching
induced by this drug, which only managed to re-emphasize the
central role for TRPV1 in modulating or gating different itch
modalities.14 It thus became obvious that a specific
subset of TRPV1-positive neurons could be equipped with diverse
intracellular mechanisms in order to respond to histamine,
chloroquine and imiquimod. The translational potential of this
finding has been disputed, however, as imiquimod rarely causes itch
in humans.
Recent discoveries suggest that the SLIGRL peptide, formerly
considered to be a typical PAR2 agonist for induction of itch in
mice, works through the newly discovered MrgprC11
receptor.15 Among the four types of MrgrprX found in
humans, the corresponding PAR2 peptide human agonist SLIGKV was
found to activate MrgprX2 specifically. However, the role of these
receptors, and their subsequent signaling pathways, may function
differently across species, and thus PAR2 can still function as a
primary itch transducer in humans - for example, by mediating the
action of tryptase. In a comparative biology context, the
confirmation of a specific itch pathway mediated via GRPR has yet
to be produced in humans, which is needed in order for the current
models developed in mice to gain more traction and to encourage the
development of therapies targeting specific itch mechanisms.
Figure 1. Signaling pathways for itch involve
transduction at the peripheral nerve fibers in the skin, synaptic
transmission in the spinal cord, and central projections to the
thalamus. Cowhage-induced itch is mediated by PAR2
receptors and conducted by polymodal C-fibers, whereas histamine
itch is mediated by a population of mechanically insensitive
C-fibers; both terminate in the dorsal horn of the spinal cord,
where they synapse with distinct spinothalamic tract neurons.
Therefore, histaminergic and non-histaminergic itch pathways are
separated in primates. The antimalarial chloroquine can induce itch
acting upon the MgrprA3 receptor. B1 or B2, bradykinin receptors;
CGRP, calcitonin gene-related peptide; GRPR, gastrin-releasing
peptide receptor; MgrprA3, MAS-related gene-related product A3;
PLA2, phospholipase A2; PLC, phospholipase C; SP, substance P;
TRPV1 and TRPA1, transient receptor potential vanilloid-1 and
ankyrin-1. Reprinted with permission from Davidson and
Giesler.21
Advances in our Understanding of Systemic Itch
Itch of systemic origin can embrace many clinical forms and
could be produced by various mechanisms. Progress has been made in
understanding the etiology of cholestatic pruritus, in which
lysophosphatidic acid (LPA) produced by autotaxin from
lysophosphatidylcholine has been proposed as a novel
mediator.16 LPA is a signaling molecule that can
activate neurons through LPA receptors and provokes itch in mice
upon intradermal injection. Autotaxin serum levels were reported to
be highly elevated in patients with chronic cholestatic pruritus.
Another severe form of systemic itch with a complex etiology is
uremic pruritus. The underlying processes were hard to identify
owing to the multitude of metabolic, electrolytic and endocrine
disturbances present in end-stage renal disease; however, recent
findings converge to suggest that uremic pruritus can be understood
as a systemic inflammatory disease that is characterized by an
imbalance in T helper cell (Th1/Th2) differentiation favoring Th1,
which is subsequently aggravated by an excess production of
Th1-derived cytokines, such as interleukin-2, a well-known
pruritogen.17
The Complex Dialectic Relationship Between Itch and Pain, and
the Implications for Itch Signaling
It is currently established that neurons specialized in itch
transmission can also convey pain. However, some nociceptive
neurons are uniquely equipped with itch-sensing capabilities -
through itch receptors or pruriceptors - whereas others (the
majority of them) are strictly nociceptive. The molecular basis for
this distinction is still a matter of intense
investigation.18 Itch and pain appear to share the same
neuronal afferent pathways, but with a twist: pain can suppress
itch, whereas the relief of pain can induce, unmask or amplify
pruritus. For example, the pharmacologic segmental analgesia
acquired with μ-opioid receptor agonists, such as morphine, is
accompanied by an induction of segmental itch, whereas conversely,
κ-opioid agonists can relieve itch. This suggests that the
interplay between pain and itch can be regulated by the balance in
μ- versus κ-opioid receptor activation. Recently, spinal cord
neurons expressing the Nav1.8 ion channel and which deliver
glutamate via the vesicular transporter VGLUT2 were proposed as a
molecular basis for the switch underlying pain transmission and
itch inhibition, as transgenic mice lacking VGLUT2 were impervious
to pain stimuli, but displayed an increased scratching
behavior.19,20
The current models for neuronal itch transmission recognize
distinct pathways for histamine-mediated and non-histaminergic
forms of itch, the latter involving several receptors. To date, no
consensus has been reached on whether itch is conveyed via a
dedicated (labeled) line, or whether it is encoded by the
differential participation of subpopulations of neurons expressing
specific pruriceptors. It is becoming increasingly likely that
itch-specific information is primarily encoded or regulated at the
spinal level by a delicate interplay of inputs from peripheral
afferents, spinal cord interneurons, inhibitory inputs from
strictly nociceptive afferents, and top-bottom
regulatory/inhibitory inputs from higher CNS structures (possibly
relayed via periaqueductal gray formation).21,22 It is
also possible that neurons in the thalamus can distinguish
nociceptive versus pruriceptive information via a selection
mechanism.
Neuroimaging of Itch
Because the exact projections of the third neuron conveying
"itch information" from the thalamus to the cerebral cortex have
not been identified, they instead can be inferred from brain
imaging studies. Imaging the central processing of itch can help us
better understand itch perception and its mechanisms, can provide a
valuable insight into potentially altered CNS processing in
pathologic chronic itch states, and can explain the phenomenon of
"central sensitization" (a heightened sensitivity to itch stimuli
arising within the CNS). There is still much to learn about how the
itch sensation is formed, processed, centrally modulated or
possibly inhibited. An increased understanding of the central
nervous processes involved in itch will therefore be critical to
develop specific itch treatments.
The current picture emerging from neuroimaging studies shows
that the brain processing of itch is complex and involves
somatosensory, multiple primary and secondary motor centers
(confirming the important link between itch and scratching), as
well as extensive areas in the posterior and lateral parietal
cortex, which is not observed in pain. Itch activates deep-seated
areas of the limbic system and the posterior and anterior cingulate
cortices (related to affective, emotional and motivational
functions), and it also involves areas controlling addictive
behavior (insula). Recent studies using arterial spin-labeling fMRI
(functional magnetic resonance imaging), which contrasted the
processing of cowhage and histamine itches, emphasized the
involvement of a previously under-investigated formation - the
claustrum - a "hidden" structure with anatomical connectivity
features and functional specializations seemingly fitting for itch
processing.23 The claustrum appears strategically
situated to intercept somatosensory information travelling from the
thalamus to the cortex, and it is connected with almost all
cortical regions. The claustrum and insula registered the cowhage
itch more significantly than the histamine itch.23 The
addictive character of the itch-scratch cycle has a profound impact
on the networks processing emotional experiences via the cingulate
cortex and the Papez circuit. The involvement of itch in modulation
of affective states and its correlation with stress are reflected
in the involvement of the limbic system, amygdala and the anterior
cingulate cortex.
Conclusions
The recent advances made in the study of itch have unveiled new
classes of receptors and novel signaling pathways, acting both
peripherally and centrally, that can be further explored and
utilized. This brings hope that the days of developing specific
itch therapies are near.
References
- Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA.
Cowhage-evoked itch is mediated by a novel cysteine protease: a
ligand of protease-activated receptors. J Neurosci
2008;28:4331-4335.
- Steinhoff M, Neisius U, Ikoma A, et al.
Proteinase-activated receptor-2 mediates itch: a novel pathway for
pruritus in human skin. J Neurosci 2003;23:6176-6180.
- Reddy VB, Shimada SG, Sikand P, Lamotte RH, Lerner EA.
Cathepsin S elicits itch and signals via protease-activated
receptors. J Invest Dermatol 2010;130:1468-1470.
- Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD,
Julius D. The capsaicin receptor: a heat-activated ion channel in
the pain pathway. Nature 1997;389:816-824.
- Papoiu ADP, Yosipovitch G. Topical capsaicin. The fire of a hot
medicine is reignited. Exp Opin Pharmacother
2010;11:1359-1371.
- Bíró T, Tóth BI, Marincsák R, Dobrosi N, Géczy T, Paus R. TRP
channels as novel players in the pathogenesis and therapy of itch.
Biochim Biophys Acta 2007;1772:1004-1021.
- Yoshioka T, Imura K, Asakawa M, et al. Impact of the
Gly573Ser substitution in TRPV3 on the development of allergic and
pruritic dermatitis in mice. J Invest Dermatol
2009;129:714-722.
- Steinhoff M, Bíró T. A TR(I)P to pruritus research: role of
TRPV3 in inflammation and itch. J Invest Dermatol 2009;129:531-535.
Erratum in: J Invest Dermatol 2010;130:908.
- Sun YG, Zhao ZQ, Meng XL, et al. Cellular basis of
itch sensation. Science 2009;325:1531-1534.
- Liu Q, Tang Z, Surdenikova L, et al. Sensory
neuron-specific GPCR Mrgprs are itch receptors mediating
chloroquine-induced pruritus. Cell
2009;139:1353-1365.
- Sikand P, Dong X, LaMotte RH. BAM8-22 peptide produces itch and
nociceptive sensations in humans independent of histamine release.
J Neurosci 2011;31:7563-7567.
- Wilson SR, Gerhold KA, Bifolck-Fisher A, et al. TRPA1
is required for histamine-independent, Mas-related G
protein-coupled receptor-mediated itch. Nat Neurosci
2011;14:595-602.
- Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7
mediates pruritus. Nat Neurosci 2010;13:1460-1462.
- Kim SJ, Park GH, Kim D, et al. Analysis of cellular
and behavioral responses to imiquimod reveals a unique itch pathway
in transient receptor potential vanilloid 1 (TRPV1)-expressing
neurons. Proc Natl Acad Sci USA 2011;108:3371-3376.
- Liu Q, Weng HJ, Patel KN, et al. The distinct roles of
two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci
Signal 2011;4: ra45.
- Oude Elferink RP, Kremer AE, Martens JJ, Beuers UH. The
molecular mechanism of cholestatic pruritus. Dig Dis
2011;29:66-71.
- Fallahzadeh MZ, Roozbeh J, Geramizadeh B, Namazi MR.
Interleukin-2 serum levels are elevated in patients with uremic
pruritus: a novel finding with practical implications. Nephrol
Dial Transpl 2011 [ePub ahead of print].
- Han S-K, Melvin IS. Intracellular signaling and the origins of
the sensations of itch and pain. Sci Signal
2011;4:pe38.
- Liu Y, Abdel Samad O, Zhang L, et al. VGLUT2-dependent
glutamate release from nociceptors is required to sense pain and
suppress itch. Neuron 2010;68:543-556.
- Lagerström MC, Rogoz K, Abrahamsen B, et al.
VGLUT2-dependent sensory neurons in the TRPV1 population regulate
pain and itch. Neuron 2010; 68:529-542.
- Davidson S, Giesler GJ. The multiple pathways for itch and
their interactions with pain. Trends Neurosci
2010;33:550-558.
- Gotoh Y, Andoh T, Kuraishi Y. Clonidine inhibits itch-related
response through stimulation of α(2)-adrenoceptors in the spinal
cord in mice. Eur J Pharmacol 2011;650:215-259.
- Papoiu ADP, Coghill RC, Kraft RA, Wang H, Yosipovitch G. A tale
of two itches. Common features and notable differences in brain
activation revealed in a comparative fMRI study of cowhage and
histamine induced itch. Acta Derm Venereol
2009;89:692.
Back