16.1. INTRODUCTION

Members of the transient receptor potential (TRP) family have emerged as key players in itch transduction in the periphery. TRP family members are tetrameric cation selective channels that are expressed in diverse species, from flies to humans. The founding member of the TRP channel superfamily is Drosophila TRP, a transduction channel required for light-evoked excitation of photoreceptors. In phototransduction, activation of the phospholipase C (PLC) pathway leads to the opening of TRP and its homolog TRP-L; flies lacking these channels display no light-evoked transduction currents and are blind. Over 27 members have since been identified in a variety of cell types and tissues (Figure 16.1).^1–5

FIGURE 16.1

Transient receptor potential (TRP) ion channel family. TRP channels are tetrameric cation selective channels with six transmembrane spanning helices. Distinct TRP channels have (left) intracellular N- and C-termini that vary dramatically in size and contain (more...)

TRP channels are divided into seven subgroups based on protein homology rather than function: TRPC, TRPV, TRPM, TRPA, TRPN, TRPP, and TRPML. Generally, TRP channels function as polymodal cellular sensors involved in a wide variety of cellular processes. Many TRPs have been found to participate in sensory transduction pathways, including thermosensation, mechanosensation, taste, perception of pungent compounds, pheromone sensing, and osmolarity regulation. A number of excellent reviews describe the vast roles of TRP channels which will not be discussed.^1–5

Here, we discuss the role of four TRP channels that have been proposed to play a role in itch transduction: TRPV1, TRPA1, TRPM8, and TRPV3. Historically, these four channels have been implicated in the transduction of noxious thermal, chemical, and/or mechanical stimuli, and more recent studies have implicated these channels in the transduction of itch.

16.2. TRPV1

TRPV1 was first identified as a receptor for capsaicin, the active ingredient in hot chili peppers that elicits a burning sensation when eaten. TRPV1 is a heat- and ligand-activated, nonselective cation channel.⁶ This channel is highly expressed in a subset of temperature-sensitive somatosensory neurons that have cell bodies in the dorsal root and trigeminal sensory ganglia and project afferents to innervate target organs in the periphery, such as the skin.^6,7

Capsaicin activates TRPV1 by binding to an intracellular region of the channel in between the second and third transmembrane domain.⁸ TRPV1 is also activated by heat, with a threshold of activation of approximately 43°C and a coefficient of temperature dependence (Q10) of ~40°C.⁶ A number of endogenous ligands also activate TRPV1; protons, anandamide, lipoxygenase products, and N-arachidonoyl dopamine have all been proposed to modulate TRPV1 activity in vivo.^9–11 Activation of TRPV1 permits the influx of cations into the peripheral nerve terminal to promote depolarization and action potential propagation to the central nervous system.

The localization of TRPV1 in heat-sensitive neurons, and the ability of TRPV1 to be directly activated by heat, support a model where this channel functions as an in vivo thermoreceptor. Indeed, TRPV1-deficient mice display decreased sensitivity to noxious heat in acute behavioral assays.^12,13 TRPV1 also plays a key role in thermal hypersensitivity following injury or inflammation. WT mice display thermal hyperalgesia and allodynia, the increased pain sensitivity to both noxious and previously innocuous stimuli, respectively, after injury or inflammation. Mice lacking TRPV1 fail to develop hyperalgesia and allodynia in these models, demonstrating the importance of TRPV1 in pain hypersensitivity.^12,13

How does inflammation change TRPV1 activity to promote thermal hypersensitivity? Many of the inflammatory mediators responsible for pain hypersensitivity, including NGF, ATP, chemokines, and prostaglandins, activate G-protein coupled receptors (GPCRs) that signal via PLC.¹⁴ PLC signaling in turn modulates TRPV1 activity, such that the open probability of the channel is increased at body temperature; thus, TRPV1 promotes neuronal excitability in the absence of heat.⁸ Indeed, most TRP channels are activated or modulated downstream of GPCRs.¹ As most pruritogens activate GPCRs, and trigger itch via activation of somatosensory afferents, TRP channels, including TRPV1, are attractive candidate itch transducers.¹⁵

A link between thermal pain and itch has been established for centuries. First, patients with chronic itch conditions have long reported that scalding heat helps to alleviate their pruritus. Second, topical application of the TRPV1 agonist, capsaicin, has been used to treat itch associated with many skin conditions. In 1850, the first formal report of the use of capsaicin to treat itch, and pain, appeared in a publication recommending the use of a hot pepper extract on burning or itching extremities.¹⁶ Today, topical capsaicin formulations are widely used to manage pain and beneficial effects of capsaicin have been reported in chronic, localized pruritic disorders, particularly those of neuropathic origin, such as notalgia paresthetica, brachioradial pruritus, prurigo nodularis, aquagenic pruritus, and pruritus associated with chronic kidney disease.^17–21 Consistent with these treatments in humans, neonatal capsaicin treatment decreases allergy-associated scratching in mice.²²

The antinociceptive and antipruritic effects of topical capsaicin are thought to manifest through the defunctionalization of TRPV1-expressing primary afferents, mediated by direct desensitization of TRPV1, or voltage gated sodium channels in the short term, and nerve terminal retraction due to excitotoxic terminal damage induced by excessive calcium and inhibition of mitochondrial respiration in the long term.²³ Indeed, immunohistochemical studies using antibodies to nerve terminal proteins, like PGP 9.5, show that capsaicin application induces localized loss of nociceptive nerve fiber terminals in the epidermis and dermis.²⁴ Therefore, the use of capsaicin to treat pruritus implicates either TRPV1 or TRPV1-containing primary afferents in pruriception.

A number of early studies suggested that TRPV1 may mediate histamine signal transduction in primary sensory neurons. First, many histamine-sensitive fibers are also capsaicin-sensitive. Second, histamine sensitizes primary afferent fibers to heat stimuli. These experiments strongly suggested that the histamine receptor and TRPV1 are coexpressed in sensory afferents.^25–27 Third, histamine-evoked calcium transients in rat dorsal root ganglia neurons are inhibited by the TRPV1 antagonists, capsazepine and SC0030.²⁸ Trypsin-evoked itch behaviors are attenuated in both capsazepine treated and TRPV1-deficient mice.²⁹ Fifth, patients with allergic rhinitis display an increased itch response to TRPV1 stimulation from seasonal allergen exposure.³⁰ Finally, TRPV1 antagonists inhibit pruritus in atopic dermatitis and the commonly prescribed antipruritic, tacrolimus, has been suggested to work in part by inhibiting/desensitizing TRPV1.^31,32

A definitive role for TRPV1 in histamine-evoked itch behavior was finally established in 2009 when it was shown that TRPV1-deficient mice displayed significantly attenuated itch behavior in response to injection of histamine. This study also found that histamine-evoked scratching behavior is attenuated in mice deficient in PLCß3, the PLC isoform activated downstream of the Gq coupled H1 receptor.³³ As such, a model emerged where activation of histamine H1 G_q-coupled GPCRs signals via PLCß3 to open TRPV1, through an unknown mechanism, in murine primary afferents (Figure 16.2). However, while itch behavior was attenuated in TRPV1 deficient mice, the behavior was not completely ablated and in addition to histamine receptor 1, histamine receptors 3 and 4 are also expressed in primary sensory neurons.³⁴ Similarly, not all histamine-sensitive sensory neurons are capsaicin sensitive.²⁸ This suggests that other channels, potentially downstream of other histamine receptors, may be involved in transducing histamine-evoked itch signals.

FIGURE 16.2

TRPA1 and TRPV1 play key roles in acute itch stimuli transduction. TRPV1 and TRPA1 are calcium-permeable cation channels that can be activated downstream of numerous pruritogen GPCRs. (left) Fibers expressing TRPV1 are responsible for transmitting histamine-dependent (more...)

16.3. TRPV1-EXPRESSING AFFERENTS AND ACUTE ITCH

While a role for TRPV1 in histamine-evoked itch is well established, many pruritogens act independently of TRPV1. How do other pruritogens promote excitability in sensory neurons? A hint came from the original TRPV1-directed studies. Two potent pruritogens, serotonin and endothelin-1, were shown to evoke robust scratching in TRPV1-deficient mice. However, itch behavior was significantly attenuated in mice treated with intrathecal capsaicin to ablate TRPV1-positive afferents.³³ Intrathecal capsaicin injections in mice, similar to the topical capsaicin applications in humans discussed above, promotes receptor defunctionalization, as well as excitotoxic neuronal ablation; as such, this treatment results in mice lacking TRPV1-positive neurons.³⁵ Taken together, these data suggest that other channels, expressed in TRPV1-positive afferents, are required for histamine-independent itch. Consistent with this idea, two drugs that evoke antihistamine resistant itch, imiquimod and chloroquine, trigger itch-evoked scratching in TRPV1-deficient mice, but not TRPV1-ablated mice.^33,36,37,38

16.4. TRPA1 AND HISTAMINE-INDEPENDENT ITCH

The ion channel, TRPA1, is highly expressed in a subset of TRPV1-positive neurons and plays a key role in multiple types of histamine-independent itch. TRPA1 is robustly activated by a wide variety of exogenous irritants that cause pain and inflammation. Environmental chemicals that target TRPA1 include allyl isothiocyanate (AITC), cinnamaldehyde, and allicin, the pungent compounds found in mustard, cinnamon, and garlic extracts, respectively.^39–42 TRPA1 is also a target of endogenous inflammatory agents, such as 15dPGJ2, PGA2, and Δ12-PGJ2 and can be modulated by PLC-coupled receptors mediating inflammation, such as the bradykinin receptor.^41–45 Many studies also suggest that TRPA1 can be activated directly by reactive oxygen species including hydrogen peroxide and the lipid peroxidation products 4-HNE, 4-ONE, and 4-HHE.^43,46,47 Data from TRPA1-deficient mice have shown that TRPA1 is required both for acute behavioral responses to AITC and for prolonged mechanical and thermal hypersensitivity following AITC exposure.⁴⁸ TRPA1 is also required for inflammatory responses to formalin and the α,β-unsaturated aldehyde acrolein, an airway irritant present in tear gas, vehicle exhaust, and smoke.^48,49 These studies show that TRPA1 acts as a general mediator of inflammation that can be activated by a host of endogenous and exogenous irritants.

There is now a growing body of evidence that suggests a significant role for TRPA1 in histamine-independent itch. Members of the novel Mas-related G-protein coupled receptor (Mrgpr) family, MrgprA3 and MrgprC11, are activated by two different histamine-independent pruritogens, chloroquine (CQ) and BAM8-22 (BAM), respectively.⁵⁰ TRPA1 is required for both CQ- and BAM-evoked calcium signals and action potential firing in somatosensory neurons, as well as CQ- and BAM-evoked scratching in mice (Figure 16.2).⁵¹ TRPA1 has since been shown to be specifically required for scratching in an oxidative stress model of itch.⁵² In this model, RTX ablation also reduces scratching, suggesting involvement of C fibers. Genetic or pharmacological blockade of TRPA1 activity, but not TRPV1, decreases oxidative stress-evoked scratching. Taken together, these data demonstrate that TRPA1 is a downstream transduction channel onto which multiple histamine-independent acute itch pathways converge.

16.5. TRPV3 AND KERATINOCYTE-MEDIATED ITCH PATHWAYS

Keratinocytes, the epithelial cells that make up the stratified epidermis of the skin, play a key role in itch by secreting a variety of mediators that target sensory neurons and immune cells.⁵³ TRPV3 is expressed in keratinocytes and has been proposed to play a role in promoting itch signaling and behaviors.

TRPV3 was originally identified as a heat sensitive ion channel in keratinocytes. Mouse TRPV3 is preferentially activated by innocuous, warm temperature with a threshold of ~33°C.⁵⁴ Warmth-evoked currents in cultured keratinocytes display biophysical properties that match those of TRPV3 currents in heterologous cells. Consistent with a role in warm sensing, mice lacking TRPV3 display deficits in responses to innocuous and noxious heat, and keratinocyte-specific TRPV3 knockin mice display increased avoidance of noxious heat, in the absence of functional TRPV1 channels.^54–57 While it is unclear how TRPV3-dependent signaling in keratinocytes promotes sensory neurons, one model suggests that ATP is the signaling molecule linking keratinocytes and neurons.⁵⁸ Like most TRP channels, TRPV3 is a polymodal sensor that can be activated by the natural plant product, camphor, and by nitrates that lead to nitric oxide production in the skin.^55,59–61

The characterization of rodent strains that spontaneously develop atopic dermatitis-like lesions first implicated TRPV3 in pruritus. Sequencing revealed that these mice had gain of function mutations in TRPV3 (Gly573Ser) that were found to be sufficient to drive AD-like skin alterations.^62,63 Likewise, gain of function mutations in TRPV3 in humans have been linked to Olmsted syndrome, a condition that results in severe chronic itch.⁶⁴ Consistent with a role for TRPV3 in chronic itch, TRPV3-deficient mice do not develop chronic itch in a dry skin model of chronic itch and overexpression of TRPV3 in keratinocytes is sufficient to promote secretion of the pruritogen, prostaglandin E2.^57,65 However, how prostaglandin, or other keratinocyte-released mediators, promote pruritus remains unknown.

16.6. TRPM8 IN INHIBITION OF ITCH

Unlike other TRP channels that promote itch signaling, TRPM8, the cold and menthol receptor, is hypothesized to inhibit itch signal transmission. Phenomenologically, cooling is known to soothe and relieve itch sensations. In humans, cooling of the skin inhibits atopic dermatitis-evoked itch in patients.⁶⁶ Menthol, icillin, and cooling have also been shown to inhibit histamine and lichenification-evoked itch in humans.^67,68 Likewise, skin cooling attenuates spinal neuron responses to subcutaneous histamine injection.⁶⁹

TRPM8 is activated by a variety of natural plant products that induce cooling sensations, including menthol, menthone, and eucalyptol. It is also activated by cold, with an activation temperature of ~25°C.^70,71 TRPM8 is expressed in a subset of primary afferent sensory neurons.^70–72 Importantly, sensory neurons isolated from TRPM8-deficient mice have attenuated responses to menthol, icillin, and cold.^70–72 Behavioral studies also reveal severe deficits in cold-evoked responses in these knockout mice, as measured by acetone evaporative cooling, cold plate, and two-choice temperature assays.^73,74 However, TRPM8-deficient mice show normal cold-evoked behavior in response to noxious cold (<10°C), suggesting that other channels may also play a role in cold temperature detection.

The requirement of TRPM8 in menthol and cold sensitivity in vivo suggests that TRPM8, or TRPM8-positive neurons, may mediate the attenuation of itch by cold, and cold mimetics. However, future studies are required to test this directly. It will be of particular interest to determine whether these neurons are linked to inhibitory itch interneurons in the spinal cord.⁷⁵

16.7. CONCLUSIONS AND FUTURE PROSPECTS

Research over the last decade shows a critical role of TRP channels in acute itch transduction. As such, TRP channel antagonists may be useful for the selective attenuation of itch. However, most studies have focused on acute rather than chronic itch. Little is known about the molecules that mediate chronic itch in primary sensory neurons and skin. Whether TRP channel signaling contributes to chronic itch is unknown and represents a major question in itch biology.

The TRP channels discussed here have dual roles in itch and in other somatosensory pathways and modalities like pain. A question that emerges from these studies is how any one channel can drive distinct itch or pain behaviors in response to differing stimuli. Multiple models have been proposed to account for this dual role of TRP channels. One is based on population coding, where a TRP agonist would evoke excitation of both itch-specific and pain- or temperature-specific fibers, and computation in the CNS would determine which signal is transmitted. Alternatively, the spatial contrast theory of itch posits that itch is triggered by the activation of a small number of pain fibers in a receptive field and pain is initiated when a larger cohort of cells is activated. Strong support of both itch theories has led to a modified “selectivity” theory of itch that incorporates aspects of both itch models.^76,77 The recent discovery of itch-specific spinal cord neurons suggests that central circuits may generate the specificity observed in itch signaling.^78,79 However, the relationship between itch and pain remains a pressing question in somatosensation.

REFERENCES

1.

Clapham DE. TRP channels as cellular sensors. Nature. 2003;426:517–524. [PubMed: 14654832]

2.

Julius D. From peppers to peppermints: Natural products as probes of the pain pathway. Harvey Lect. 2005;101:89–115. [PubMed: 18030977]

3.

Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Rev. 2002;82:429–472. [PubMed: 11917094]

4.

Nilius B, Mahieu F. A road map for TR(I)Ps. Mol Cell. 2006;22:297–307. [PubMed: 16722014]

5.

Nishida M, Hara Y, Yoshida T, Inoue R, Mori Y. TRP channels: Molecular diversity and physiological function. Microcirculation. 2006;13:535–550. [PubMed: 16990213]

6.

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD. et al. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824. [PubMed: 9349813]

7.

Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–543. [PubMed: 9768840]

8.

Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch. 2005;451:143–150. [PubMed: 15971082]

9.

Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L. et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA. 2002;99:8400–8405. [PMC free article: PMC123079] [PubMed: 12060783]

10.

Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ. et al. Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. Proc Natl Acad Sci USA. 2000;97:6155–6160. [PMC free article: PMC18574] [PubMed: 10823958]

11.

Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–457. [PubMed: 10440374]

12.

Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288:306–313. [PubMed: 10764638]

13.

Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT. et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature. 2000;405:183–187. [PubMed: 10821274]

14.

Rohacs T, Thyagarajan B, Lukacs V. Phospholipase C mediated modulation of TRPV1 channels. Mol Neurobiol. 2008;37:153–163. [PMC free article: PMC2568872] [PubMed: 18528787]

15.

Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547. [PubMed: 16791143]

16.

Turnbull A. Tincture of capsaicin as a remedy for chilblains and toothache. Dublin Free Press. 1850;1:95–96.

17.

Breneman DL, Cardone JS, Blumsack RF, Lather RM, Searle EA. et al. Topical capsaicin for treatment of hemodialysis-related pruritus. J Am Acad Dermatol. 1992;26:91–94. [PubMed: 1732343]

18.

Goodless DR, Eaglstein WH. Brachioradial pruritus: Treatment with topical capsaicin. J Am Acad Dermatol. 1993;29:783–784. [PubMed: 8227554]

19.

Leibsohn E. Treatment of notalgia paresthetica with capsaicin. Cutis. 1992;49:335–336. [PubMed: 1521492]

20.

Lotti T, Teofoli P, Tsampau D. Treatment of aquagenic pruritus with topical capsaicin cream. J Am Acad Dermatol. 1994;30:232–235. [PubMed: 7507135]

21.

Stander S, Luger T, Metze D. Treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol. 2001;44:471–478. [PubMed: 11209117]

22.

Nakano T, Andoh T, Sasaki A, Nojima H, Kuraishi Y. Different roles of capsaicin-sensitive and H1 histamine receptor-expressing sensory neurones in itch of mosquito allergy in mice. Acta Derm Venereol. 2008;88:449–454. [PubMed: 18779880]

23.

Anand P, Bley K. Topical capsaicin for pain management: Therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107:490–502. [PMC free article: PMC3169333] [PubMed: 21852280]

24.

Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW. et al. The time course of epidermal nerve fibre regeneration: Studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–1615. [PubMed: 15128618]

25.

Koda H, Minagawa M, Si-Hong L, Mizumura K, Kumazawa T. H1-receptor-mediated excitation and facilitation of the heat response by histamine in canine visceral polymodal receptors studied in vitro. J Neurophysiol. 1996;76:1396–1404. [PubMed: 8890260]

26.

Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE. et al. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol. 2003;89:2441–2448. [PubMed: 12611975]

27.

Mizumura K, Koda H, Kumazawa T. Possible contribution of protein kinase C in the effects of histamine on the visceral nociceptor activities in vitro. Neurosci Res. 2000;37:183–190. [PubMed: 10940452]

28.

Kim BM, Lee SH, Shim WS, Oh U. Histamine-induced Ca(2+) influx via the PLA(2)/lipoxygenase/TRPV1 pathway in rat sensory neurons. Neurosci Lett. 2004;361:159–162. [PubMed: 15135918]

29.

Costa R, Marotta DM, Manjavachi MN, Fernandes ES, Lima-Garcia JF. et al. Evidence for the role of neurogenic inflammation components in trypsin-elicited scratching behaviour in mice. Br J Pharmacol. 2008;154:1094–1103. [PMC free article: PMC2451046] [PubMed: 18454165]

30.

Alenmyr L, Hogestatt ED, Zygmunt PM, Greiff L. TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009;64:807–810. [PubMed: 19220220]

31.

Lim KM, Park YH. Development of PAC-14028, a novel transient receptor potential vanilloid type 1 (TRPV1) channel antagonist as a new drug for refractory skin diseases. Arch Pharm Res. 2012;35:393–396. [PubMed: 22477184]

32.

Pereira U, Boulais N, Lebonvallet N, Pennec JP, Dorange G. et al. Mechanisms of the sensory effects of tacrolimus on the skin. Br J Dermatol. 2010;163:70–77. [PubMed: 20302583]

33.

Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI. et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci USA. 2009;106:11330–11335. [PMC free article: PMC2708751] [PubMed: 19564617]

34.

Rossbach K, Nassenstein C, Gschwandtner M, Schnell D, Sander K. et al. Histamine H1, H3 and H4 receptors are involved in pruritus. Neuroscience. 2011;190:89–102. [PubMed: 21689731]

35.

Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci USA. 2009;106:9075–9080. [PMC free article: PMC2683885] [PubMed: 19451647]

36.

Kim SJ, Park GH, Kim D, Lee J, Min H. 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. [PMC free article: PMC3044410] [PubMed: 21300878]

37.

Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13:1460–1462. [PMC free article: PMC2991508] [PubMed: 21037581]

38.

Lagerstrom MC, Rogoz K, Abrahamsen B, Persson E, Reinius B. et al. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron. 2010;68:529–542. [PMC free article: PMC3052264] [PubMed: 21040852]

39.

Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003;112:819–829. [PubMed: 12654248]

40.

Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004;427:260–265. [PubMed: 14712238]

41.

Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR. et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004;41:849–857. [PubMed: 15046718]

42.

Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O. et al. Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci USA. 2005;102:12248–12252. [PMC free article: PMC1189336] [PubMed: 16103371]

43.

Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci. 2008;28:2485–2494. [PMC free article: PMC2709206] [PubMed: 18322093]

44.

Taylor-Clark TE, Undem BJ, Macglashan DW Jr, Ghatta S, Carr MJ. et al. Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1). Mol Pharmacol. 2008;73:274–281. [PubMed: 18000030]

45.

Wang S, Dai Y, Fukuoka T, Yamanaka H, Kobayashi K. et al. Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: A molecular mechanism of inflammatory pain. Brain. 2008;131:1241–1251. [PubMed: 18356188]

46.

Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE. et al. An ion channel essential for sensing chemical damage. J Neurosci. 2007;27:11412–11415. [PMC free article: PMC6673017] [PubMed: 17942735]

47.

Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R. et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci USA. 2007;104:13519–13524. [PMC free article: PMC1948902] [PubMed: 17684094]

48.

Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006;124:1269–1282. [PubMed: 16564016]

49.

Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS. et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron. 2006;50:277–289. [PubMed: 16630838]

50.

Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN. et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009;139:1353–1365. [PMC free article: PMC2989405] [PubMed: 20004959]

51.

Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN. et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci. 2011;14:595–602. [PMC free article: PMC3181150] [PubMed: 21460831]

52.

Liu T, Ji RR. Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull. 2012;28:145–154. [PMC free article: PMC3339413] [PubMed: 22466125]

53.

Raap U, Stander S, Metz M. Pathophysiology of itch and new treatments. Curr Opin Allergy Clin Immunol. 2011;11:420–427. [PubMed: 21772138]

54.

Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002;296:2046–2049. [PubMed: 12016205]

55.

Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 2005;307:1468–1472. [PubMed: 15746429]

56.

Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ. TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem. 2004;279:21569–21575. [PubMed: 15004014]

57.

Huang SM, Lee H, Chung MK, Park U, Yu YY. et al. Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2. J Neurosci. 2008;28:13727–13737. [PMC free article: PMC2676929] [PubMed: 19091963]

58.

Mandadi S, Sokabe T, Shibasaki K, Katanosaka K, Mizuno A. et al. TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP. Pflugers Arch. 2009;458:1093–1102. [PMC free article: PMC2745623] [PubMed: 19669158]

59.

Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ. 2-aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3. J Neurosci. 2004;24:5177–5182. [PMC free article: PMC6729202] [PubMed: 15175387]

60.

Hu H, Grandl J, Bandell M, Petrus M, Patapoutian A. Two amino acid residues determine 2-APB sensitivity of the ion channels TRPV3 and TRPV4. Proc Natl Acad Sci USA. 2009;106:1626–1631. [PMC free article: PMC2635798] [PubMed: 19164517]

61.

Miyamoto T, Petrus MJ, Dubin AE, Patapoutian A. TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin. Nat Commun. 2011;2:369. [PMC free article: PMC3320851] [PubMed: 21712817]

62.

Asakawa M, Yoshioka T, Matsutani T, Hikita I, Suzuki M. et al. Association of a mutation in TRPV3 with defective hair growth in rodents. J Invest Dermatol. 2006;126:2664–2672. [PubMed: 16858425]

63.

Yoshioka T, Imura K, Asakawa M, Suzuki M, Oshima I. 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. [PubMed: 18754035]

64.

Lin Z, Chen Q, Lee M, Cao X, Zhang J. et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet. 2012;90:558–564. [PMC free article: PMC3309189] [PubMed: 22405088]

65.

Yamamoto-Kasai E, Imura K, Yasui K, Shichijou M, Oshima I. et al. TRPV3 as a therapeutic target for itch. J Invest Dermatol. 2012;132:2109–2112. [PubMed: 22475759]

66.

Fruhstorfer H, Hermanns M, Latzke L. The effects of thermal stimulation on clinical and experimental itch. Pain. 1986;24:259–269. [PubMed: 3960572]

67.

Bromm B, Scharein E, Darsow U, Ring J. Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett. 1995;187:157–160. [PubMed: 7624016]

68.

Han JH, Choi HK, Kim SJ. Topical TRPM8 Agonist (icilin) relieved vulva pruritus originating from lichen sclerosus et atrophicus. Acta Derm Venereol. 2012;92:561–562. [PubMed: 22042233]

69.

Carstens E, Jinks SL. Skin cooling attenuates rat dorsal horn neuronal responses to intracutaneous histamine. Neuroreport. 1998;9:4145–4149. [PubMed: 9926864]

70.

McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–58. [PubMed: 11882888]

71.

Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA. et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–715. [PubMed: 11893340]

72.

Colburn RW, Lubin ML, Stone DJ Jr, Wang Y, Lawrence D. et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron. 2007;54:379–386. [PubMed: 17481392]

73.

Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI. et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448:204–208. [PubMed: 17538622]

74.

Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ. et al. TRPM8 is required for cold sensation in mice. Neuron. 2007;54:371–378. [PubMed: 17481391]

75.

Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S. et al. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron. 2010;65:886–898. [PMC free article: PMC2856621] [PubMed: 20346763]

76.

Ma Q. Labeled lines meet and talk: Population coding of somatic sensations. J Clin Invest. 2010;120:3773–3778. [PMC free article: PMC2964985] [PubMed: 21041959]

77.

Ross SE. Pain and itch: Insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol. 2011;21:880–887. [PubMed: 22054924]

78.

Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature. 2007;448:700–703. [PubMed: 17653196]

79.

Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY. et al. Cellular basis of itch sensation. Science. 2009;325:1531–1534. [PMC free article: PMC2786498] [PubMed: 19661382]