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Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons

Radhika Palkar?1,?Serra Ongun?2,?Edward Catich?1,?Natalie Li?3,?Neil Borad?3,?Angela Sarkisian?3,?David D McKemy?4

Affiliations?expand

PMID:?***

DOI:?10.1016/j.jid.2017.12.025

Abstract

Cooling or the application of mentholated liniments to the skin has been used to treat itch for centuries, yet remarkably little is known about how counter-stimuli such as these induce itch relief. Indeed, there is no clear consensus in the scientific literature as to whether or not cooling does in fact block the transduction of itch signals or if it is simply a placebo effect. This gap in our understanding led us to hypothesize that cooling is antipruritic and, like cooling analgesia, requires function of the cold-gated ion channel TRPM8, a receptor for menthol expressed on peripheral afferent nerve endings. Using a combination of pharmacologic, genetic, and mouse behavioral assays, we find that cooling inhibits both histaminergic and non-histaminergic itch pathways, and that inhibition of itch by cooling requires TRPM8 channels or intact and functional TRPM8-expressing afferent neurons. The cold mimetic menthol is also effective in ameliorating itch in a TRPM8-dependent manner. Moreover, we find that chronic itch can be ameliorated by cooling, demonstrating that this counter-stimulus activates a specific neural circuit that leads to broad itch relief and a potential cellular mechanism for treatment of chronic itch.

Introduction

Itch (pruritus) management is an important aspect of the health care system. The etiology of itch involves the immune system, skin cells, and sensory neurons, with the latter divided into sub-populations based on the different molecular mediators of pruritogens (Bautista et?al., 2014). The best-understood molecular mechanism of itch is the histaminergic pathway, yet antihistamines are only marginally effective in resolving chronic forms of itch (Liu and Ji, 2013). The definition of itch as an “unpleasant sensation evoking the desire to scratch” may hold the key?to the problem of itch therapy, as it implies that mechanical (scratching) and thermal counter-stimuli ameliorates all types of itch (Schmelz et?al., 1997,?Schmelz et?al., 2003). These stimuli do not act directly on pruriceptors, but rather through inhibitory pathways in the spinal cord dorsal horn?(Ma,?2012).

Cold has been used traditionally to relieve itch and pain, but the mechanisms underlying its actions are not well understood. Cooling diminishes nerve conduction velocity, vesicle release, and general protein function (Chung and Wang, 2011,?Kichko and Reeh, 2004,?Rutkove, 2001), yet this does not account for the efficacy of cold mimetics like menthol. Cold and menthol activate the ion channel TRPM8 (McKemy et?al., 2002,?Peier et?al., 2002), a molecule that has been shown to be the principle mediator of cold stimuli in the mammalian peripheral nervous system (Bautista et?al., 2007,?Colburn et?al., 2007,?Dhaka et?al., 2007,?Knowlton et?al., 2013). In addition to its role as a thermosensor, activation of TRPM8 also underlies cooling-induced pain relief (analgesia). For example, mild cooling, between 17°C and 20°C, of rodent hindpaws has been shown to inhibit mechanical and thermal (heat) hyperalgesia in a TRPM8-dependent manner (Knowlton et?al., 2013,?Proudfoot et?al., 2006). Furthermore, cooling-induced relief from neurogenic inflammation also requires TRPM8 (Dhaka et?al., 2007). Chemical cooling with TRPM8 agonists also leads to analgesia in inflammatory and neuropathic conditions (Liu et?al., 2013,?Proudfoot et?al., 2006). Remarkably, these studies find that only mild cooling or low doses of TRPM8 agonists lead to analgesia, with more robust stimulation leading to cold pain in the injured states (Fleetwood-Walker et?al., 2007,?Proudfoot et?al., 2006). Lastly, we have shown that in addition to TRPM8 channels, this process is also dependent on TRPM8 neurons (Knowlton et?al., 2013), yet the role of TRPM8 and TRPM8 afferents in cooling-induced antipruritus is unclear.

Here we test the hypotheses that cooling suppresses acute itch in a process that is TRPM8-dependent. Our results show that cold reduces both histamine-dependent and histamine-independent itch, a process that only partially requires TRPM8 channels, but is dependent on intact TRPM8-positive neurons. These data show that cooling alleviates itch by activating specific afferents that are likely part of a larger counter-stimulus pathway that attenuates pruritic signaling in the spinal cord dorsal horn.

Results

Pruritogen-induced behaviors in the mouse hindpaw

To test cooling on itch, we assessed behaviors directed toward a pruritogen-injected mouse hind paw in animals standing on a thermally controlled surface. This approach was used in lieu of the traditional cheek or nape assays, as applying a cold stimulus to these regions requires excessive animal handling, which strongly alters itch behaviors, and because human studies show itch relief by cooling requires continual stimulation (Fruhstorfer et?al., 1986,?Shimada and LaMotte, 2008). Hind-paw analysis has been used previously as a reliable measure of itch by several investigators (Akiyama et?al., 2010b,?Nojima et?al., 2004). Moreover, we and others have used these models to measure thermal discrimination and cooling analgesia (Knowlton et?al., 2013,?Pogorzala et?al., 2013,?Proudfoot et?al., 2006), suggesting that a similar approach can test whether cooling alleviates itch-like behaviors.

First, to define behaviors induced by intradermal hind-paw pruritogen injections, we compared the algogen capsaicin to the pruritogens histamine and chloroquine (Cqx), finding that, in addition to significant time spent flinching and lifting the injected paw, capsaicin (5 μg) also evoked robust biting and licking (Figure?1a). Histamine (100 μg) produced similar behaviors, consistent with reports of histamine evoking both pain and itch under certain conditions (LaMotte et?al., 2011,?Snyder and Ross, 2015). Cqx (200 μg), a substance that induces itch but not pain (Bautista et?al., 2014,?LaMotte et?al., 2011,?Snyder and Ross, 2015), also evoked robust licking and biting behaviors. However, unlike with capsaicin and histamine, we observed no flinching or lifting, demonstrating differences in the responses to an algogen versus a pruritogen. We then tested lower doses of histamine, finding that amounts down to 0.5 μg produced licking and biting behaviors similar to those at 100 μg (P?> 0.05), but with minimal flinching and lifting (Figure?1a;?P?< 0.001). Similar behaviors were observed with endogenous histamine release induced by 0.5 μg of the mast cell degranulator compound 48/80 and 30 μg of the serotonin receptor agonist α-methyl 5-HT (αMe5-HT,?Figure?1a), and all flinch/lift behaviors of the latter were not significantly different than that observed with injection of vehicle (P?> 0.05). Lastly, analysis of all behaviors (flinches, lifts, licks, bites) showed that licking and biting dominated the duration of animals’ responses.

Figure?1

Hind paw pruritogen injections promote itch-like behaviors in mice.?(a) In wild-type mice, unilateral intradermal hind paw injections of both pruritogens and algogens induce robust lick and biting behaviors (P?< 0.001 compared to vehicle, one-way ANOVA followed by Neuman-Keuls post-test) measured as duration of behaviors in a 30-minute period post-injection, with no differences between injections of 100 or 0.5 μg histamine (P?> 0.05, one-way ANOVA, Neuman-Keuls post-test). Capsaicin, α-methyl 5-HT (αMe5-HT), and a high dose of histamine (100 μg, n?= 8) produced flinching and hind paw lifts (P?< 0.01 compared to vehicle, one-way ANOVA, Neuman-Keuls post-test), whereas chloroquine (Cqx; 200 μg, n?= 8), 48/80 (0.5 μg, n?= 6), and a low dose of histamine (0.5 μg, n?= 6) did not induce these behaviors (P?> 0.05 compared to vehicle, one-way ANOVA, Neuman-Keuls post-test). The duration 内容过长，仅展示头部和尾部部分文字预览，全文请查看图片预览。 berhart, D., Urban, R., Meda, K., Solorzano, C. et al.?Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch.?Neuron.?2013;?78:?312–324

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Yosipovitch, G., Szolar, C., Hui, X.Y., and Maibach, H.?Effect of topically applied menthol on thermal, pain and itch sensations and biophysical properties of the skin.?Arch Dermatol Res.?1996;?288:?245–248

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