TRP channels as novel players in the pathogenesis and therapy of itch

Abstract

Itch (pruritus) is a sensory phenomenon characterized by a (usually) negative affective component and the initiation of a special behavioral act, i.e. scratching. Older studies predominantly have interpreted itch as a type of pain. Recent neurophysiological findings, however, have provided compelling evidence that itch (although it indeed has intimate connections to pain) rather needs to be understood as a separate sensory modality. Therefore, a novel pruriceptive system has been proposed, within which itch-inducing peripheral mediators (pruritogens), itch-selective receptors (pruriceptors), sensory afferents and spinal cord neurons, and defined, itch-processing central nervous system regions display complex, layered responses to itch. In this review, we begin with a current overview on the neurophysiology of pruritus, and distinguish it from that of pain. We then focus on the functional characteristics of the large family of transient receptor potential (TRP) channels in skin-coupled sensory mechanisms, including itch and pain. In particular, we argue that - due to their expression patterns, activation mechanisms, regulatory roles, and pharmacological sensitivities - certain thermosensitive TRP channels are key players in pruritus pathogenesis. We close by proposing a novel, TRP-centered concept of pruritus pathogenesis and sketch important future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

Excitation and Modulation of TRPA1, TRPV1, and TRPM8 Channel-expressing Sensory Neurons by the Pruritogen Chloroquine

“…CQ Inhibits TRPM8 in a Subpopulation of DRG Neurons-In contrast to TRPV1 and TRPA1, which mediate the sensations of pain and itch, activation of TRPM8 by moderate cooling or menthol inhibits pain and itch (20). Because CQ-excited neurons were also found to overlap partly with TRPM8 ϩ neurons (Fig.…”

“…Activation of TRPM8 by cooling was reported to inhibit pain and itch (20); thus, concomitant inhibition of TRPM8 could also lead indirectly to enhanced sensations of pain and itch.…”

“…Interestingly, activation of TRPM8 by cooling or by the cooling compound menthol inhibits pain and itch through both peripheral and central mechanisms (6, 19 -21). It is thus not surprising that there is a complex and antagonistic relationship among the pain, itch, and cold pathways (20,(22)(23)(24). However, it is unclear how itching stimuli such as CQ affect the pain and cold pathways.…”

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

“…The purpose of the scratch is to introduce pain stimuli at the site of the itch, as GRPR and MOR1D-negative, dorsal horn neurons are able to inhibit GRPR and MOR1D-positive itch neurons in the presence of pain via Bhlhb5 positive interneurons [210]. Notably, topical capsaicin has been shown to prevent histamine-induced itch experimentally, and it is widely used by dermatologists clinically to treat various disorders associated with itch [214].…”

Potentiation of the Transient Receptor Potential Vanilloid 1 Channel Contributes to Pruritogenesis in a Rat Model of Liver Disease

“…Binding of pruritogens to their receptors, whose identity is often unclear, can trigger distinct and specific intracellular signaling pathways that can activate and potentiate TRPV1 function (2,22). Hence, TRPV1 may be a common downstream effector in the itch signaling pathway.…”