TRP Channels and Pruritus

Abstract

Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Indeed, scratching blocks responses of spinal second-order neurons to pruritic, but not algesic, stimuli (Nishida et al, 2013). The intensity theory states that the very same primary afferents are capable of triggering of both pruritus and pain (reviewed in Ross, 2011;Tóth and Bíró, 2013;Tóth et al, 2014). This model is supported by the observations that 1) intradermal capsaicin injection can cause both itch and pain Klein et al, 2011;Sikand et al, 2011) in a dose-dependent manner, and 2) desensitization to topical capsaicin creams alleviates both pain and pruritus (see Szallasi and Blumberg, 1999).…”

“…28), organized more or less independently from nociception (labeled-line theory) (reviewed in Ma, 2012;Tóth et al, 2014). This pruriceptive system is thought to have two functionally and anatomically distinct subdivisions, distinguished by a characteristic response (or the lack of it) to histamine (see Tóth and Bíró, 2013).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…In contrast to the classic theory that itch as a "subthreshold pain" evoked by weak activation of nociceptors, the "specificity theory of itch" describes the differentiation of pain and itch sensory pathways (Han et al, 2013;Tóth and Bíró, 2013). The sensations of itch and pain are distinct; however, they are both protective mechanisms and involve a similar neuronal pathway of transmission.…”

“…The circuitry controlling itch is complex and involves many pruritogenic substances (histamine, tryptase, serotonin, kinins, chemokines) released from neurons and cutaneous cells, including keratinocytes, mast, endothelial, and immune cells (Tóth and Bíró, 2013). TRPA1, TRPV1, TRPV3, and TRPV4 are expressed on all of these cell types and contribute to acute and chronic itch processes either by facilitating pruritogen release or sensory itch responses in neurons (Ikoma et al, 2006).…”

Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists

“…There is good evidence that TRPA1 is a major mediator of histamine-independent itch [42]. For example, selective pharmacological blockade of TRPA1 and/or its genetic deletion reduced scratching behavior induced by intradermal hydrogen peroxide or tertbutylhydroperoxide injection [43].…”