Regulation of Pain and Itch by TRP Channels

Abstract

Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.

Pathophysiological mechanisms of persistent orofacial pain

“…The transient receptor potential (TRP) channel superfamily plays an important role in functions associated with sensing pain [11]. Furthermore, TRP vanilloid 1 (TRPV1) is activated in the presence of high-temperature conditions (>42°C), low pH, capsaicin, and vanilloid, while TRPA1 is activated by low temperatures (<15°C) and in the presence of numerous chemical irritants [12]. Facial inflammation subsequently reduces the acidity in the inflamed site, which increases TRPV1 expression in nociceptors.…”

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues

“…In particular, mechanosensitive ion channels are sensitive to both context and deformation mode, making them uniquely suited as mechanotherapeutic sensors (13)(14)(15)(16). The transient receptor potential (TRP) family is a class of selective ion channels including some mechanically-sensitive members, such as TRPA1, TRPV1, and TRPV4 (17,18). TRPV4 is activated by osmotic fluctuations and plays an important role in the mechanosensitivity of articular cartilage, bladder, uterus, skin, and the dorsal root ganglion (19)(20)(21)(22)(23)(24)(25)(26).…”

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…Liedtke, Jordt, and their coworkers discuss the mechanisms by which the TRP channels modulate pain and itch. They also emphasize the translational potentials for treating pain and itch with TRP channel modulators [30].…”