TRPM8 and TRPA1 Ideal Targets for Treating Cold-Induced Pain

Abstract

TRP channels are essential for detecting variations in external temperature and are ubiquitously expressed in both the peripheral and central nervous systems as integral channel proteins. They primarily mediate a range of sensory responses, including thermal sensations, nociception, mechanosensation, vision, and gustation, thus playing a critical role in regulating various physiological functions. In colder climates, individuals often experience pain associated with low temperatures, leading to significant discomfort. Within the TRP channel family, TRPM8 and TRPA1 ion channels serve as the primary sensors for cold temperature fluctuations and are integral to both cold nociception and neuropathic pain pathways. Recent advancements in the biosynthesis of inhibitors targeting TRPM8 and TRPA1 have prompted the need for a comprehensive review of their structural characteristics, biological activities, biosynthetic pathways, and chemical synthesis. This paper aims to delineate the distinct roles of TRPM8 and TRPA1 in pain perception, elucidate their respective protein structures, and compile various combinations of TRPM8 and TRPA1 antagonists and agonists. The discussion encompasses their chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, with a particular focus on the conformational relationships between antagonists and the channels. This review seeks to provide in-depth insights into pharmacological strategies for managing pain associated with TRPM8 and TRPA1 activation and will pave the way for future investigations into pharmacotherapeutic approaches for alleviating cold-induced pain.