Abstract
Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.
Highlights
Pain constitutes an “unpleasant sensory and emotional experience associated with actual or potential tissue damage”, as defined by The International Association for the Study of Pain [1]
This review summarizes a comprehensive knowledge on the molecular characterization of nociceptive transient receptor potential (TRP) channels, their constitutive and modulatory functions, expression and tissue distribution, as well as how these channels and their specific properties are critically involved in various pain conditions
Nociceptive TRP channels have been shown to be involved in several pain-related pathological conditions/modalities, including inflammatory, neuropathic, visceral and dental pain, as well as pain associated with cancer [9,11,13]
Summary
Pain constitutes an “unpleasant sensory and emotional experience associated with actual or potential tissue damage”, as defined by The International Association for the Study of Pain [1]. Nociceptive neurons are functionally characterized by the type of sensory receptors and ion channels expressed on the plasma membrane throughout the cell body (somata) and nerve fibers. These receptors/channels are vital for the detection of various noxious stimuli. TRPs are non-selective cation channels with relatively high Ca2+-permeability, and are expressed in a wide variety of cell/tissue types, both on the plasma membrane and intracellular organelle membranes [4,5] They share identical overall membrane topology, consisting of tetramers of 6-transmembrane (6-TM) segment polypeptide subunits with a central ion conduction pore, which is similar to voltage-gated K+ channels. Recent developments in analgesic targeting of nociceptive TRP channels are outlined here
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