Transient Receptor Potential Channels in Pain and Itch
DOI:
https://doi.org/10.52340/ijch.2026.03.01Keywords:
algesia, allodynia, hyperalgesia, nociception, pruriceptionAbstract
Pain and itch (pruritus) are distinct, complex sensory sensations that indicate actual or potential tissue damage. While both involve neural network activation, their physiological mechanisms differ: pain is a necessary signal of harm that triggers protective responses, whereas itch primarily provokes the urge to scratch. In pruritus, the general discourse deals with histaminergic and nonhistaminergic itch. Painful or itching stimulation applied to peripheral receptors evokes a cascade of nociceptive signaling in ascending somatosensory pathways, culminating in a distributed, multidimensional brain representation that is required to localize, interpret, modulate, and appropriately respond to the stimulus.
The Transient Receptor Potential (TRP) channel superfamily is distinct in that channels are nonselective for cations (for sodium and calcium) and are involved in a diverse array of biological functions, making them attractive targets for synthesizing novel therapeutics. They regulate many functions, such as sensory perception, pain and itch, immunity, digestion, cancer, development, urological, cardiovascular, and nervous systems. Moreover, these channels are widely distributed in various tissue membranes, and TRP channel mutations are observed in several diseases, such as hereditary diseases and many other TRP channelopathies. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and members of the melastatin subfamily (TRPM2, TRPM3, and TRPM8).
TRP ankyrin 1 (TRPA1) is a calcium-permeable channel that is co-expressed on a subpopulation of TRPV1-expressing nociceptive nerve fibers’ terminals and distal endings of mechanosensitive C-fibers, contributing to the transduction of noxious signals. TRPA1 is considered to detect non-histaminergic itch and hypersensitivity to noxious cold. Various irritant chemicals (e.g., pungent compounds) and endogenous products of tissue injury activate TRPA1.
TRP vanilloid 1 (TRPV1) is also a nonselective ion channel with high calcium permeability that is activated by capsaicin, heat (>43°C), and pH (below < 6). It is a prominent nociceptor in C-fiber sensory neurons involved in pain and itch pathways. TRPV1 is considered to detect non-histaminergic itch. It has become the first family member with a postulated and subsequently verified link to pain and itch, suggesting this protein receptor as a hub for algesic and pruritogenic signals. Both channels are attractive therapeutic targets in pain and itch.
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