TRP channels: potential drug target for neuropathic pain

Abstract

Neuropathic pain is a debilitating disease which affects central as well as peripheral nervous system. Transient receptor potential (TRP) channels are ligand-gated ion channels that detect physical and chemical stimuli and promote painful sensations via nociceptor activation. TRP channels have physiological role in the mechanisms controlling several physiological responses like temperature and mechanical sensations, response to painful stimuli, taste, and pheromones. TRP channel family involves six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1) which are expressed in pain sensing neurons and primary afferent nociceptors. They function as transducers for mechanical, chemical, and thermal stimuli into inward currents, an essential first step for provoking pain sensations. TRP ion channels activated by temperature (thermo TRPs) are important molecular players in acute, inflammatory, and chronic pain states. Different degree of heat activates four TRP channels (TRPV1-4), while cold temperature ranging from affable to painful activate two indistinctly related thermo TRP channels (TRPM8 and TRPA1). Targeting primary afferent nociceptive neurons containing TRP channels that play pivotal role in revealing physical stimuli may be an effective target for the development of successful pharmacotherapeutics for clinical pain syndromes. In this review, we highlighted the potential role of various TRP channels in different types of neuropathic pain. We also discussed the pharmacological activity of naturally and synthetically originated TRP channel modulators for pharmacotherapeutics of nociception and neuropathic pain.

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

“…Interestingly, CBDA also targets the TRP family of ion channels (De Petrocellis et al, ), including TRPV1 (Ligresti et al, ). TRP channels detect physical and chemical stimuli and promote painful sensations via nociceptor activation (Marwaha et al, ) and the stimulating effects of cannabinoids at TRPV1 may lead to desensitization of this channel (Morita et al, ; Ursu, Knopp, Beattie, Liu, & Sher, ). Furthermore, CBDA has been shown, by computational modelling and cell culture‐based experiments, to act as a dual PPAR‐α and PPAR‐γ agonist (D'Aniello et al, ).…”

Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

“…Blocking the activity of the channel by the administration of TRPM8 antagonists or by genetic ablation using mice lacking TRPM8, significantly attenuated thermal responses in nerve injury‐induced pain (Knowlton et al, ; Patel et al, ). This evidence suggests that the in vivo antagonism of TRPM8 holds promise for the successful treatment of neuropathic cold hypersensitivity (Marwaha et al, ; Weyer and Letho, ). A key challenge in the discovery of TRPM8 blockers is the identification of highly selective molecules with a good pharmacokinetic profile suitable to provide an efficacious dose response.…”

“…Specifically, it is widely expressed on terminals of thermosensitive neurons that innervate peripheral tissues including the skin, tongue, teeth and cornea (Abe et al, ; Parra et al, ). Several studies in animals and humans have clearly demonstrated the role of TRPM8 in pain perception (Marwaha et al, ); nevertheless, its precise role in pain modulation remains a matter of debate (Namer et al, ; Proudfoot et al, ). Application of relatively low doses of menthol (TRPM8 agonist) is associated with a cooling sensation and even pain relief, while at higher doses, the same drug causes burning, irritation and pain (Wasner et al, ; Hatem et al, ).…”

Extraoral Taste Receptor Discovery: New Light on Ayurvedic Pharmacology

“…Mammalian TRP channels have not only oral location, but a broad tissue distribution (at least one type of TRP present virtually in all cells), this ubiquity bringing them to the vanguards of the chemosensorial system [132, 347, 348]. …”