Targeting TRPV1 for pain relief: limits, losers and laurels.
BACKGROUND
With 336 reviews, the capsaicin receptor TRPV1 arguably represent today's most extensively reviewed analgesic target. TRPV1 is strategically located at the peripheral terminals of primary sensory neurons where pain is generated. TRPV1 as a target for analgesic drugs has been validated in preclinical studies.


METHODS
The therapeutic potential of targeting TRPV1 by agonists and antagonists for pain relief is discussed based on our experience and a critical review of the literature. Strategies to overcome adverse effects are explored.


CONCLUSIONS
Since its discovery in 1997, TRPV1 has run the gamut from excitement to disappointment to cautious optimism. Topical capsaicin has been disappointing for pain relief. By contrast, intrathecal resiniferatoxin is currently undergoing clinical trials in patients with intractable cancer pain. Some of the small-molecule TRPV1 antagonists have successfully passed Phase I safety and tolerability studies in healthy volunteers into Phase II studies to access efficacy in patients. Others showed worrisome unforeseen adverse effects, most important, hyperthermia and impaired noxious heat sensation. We conclude that TRPV1 blockade and desensitization are two promising, complimentary approaches for pain relief. Despite the roadblocks, TRPV1 remains a powerful tool in pain research and a promising therapeutic target.
Monmouth Medical Center, Pathology, Long Branch, USA. aszallasi@sbhcs.com
Arpad
A
Szallasi
Mohamed
M
Sheta
D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000700:Analgesics; D004224:Diterpenes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C024353:resiniferatoxin; D002211:Capsaicin