Therapeutic Potential Of Vanilloid Receptor TRPV1 Agonists And Antagonists As Analgesics: Recent Advances And Setbacks

Main Category: Urology / Nephrology
Article Date: 31 Mar 2009 - 0:00 PDT

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UroToday.com - Capsaicin and its ultra potent vaniloid analogue resiniferatoxin (RTX) from Euphobia resinifera are well known to urologists. They elicit burning pain by activating a non-selective cation channel expression in the sensory nerve ending. Both of these molecules were found to be analgesics in preclinical species. The vanilloid receptor TRPV1 was found to be the pain target and in a very comprehensive, state of the art article, the development of both agonists and antagonists of TRPV1 are reviewed by Drs. Gilbert Wong and Narender Gavva from California.

Capsaicin and RTX are agonists, and demonstrated efficacy in preclinical models of pain, but at certain higher doses several undesirable effects on blood pressure, breathing, and other reflex pathways were observed. Subsequent clinical trials were focused on topical or local delivery. Although it was unknown about the outcomes of early trials sponsored by Afferon, which was later acquired by Icos, the ICOS RTX Study Group and Stanford University researchers reported negative results in RTX clinical trials in interstitial cystitis patients. NGX-4010 (capsaicin) has been shown effective in patients experiencing neuropathic pain due to various etiologies including post-herpetic neuralgia, painful HIV-associated neuropathy, and diabetic neuropathy when administered topically.

An early structure-activity relationship effects around capsaicin identified the first antagonist, capsazepine, which has been used extensively as a tool for in vitro and in vivo pharmacology studies. The idea that antagonism of all modes of TRPV1 activation is necessary to achieve significant anihyperalgesic effects in the antagonist group has recently been challenged. Brain penetration does appear to improve efficacy compared to peripherally restricted antagonists. In the course of evaluating the ability of TRPV1 antagonists to block capsaicin-induced hypothermia, it was found that antagonists themselves cause an increase in body temperatures. TRPV1-induced hyperthermia was found to be transient because it disappears within 4-20 hours, although hyperthermia causing plasma concentrations were observed for long half-life compounds. Clinical trials of one antagonist, AMG-517, have been discontinued due to TRPV1 blockade elicited hyperthermia. AstraZeneca, Glenmark/Lilly, Japan Tobacco, Neurogen/Merck, and Renovis/Pfizer are all trying to understand whether the hyperthermia liability for the promising class of TRPV1 antagonists can be managed.

The authors conclude that although TRPV1 agonists may potentially cause transient hypothermia at higher doses, it appears that agonist-induced hypothermia is not an issue for their clinical development. Agonists not only cause desensitization, but also potentially ablate the neurons that express TRPV1 and hence a greater magnitude of efficacy can be expected compared to antagonists that block only TRPV1 mediated sensitization of neuronal excitation during pain states. The authors believe that TRPV1 antagonists are where the action is, and that antagonists free of hyperthermia will be evaluated in the near future.

Wong GY, Gavva
Brain Res Rev. 2008 Dec 25. (Epub ahead of print)
10.1016/j.brainresrev.2008.12.006

Written by UroToday.com Contributing Editor Philip M. Hanno, MD, MPH

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