A-995662 [(R)-8-(4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol], a novel, selective TRPV1 receptor antagonist, reduces spinal release of glutamate and CGRP in a rat knee joint pain model

Pain. 2010 Aug;150(2):319-326. doi: 10.1016/j.pain.2010.05.015. Epub 2010 Jun 19.


The TRPV1 antagonist A-995662 demonstrates analgesic efficacy in monoiodoacetate-induced osteoarthritic (OA) pain in rat, and repeated dosing results in increased in vivo potency and a prolonged duration of action. To identify possible mechanism(s) underlying these observations, release of neuropeptides and the neurotransmitter glutamate from isolated spinal cord was measured. In OA rats, basal release of glutamate, bradykinin and calcitonin gene-related peptide (CGRP) was significantly elevated compared to naïve levels, whereas substance P (SP) levels were not changed. In vitro studies showed that capsaicin-evoked TRPV1-dependent CGRP release was 54.7+/-7.7% higher in OA, relative to levels measured for naïve rats, suggesting that TRPV1 activity was higher under OA conditions. The efficacy of A-995662 in OA corresponded with its ability to inhibit glutamate and CGRP release from the spinal cord. A single, fully efficacious dose of A-995662, 100 micromol/kg, reduced spinal glutamate and CGRP release, while a single sub-efficacious dose of A-995662 (25 micromol/kg) was ineffective. Multiple dosing with A-995662 increased the potency and duration of efficacy in OA rats. Changes in efficacy did not correlate with plasma concentrations of A-995662, but were accompanied with reductions in spinal glutamate release. These findings suggest that repeated dosing of TRPV1 antagonists enhances therapeutic potency and duration of action against OA pain, at least in part, by the sustained reduction in release of glutamate and CGRP from the spinal cord.

MeSH terms

  • Analysis of Variance
  • Animals
  • Bradykinin / metabolism
  • Calcitonin Gene-Related Peptide / metabolism*
  • Glutamic Acid / metabolism*
  • Osteoarthritis, Knee / chemically induced
  • Osteoarthritis, Knee / metabolism*
  • Pain / chemically induced
  • Pain / metabolism*
  • Pain Measurement
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects*
  • Spinal Cord / metabolism
  • Substance P / metabolism
  • TRPV Cation Channels / antagonists & inhibitors*
  • Tetrahydronaphthalenes / pharmacology*


  • A-995662
  • TRPV Cation Channels
  • TRPV1 receptor
  • Tetrahydronaphthalenes
  • Substance P
  • Glutamic Acid
  • Calcitonin Gene-Related Peptide
  • Bradykinin