Faculty Collaboration Database

Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: antinociceptive actions of CB1 inverse agonists. J Neurosci 2008 Nov 05;28(45):11593-602

Date

11/07/2008

Pubmed ID

18987195

Pubmed Central ID

PMC2744288

DOI

10.1523/JNEUROSCI.3322-08.2008

Scopus ID

2-s2.0-58149266680 (requires institutional sign-in at Scopus site)   76 Citations

Abstract

The potential modulation of TRPV1 nociceptive activity by the CB(1) receptor was investigated here using CB(1) wild-type (WT) and knock-out (KO) mice as well as selective CB(1) inverse agonists. No significant differences were detected in baseline thermal thresholds of ICR, CB(1)WT or CB(1)KO mice. Intraplantar capsaicin produced dose- and time-related paw flinch responses in ICR and CB(1)WT mice and induced plasma extravasation yet minimal responses were seen in CB(1)KO animals with no apparent differences in TRPV1 channel expression. Capsaicin-evoked CGRP release from spinal cord tissue and capsaicin-evoked action potentials on isolated skin-nerve preparation were significantly decreased in CB(1)KO mice. Pretreatment with intraplantar galanin and bradykinin, compounds known to sensitize TRPV1 receptors, restored capsaicin-induced flinching in CB(1)KO mice. The possibility that constitutive activity at the CB(1) receptor is required to maintain the TRPV1 receptor in a "sensitized" state was tested using CB(1) inverse agonists. The CB(1) inverse agonists elicited concentration-related inhibition of capsaicin-induced calcium influx in F-11 cells and produced dose-related inhibition of capsaicin-induced flinching in ICR mice. These data suggest that constitutive activity at the CB(1) receptor maintains the TRPV1 channel in a sensitized state responsive to noxious chemical stimuli. Treatment with CB(1) inverse agonists may promote desensitization of the channel resulting in antinociceptive actions against chemical stimulus modalities. These studies propose possible therapeutic exploitation of a novel mechanism providing pain relief by CB(1) inverse agonists.

Author List

Fioravanti B, De Felice M, Stucky CL, Medler KA, Luo MC, Gardell LR, Ibrahim M, Malan TP Jr, Yamamura HI, Ossipov MH, King T, Lai J, Porreca F, Vanderah TW

Author

Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Animals
Behavior, Animal
Bradykinin
Calcitonin Gene-Related Peptide
Calcium
Capsaicin
Cell Line, Tumor
Dose-Response Relationship, Drug
Galanin
Gene Expression Regulation
Male
Mice
Mice, Inbred ICR
Mice, Knockout
Morphine
Narcotics
Nerve Fibers, Unmyelinated
Neuroblastoma
Pain
Pain Measurement
Pain Threshold
Piperidines
Pyrazoles
Rats
Reaction Time
Receptor, Cannabinoid, CB1
Stimulation, Chemical
Sulfonamides
TRPV Cation Channels