title: Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: antinociceptive actions of CB1 inverse agonists.
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.
authors.affiliation: Departments of Pharmacology and Anesthesiology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Fioravanti
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Stucky
authors.forename: Karen A
authors.initials: KA
authors.lastname: Medler
authors.forename: Miaw-Chyi
authors.initials: MC
authors.lastname: Luo
authors.forename: Luis R
authors.initials: LR
authors.lastname: Gardell
authors.forename: Mohab
authors.initials: M
authors.lastname: Ibrahim
authors.forename: T Phil
authors.initials: TP
authors.lastname: Malan
authors.forename: Henry I
authors.initials: HI
authors.lastname: Yamamura
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Tamara
authors.initials: T
authors.lastname: King
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000009:adverse effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019004:Galanin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009020:Morphine / Q000627:therapeutic use; D009294:Narcotics / Q000627:therapeutic use; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D000077285:Rimonabant; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D001920:Bradykinin; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium; D002211:Capsaicin; D019004:Galanin; D009020:Morphine; D009294:Narcotics; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D013449:Sulfonamides; D050916:TRPV Cation Channels; C473783:2,4,6-trimethyl-N-(meta-3-trifluoromethylphenyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C493921:TRPV1 protein, mouse