title: Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin.
abstract: Cannabinoid-induced antinociception relies on activation of inhibitory cannabinoid receptors (CB1) in the peripheral and central nervous system. However, most cannabinoids at higher concentration also activate excitatory ionotropic transient receptor potential (TRP) channels coexpressed with CB1 in primary nociceptive neurons that contain and release calcitonin gene-related peptide (CGRP) upon activation. Over a wide concentration range (0.01-100μM) we investigated the molecular action principles of the endocannabinoid anandamide and of the plant-derived Δ(9)-THC that can be prescribed for analgesia. Isolated rat and mouse skin preparations were used to measure CGRP release induced by noxious heat (47°C) and capsaicin (0.5μM), stimuli known to activate the capsaicin receptor TRPV1. At low concentration (0.1μM) both cannabinoids inhibited stimulated CGRP release by 34-65%, which effects were absent under CB1 block by AM 251 and in global CB1 but not TRPV1 knockout mice. At high concentration (100μM) both cannabinoids evoked CGRP release by themselves and desensitized subsequent heat responses, which effects were absent under TRPV1 block by BCTC and in global TRPV1 but not CB1 knockouts. A lower (0.01μM) and the intermediate concentrations (1 and 10μM) of cannabinoids were ineffective. Excitatory and desensitizing effects were not more expressed (disinhibited) in CB1(-/-), inhibitory effects not stronger in TRPV1(-/-). CGRP release induced by unspecific depolarization (KCl) was not modulated by cannabinoids. An incidental finding was that global CB1(-/-) showed reduced heat sensitivity, almost as low as TRPV1(-/-) and in accord with their behavioral phenotype. In conclusion, the antinociceptive potency of peripherally acting CB1 agonists is not restrained by opposing irritant effects through TRPV1 but by their own limited efficacy and narrow concentration-response relationship.
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. Erlangen, Germany. reeh@physiologie1.uni-erlangen.de
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Engel
authors.forename: Iwona
authors.initials: I
authors.lastname: Izydorczyk
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Mueller-Tribbensee
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D006358:Hot Temperature; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013759:Dronabinol; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C078814:anandamide