title: Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret.
abstract: Cannabinoid (CB) agonists suppress nausea and vomiting (emesis). Similarly, transient receptor potential vanilloid-1 (TRPV1) receptor agonists are anti-emetic. Arvanil, N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide, is a synthetic 'hybrid' agonist of CB1 and TRPV1 receptors. Anandamide and N-arachidonoyl-dopamine (NADA) are endogenous agonists at both these receptors. We investigated if arvanil, NADA and anandamide were anti-emetic in the ferret and their mechanism of action. All compounds reduced the episodes of emesis in response to morphine 6 glucuronide. These effects were attenuated by AM251, a CB1 antagonist that was pro-emetic per se, and TRPV1 antagonists iodoresiniferatoxin and AMG 9810, which were without pro-emetic effects. Similar sensitivity to arvanil and NADA was found for prodromal signs of emesis. We analysed the distribution of TRPV1 receptors in the ferret brainstem and, for comparison, the co-localization of CB1 and TRPV1 receptors in the mouse brainstem. TRPV1 immunoreactivity was largely restricted to the nucleus of the solitary tract of the ferret, with faint labeling in the dorsal motor nucleus of the vagus and sparse distribution in the area postrema. A similar distribution of TRPV1, and its extensive co-localization with CB1, was observed in the mouse. Our findings suggest that CB1 and TRPV1 receptors in the brainstem play a major role in the control of emesis by agonists of these two receptors. While there appears to be an endogenous 'tone' of CB1 receptors inhibiting emesis, this does not seem to be the case for TRPV1 receptors, indicating that endogenously released endocannabinoids/endovanilloids inhibit emesis preferentially via CB1 receptors.
authors: Hotchkiss Brain Institute, Department of Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada. ksharkey@ucalgary.ca
authors: K A
authors: KA
authors: Sharkey
authors: L
authors: L
authors: Cristino
authors: L D
authors: LD
authors: Oland
authors: M D
authors: MD
authors: Van Sickle
authors: K
authors: K
authors: Starowicz
authors: Q J
authors: QJ
authors: Pittman
authors: V
authors: V
authors: Guglielmotti
authors: J S
authors: JS
authors: Davison
authors: V
authors: V
authors: Di Marzo
mesh_terms: D000178:Acrylamides / Q000009:adverse effects; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology; D031608:Area Postrema / Q000187:drug effects / Q000378:metabolism; D017776:Autonomic Pathways / Q000187:drug effects / Q000378:metabolism; D001933:Brain Stem / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004639:Emetics / Q000037:antagonists & inhibitors; D063388:Endocannabinoids; D005289:Ferrets; D008297:Male; D051379:Mice; D010880:Piperidines / Q000009:adverse effects; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000009:adverse effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism; D014839:Vomiting / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D000932:Antiemetics; D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002186:Cannabinoids; D004639:Emetics; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C474941:arachidonyl dopamine; C121153:arvanil; C103505:AM 251; D002211:Capsaicin; C078814:anandamide; D004298:Dopamine