Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret

• Published in: The European journal of neuroscience 2007-05, Vol.25 (9), p.2773-2782
• Main Authors: Sharkey, K. A., Cristino, L., Oland, L. D., Van Sickle, M. D., Starowicz, K., Pittman, Q. J., Guglielmotti, V., Davison, J. S., Di Marzo, V.
• Format: Article
• Language: English
• Subjects: Acrylamides - adverse effects; Animals; Antiemetics - pharmacology; Arachidonic Acids - pharmacology; Area Postrema - drug effects; Area Postrema - metabolism; Autonomic Pathways - drug effects; Autonomic Pathways - metabolism; Brain Stem - anatomy & histology; Brain Stem - drug effects; Brain Stem - metabolism; brainstem; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; cannabinoid receptors; Cannabinoids - pharmacology; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Dopamine - analogs & derivatives; Dopamine - pharmacology; emesis; Emetics - antagonists & inhibitors; Endocannabinoids; Ferrets; Male; Mice; Mustela putorius furo; Piperidines - adverse effects; Polyunsaturated Alkamides - pharmacology; Pyrazoles - adverse effects; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - metabolism; Solitary Nucleus - drug effects; Solitary Nucleus - metabolism; TRPV Cation Channels - agonists; TRPV Cation Channels - metabolism; TRPV1; Vagus Nerve - drug effects; Vagus Nerve - metabolism; Vomiting - drug therapy; Vomiting - metabolism; Vomiting - physiopathology
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2007.05521.x

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.