title: Anandamide modulates carotid sinus nerve afferent activity via TRPV1 receptors increasing responses to heat.
abstract: Abnormal respiratory chemosensitivity is implicated in recurrent apnea syndromes, with the peripheral chemoreceptors, the carotid bodies, playing a particularly important role. Previous work suggests that supraphysiological concentrations of the endocannabinoid endovanilloid and TASK channel blocker anandamide (ANA) excite carotid bodies, but the mechanism(s) and physiological significance are unknown. Given that carotid body output is temperature-sensitive, we hypothesized that ANA stimulates carotid body chemosensory afferents via temperature-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, we used the dual-perfused in situ rat preparation to confirm that independent perfusion of carotid arteries with supraphysiological concentrations of ANA strongly excites carotid sinus nerve afferents and that this activity is sufficient to increase phrenic activity. Next, using ex vivo carotid body preparations, we demonstrate that these effects are mediated by TRPV1 receptors, not CB1 receptors or TASK channels: in CB1-null mouse preparations, ANA increased afferent activity across all levels of Po(2), whereas in TRPV1-null mouse preparations, the stimulatory effect of ANA was absent. In rat ex vivo preparations, ANA's stimulatory effects were mimicked by olvanil, a nonpungent TRPV1 agonist, and suppressed by the TRPV1 antagonist AMG-9810. The specific CB1 agonist oleamide had no effect. Physiological levels of ANA had no effect alone but increased sensitivity to mild hyperthermia. AMG-9810 blocked ANA's effect on the temperature response. Immunolabeling and RT-PCR demonstrated that TRPV1 receptors are not expressed in carotid body glomus cells but reside in petrosal sensory afferents. Together, these results suggest that ANA plays a physiological role in augmenting afferent responses to mild hyperthermia by activating TRPV1 receptors on petrosal afferents.
authors: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Arijit
authors: A
authors: Roy
authors: Sravan
authors: S
authors: Mandadi
authors: Marie-Noelle
authors: MN
authors: Fiamma
authors: Ekaterina
authors: E
authors: Rodikova
authors: Erin V
authors: EV
authors: Ferguson
authors: Patrick J
authors: PJ
authors: Whelan
authors: Richard J A
authors: RJ
authors: Wilson
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology / Q000502:physiology*; D002186:Cannabinoids / Q000494:pharmacology; D002346:Carotid Sinus / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids; D006358:Hot Temperature; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C078814:anandamide