Stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. Interestingly, endocannabinoids such as anandamide (which interacts with CB₁ , CB₂ , TRPV1 and GPR55 receptors) can regulate the activity of perivascular sensory nerves in dural blood vessels by modulating CGRP release. Yet, since no publication has reported whether this mechanism is operative in the healthy systemic vasculature, this study has specifically analysed the receptors mediating the potential inhibitory effects of the cannabinoid (CB) receptor agonists anandamide (non-selective), JWH-015 (CB₂ ) and lysophosphatidylinositol (GPR55) on the rat vasodepressor sensory CGRPergic outflow (an index of systemic vasodilatation). Healthy pithed rats were pre-treated with consecutive i.v. continuous infusions of hexamethonium, methoxamine and the above agonists. Electrical spinal (T₉ -T₁₂ ) stimulation of the vasodepressor sensory CGRPergic outflow or i.v. injections of α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The infusions of anandamide dose-dependently inhibited the vasodepressor responses by electrical stimulation (remaining unaffected by JWH-015 or lysophosphatidylinositol), but not those by α-CGRP. After i.v. administration of antagonists, the inhibition by 3.1 μg/kg.min anandamide was: (i) potently blocked by 31-100 μg/kg NIDA41020 (CB₁ ); and (ii) unaffected by 180 μg/kg AM630 (CB₂ ), 31 μg/kg cannabidiol (GPR55) or 31-100 μg/kg capsazepine (TRPV1); and (iii) slightly blocked by 310 μg/kg AM630. The above doses of antagonists were enough to block their respective receptors. These results suggest that anandamide-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional activation of CB₁ receptors, with no pharmacological evidence for the role of CB₂ , TRPV1 or GPR55 receptors. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

PMID:

 

24118786

 

[PubMed – as supplied by publisher]