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Role of Pre‐Junctional CB 1 , But not CB 2 , TRPV 1 or GPR 55 Receptors in Anandamide‐Induced Inhibition of the Vasodepressor Sensory CGRP ergic Outflow in Pithed Rats
Author(s) -
MarichalCancino Bruno A.,
AltamiranoEspinoza Alain H.,
ManriqueMaldonado Guadalupe,
MaassenVanDenBrink Antoinette,
Villalón Carlos M.
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12152
Subject(s) - anandamide , capsazepine , trpv1 , endocannabinoid system , chemistry , calcitonin gene related peptide , cannabinoid receptor , stimulation , receptor , pharmacology , endocrinology , medicine , cannabinoid , cannabinoid receptor type 2 , agonist , transient receptor potential channel , biochemistry , neuropeptide
Stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. Interestingly, endocannabinoids such as anandamide (which interacts with CB 1 , CB 2 , TRPV 1 and GPR 55 receptors) can regulate the activity of perivascular sensory nerves in dural blood vessels by modulating CGRP release. Yet, as 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 ( CB 2 ) and lysophosphatidylinositol ( GPR 55) on the rat vasodepressor sensory CGRP ergic 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 (T 9 –T 12 ) stimulation of the vasodepressor sensory CGRP ergic outflow or i.v. injections of α– CGRP produced frequency‐dependent or dose‐dependent vasodepressor responses. The infusions of anandamide in a dose‐dependent manner 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 NIDA 41020 ( CB 1 ), (ii) unaffected by 180 μg/kg AM 630 ( CB 2 ), 31 μg/kg cannabidiol ( GPR 55) or 31–100 μg/kg capsazepine ( TRPV 1) and (iii) slightly blocked by 310 μg/kg AM 630. The above doses of antagonists were enough to block their respective receptors. These results suggest that anandamide‐induced inhibition of the vasodepressor sensory CGRP ergic outflow is mainly mediated by pre‐junctional activation of CB 1 receptors, with no pharmacological evidence for the role of CB 2 , TRPV 1 or GPR 55 receptors.