Cannabinoid receptor‐independent inhibition by cannabinoid agonists of the peripheral 5‐HT 3 receptor‐mediated von Bezold–Jarisch reflex

On the basis of previous findings that cannabinoids inhibit the function of human and rat 5‐HT 3 receptors in vitro , we investigated whether cannabinoid receptor agonists also modulate the activity of the rat peripheral 5‐HT 3 receptors on the terminals of cardiopulmonary afferent C‐fibres in vivo . In urethane‐anaesthetized rats, pre‐treated intravenously (i.v.) with the CB 1 receptor antagonist SR 141716A (3 μmol kg −1 ) and with the β 1 /β 2 adrenoceptor antagonist propranolol (0.3–0.4 μmol kg −1 ), bolus injection of the serotonin 5‐HT 3 receptor agonist phenylbiguanide (3–10 μg kg −1 , i.v.) or the vanilloid VR1 receptor agonist capsaicin (3–10 μg kg −1 , i.v.) caused an immediate decrease in heart rate and mean arterial blood pressure (the von Bezold–Jarisch reflex). The phenylbiguanide‐induced bradycardia was dose‐dependently attenuated by the cannabinoid receptor agonists CP 55,940 (0.1–1 μmol kg −1 , i.v.) and WIN 55,212‐2 (0.1–3 μmol kg −1 , i.v.) 20 min after injection, but not by the inactive S‐(−)enantiomer of the latter, WIN 55,212‐3 (1 μmol kg −1 , i.v.). The inhibition was reversible within 30 min. The extent of inhibition by the highest doses of cannabinoid receptor agonists amounted to about 50%. Both cannabinoid receptor agonists failed to affect the capsaicin‐evoked bradycardia. In conclusion, our results demonstrate that cannabinoid receptor agonists modulate the von Bezold–Jarisch reflex by inhibiting peripheral serotonin 5‐HT 3 receptors in rats in vivo . An analogous mechanism of cannabinoid receptor agonists may be assumed to be involved in other serotonin 5‐HT 3 receptor‐mediated responses.British Journal of Pharmacology (2003) 138 , 767–774. doi: 10.1038/sj.bjp.0705114