Cannabinoid receptor-independent inhibition by cannabinoid agonists of the peripheral 5-HT3 receptor-mediated von Bezold-Jarisch reflex.
(1) 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. (2) In urethane-anaesthetized rats, pre-treated intravenously (i.v.) with the CB(1) receptor antagonist SR 141716A (3 micro mol kg(-1)) and with the beta(1)/beta(2) adrenoceptor antagonist propranolol (0.3-0.4 micro mol kg(-1)), bolus injection of the serotonin 5-HT(3) receptor agonist phenylbiguanide (3-10 micro g kg(-1), i.v.) or the vanilloid VR1 receptor agonist capsaicin (3-10 micro g kg(-1), i.v.) caused an immediate decrease in heart rate and mean arterial blood pressure (the von Bezold-Jarisch reflex). (3) The phenylbiguanide-induced bradycardia was dose-dependently attenuated by the cannabinoid receptor agonists CP 55,940 (0.1-1 micro mol kg(-1), i.v.) and WIN 55,212-2 (0.1-3 micro mol kg(-1), i.v.) 20 min after injection, but not by the inactive S-(-)enantiomer of the latter, WIN 55,212-3 (1 micro mol 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. (4) 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.
Godlewski
Grzegorz
G
Zakład Fizjologii Doświadczalnej, Akademia Medyczna w Białymstoku, ul. Mickiewicza 2A, 15-230 Białystok 8, Poland. ggodl@amb.edu.pl
Göthert
Manfred
M
Malinowska
Barbara
B
D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D002186:Cannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists