Modulation of the cardiac autonomic transmission of pithed rats by presynaptic opioid OP4 and cannabinoid CB1 receptors

We studied the effects of nociceptin, the endogenous ligand of the opioid O P4 receptor, and of two cannabinoid receptor agonists WIN 55,212-2 and CP-5 5,940 (0.001-1 mu mol/kg each) on the neurogenic tachycardia and bradycardi a in pithed rats. Electrical stimulation (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sym pathetic nerve fibres and injection of nicotine 2 mu mol/kg or isoprenaline 0.5 nmol/kg increased heart rate by about 70 beats/min (bpm) in pithed rat s pretreated with atropine 1.5-2 mu mol/kg. The electrically induced tachyc ardia was reduced dose dependently by nociceptin, WIN 55,212-2 and CP-55,94 0 (by 60, 30 and 20% at the highest dose, respectively). The OP4 and cannab inoid receptor agonists diminished the nicotine- but not the isoprenaline-s timulated increase in heart rate. In pithed rats pretreated with propranolo l 3 mu mol/kg, vagal stimulation (5 Hz, 1 ms, 15 V for 10 s) or injection o f methacholine (5-10 nmol/kg) decreased heart rate by about 30 bpm. Nocicep tin, but not WIN 55,212-2 or CP-55,940 decreased the vagal bradycardia dose dependently (the inhibitory effect of 1 mu mol/kg was about 40%). Nocicept in failed to modify the methacholine-induced decrease in heart rate. The OP 4 receptor antagonists naloxone benzoylhydrazone 5 mu mol/kg and/or [Phe(1) Psi (CH2-NH)Gly(2)]-nociceptin(1-13)NH2 0.7 mu mol/kg, but not the OP1-3 re ceptor antagonist naloxone 10 mu mol/kg, diminished the inhibitory action o f nociceptin on the neurogenic tachycardia and bradycardia. The inhibitory effect of both cannabinoid receptor agonists on the neurogenic tachycardia was abolished by the CB1 receptor antagonist SR 141716 0.1 mu mol/kg. The present data suggest that the postganglionic sympathetic nerve fibres i nnervating the rat heart are endowed with presynaptic opioid OP4 and cannab inoid CB1 receptors, activation of which inhibits the neurogenic tachycardi a. The parasympathetic nerve fibres innervating the heart and causing brady cardia are endowed with presynaptic opioid OP4 but not cannabinoid receptor s.