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

Abstract.

We studied the effects of nociceptin, the endogenous ligand of the opioid OP₄ receptor, and of two cannabinoid receptor agonists WIN 55,212-2 and CP-55,940 (0.001–1 µmol/kg each) on the neurogenic tachycardia and bradycardia in pithed rats.

Electrical stimulation (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibres and injection of nicotine 2 µmol/kg or isoprenaline 0.5 nmol/kg increased heart rate by about 70 beats/min (bpm) in pithed rats pretreated with atropine 1.5–2 µmol/kg. The electrically induced tachycardia was reduced dose dependently by nociceptin, WIN 55,212-2 and CP-55,940 (by 60, 30 and 20% at the highest dose, respectively). The OP₄ and cannabinoid receptor agonists diminished the nicotine- but not the isoprenaline-stimulated increase in heart rate. In pithed rats pretreated with propranolol 3 µmol/kg, vagal stimulation (5 Hz, 1 ms, 15 V for 10 s) or injection of methacholine (5–10 nmol/kg) decreased heart rate by about 30 bpm. Nociceptin, but not WIN 55,212-2 or CP-55,940 decreased the vagal bradycardia dose dependently (the inhibitory effect of 1 µmol/kg was about 40%). Nociceptin failed to modify the methacholine-induced decrease in heart rate. The OP₄ receptor antagonists naloxone benzoylhydrazone 5 µmol/kg and/or [Phe¹Ψ(CH₂-NH)Gly²]-nociceptin(1–13)NH₂ 0.7 µmol/kg, but not the OP_1–3 receptor antagonist naloxone 10 µmol/kg, diminished the inhibitory action of 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 µmol/kg.

The present data suggest that the postganglionic sympathetic nerve fibres innervating the rat heart are endowed with presynaptic opioid OP₄ and cannabinoid CB₁ receptors, activation of which inhibits the neurogenic tachycardia. The parasympathetic nerve fibres innervating the heart and causing bradycardia are endowed with presynaptic opioid OP₄ but not cannabinoid receptors.