Prejunctional modulation by nociceptin of nerve-mediated inotropic responses in guinea-pig left atrium

The superimposition of a train of electrical stimuli (15 Hz. 1 ms, 60 V for 2.5 s) to the electrically driven (3 Hz) isolated left atria from reserpine-pretreated guinea pigs in the presence of atropine (1 microM) produces a delayed positive inotropic response due to the antidromic activation of capsaicin-sensitive primary afferents and the release of the sensory neuropeptide, calcitonin gene-related peptide (CGRP). The novel opioid peptide nociceptin, inhibited (Emax 88% inhibition at 1 microM) in a concentration-dependent manner (10 nM-1 microM) (EC50 33 nM) the delayed positive inotropic response induced by train electrical field stimulation, without affecting the positive inotropic response produced by exogenous CGRP (10 nM) or capsaicin (30 nM). The inhibitory effect of nociceptin on the delayed positive inotropic response induced by train electrical field stimulation was not antagonized by the opioid receptor antagonists naloxone, naltrindole and nor-binaltorphimine (1 microM each) nor was it modified by a cocktail of peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). A significant inhibition by nociceptin (1 microM) was also observed toward the sympathetic positive inotropic response produced by EFS at 5 Hz in the presence of atropine (1 microM) and after in vitro capsaicin desensitization and toward the parasympathetic negative inotropic response produced by EFS at 10 Hz in atria from reserpine-pretreated guinea pigs and after in vitro capsaicin desensitization. We conclude that nociceptin exerts a prejunctional inhibitory effect on evoked release of CGRP from capsaicin-sensitive sensory nerve terminals in guinea-pig left atria. The effect of nociceptin occurs independently from the activation of mu-, delta- or kappa-opioid receptors. Nociceptin, at appropriate frequency of stimulation, appears to exert a general inhibitory neuromodulation on transmitters release in guinea-pig left atria.