Pre- and postsynaptic inhibition by nociceptin in guinea pig small intestinal myenteric plexus in vitro

Actions of nociceptin on electrical and synaptic behavior of morphologicall y and neurochemically identified neurons in the guinea pig duodenal myenter ic plexus were studied with conventional techniques. Nociceptin hyperpolari zed the membrane potential in 104 of 121 AH-type and 28 of 51 S-type neuron s with an EC50 of 11.9 +/- 1.2 nM. Increased K+ conductance accounted for t he hyperpolarizing responses that were blocked by pertussis toxin and unaff ected by naloxone. The selective opioid receptor-like (ORL)(1) receptor ant agonist [Phe(1)- psi(CH2-NH)-Gly(2)] nociceptin( 1-13)-NH2 suppressed the n ociceptin-evoked responses while behaving like a partial agonist. The nonse lective ORL1 antagonist naloxone benzoylhydrazone competitively suppressed nociceptin actions with a pA(2) value of 5.8. Nociceptin acted at presynapt ic inhibitory receptors to suppress fast excitatory nicotinic postsynaptic potentials in 25 of 30 neurons (EC50 = 22.5 +/- 4.4 nM) and slow synaptic e xcitation in 38 of 45 neurons (EC50 = 15.1 +/- 1.6 nM). Presynaptic inhibit ory action of nociceptin was unaffected by naloxone and was antagonized by [Phe(1)-psi(CH2-NH)-Gly(2)]nociceptin(1-13)-NH2 or naloxone benzoylhydrazon e. The results suggest that nociceptin acts both pre- and postsynaptically by activating an ORL1 receptor that is distinct from typical naloxone-sensi tive opioid receptors.