ORL-1 Receptor Mediates the Action of Nociceptin on Ascending Myenteric Reflex Pathways in Rats

Abstract

Nociceptin is the endogenous agonist of the "orphan" opioid receptor-1 (ORL-1). We investigated whether activation of the ORL-1 receptor influences smooth muscle contractility and enteric neurotransmission within ascending myenteric reflex pathways of rats. Reverse transcriptase polymerase chain reaction was performed to evaluate the presence of ORL-1 receptors. The ascending part of the ascending myenteric reflex in rats was studied in ileal segments using a 3-chambered organ bath. Intracellular recordings were performed to evaluate pharmacologic effects on excitatory and inhibitory junction potentials (EJP; IJP). Single- and double-labeling immunohistochemistry was used to examine the distribution of ORL-1 within the intestinal wall. ORL-1 expression and immunoreactivity was found in the large majority of myenteric neurons. In addition to the cholinergic myenteric neurons, all nitrergic myenteric neurons expressed the ORL-1 receptor. Nociceptin significantly reduced cholinergic twitch contractions, an effect that was reversed by the ORL-1 receptor antagonist [Nphe(1)]nociceptin(1-13)NH(2). Neither nociceptin nor [Nphe(1)]nociceptin(1-13)NH(2) had a direct influence on smooth muscle contractility. Nociceptin significantly reduced ascending myenteric reflex contractions and prolonged the latency from stimulation to contraction. Both effects were antagonized by [Nphe(1)]nociceptin(1-13)NH(2). Intracellular recordings demonstrated that nociceptin reduces the cholinergically mediated EJP and the nitrergic phase of IJP in a concentration-dependent manner, effects that were reversible in presence of [Nphe(1)]nociceptin(1-13)NH(2). We conclude that activation of ORL-1 receptors on myenteric neurons reduce excitatory and inhibitory neurotransmission within the gastrointestinal tract. This is accompanied by a reduction of the small intestinal peristaltic reflex response. These effects might be used pharmacologically.