ORL-1 receptor mediates the action of nociceptin on ascending myenteric reflex pathways in rats

Gastroenterology. 2007 Aug;133(2):574-86. doi: 10.1053/j.gastro.2007.05.016. Epub 2007 May 18.

Abstract

Background and aims: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Action Potentials
  • Animals
  • Colon / drug effects
  • Colon / innervation*
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Ileum / drug effects
  • Ileum / innervation*
  • In Vitro Techniques
  • Interneurons / metabolism
  • Male
  • Motor Neurons / metabolism
  • Muscle Contraction
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / innervation*
  • Myenteric Plexus / chemistry
  • Myenteric Plexus / cytology
  • Myenteric Plexus / drug effects
  • Myenteric Plexus / metabolism*
  • Narcotic Antagonists
  • Neural Inhibition
  • Neurons, Afferent / metabolism
  • Nitrergic Neurons / metabolism
  • Opioid Peptides / metabolism*
  • Opioid Peptides / pharmacology
  • Peptide Fragments / pharmacology
  • Peristalsis* / drug effects
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Reaction Time
  • Receptors, Opioid / analysis
  • Receptors, Opioid / genetics
  • Receptors, Opioid / metabolism*
  • Reflex* / drug effects

Substances

  • Narcotic Antagonists
  • Opioid Peptides
  • Peptide Fragments
  • RNA, Messenger
  • Receptors, Opioid
  • nociceptin-(1-13)-NH2, NPhe(1)-
  • nociceptin
  • nociceptin receptor
  • Acetylcholine