ORL-1 receptor mediates the action of nociceptin on ascending myenteric reflex pathways in rats.
OBJECTIVE
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.
Department of Internal Medicine II, Ludwig Maximilians University Munich, Munich, Germany.
Birol
B
Yüce
Andrei
A
Sibaev
Andreas
A
Haaken
Dieter
D
Saur
Hans-Dieter
HD
Allescher
Burkhard
B
Göke
Jean-Pierre
JP
Timmermans
Martin
M
Storr
D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000294:innervation*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D007082:Ileum / Q000187:drug effects / Q000294:innervation*; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000378:metabolism; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation*; D009197:Myenteric Plexus / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009292:Narcotic Antagonists; D009433:Neural Inhibition; D009475:Neurons, Afferent / Q000378:metabolism; D026602:Nitrergic Neurons / Q000378:metabolism; D018847:Opioid Peptides / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010528:Peristalsis / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D011957:Receptors, Opioid / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000109:Acetylcholine; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C403776:nociceptin-(1-13)-NH2, NPhe(1)-; C000722285:Oprl1 protein, rat