Nociceptin effect on intestinal motility depends on opioid-receptor like-1 receptors and nitric oxide synthase co-localization

Abstract

Author contributions: Sibaev A, Fichna J, Saur D, Yuece B, Timmermans JP and Storr M contributed to study concept and design; Sibaev A, Fichna J, Saur D and Timmermans JP contributed to acquisition of data; all authors contributed to analysis and interpretation of data; Storr M contributed to drafting of the manuscript; all authors contributed to critical revision of the manuscript for important intellectual content; Sibaev A and Fichna J contributed to statistical analysis; Timmermans JP and Storr M contributed to study supervision. Nociceptin effect on intestinal motility depends on opioidreceptor like-1 receptors and nitric oxide synthase colocalization Basic StudyORIGINAL ARTICLE myenteric neurotransmission and motility. METHODS:Reverse transcriptase -polymerase chain reaction and immunohistochemistry were used to localize nociceptin and ORL1 in mouse tissues. Intracellular electrophysiological recordings of excitatory and inhibitory junction potentials (EJP, IJP) were made in a chambered organ bath. Intestinal motility was measured in vivo . RESULTS:Nociceptin accelerated whole and upper GI transit, but slowed colonic expulsion in vivo in an ORL1-dependent manner, as shown using [Nphe 1 ]NOC and AS ODN pretreatment. ORL1 and nociceptin immunoreactivity were found on enteric neurons. Nociceptin reduced the EJP and the nitric oxide-sensitive slow IJP in an ORL1-dependent manner, whereas the fast IJP was unchanged. Nociceptin further reduced the spatial spreading of the EJP up to 2 cm. CONCLUSION:Compounds acting at ORL1 are good candidates for the future treatment of disorders associated with increased colonic transit, such as diarrhea or diarrhea-predominant irritable bowel syndrome. Core tip: Here we aimed to study the effect of the endogenous opioid-receptor like-1 (ORL1) agonist nociceptin on gastrointestinal (GI) myenteric neurotransmission and motility. We observed that nociceptin reduces excitatory and inhibitory neurotransmission in motorneurons and interneurons and the overall effect on the GI tract may depend on co-localization of ORL1 receptors with nitric oxide synthase. Since ORL1 activation, unlike other opioid receptor-active drugs, is not associated with central side effects, compounds acting at the ORL1 may be good candidates for the future treatment of disorders associated with increased colonic transit, such as diarrhea or diarrhea-predominant irritable bowel syndrome.

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