Submitted on February 7, 2003
Accepted on June 12, 2003
Physiological regulation and NO-dependent inhibition of migrating myoelectric complex in the rat small bowel by orexin A
M Ehrstrom1*, E Naslund1, J Ma2, A L Kirchgessner3, and P M Hellstrom4
1 Division of Surgery, Danderyd Hospital Karolinska Institutet, Stockholm, Sweden
2 Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
3 Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA; Neurology and GI CEED, GlaxoSmithKline, Harlow, United Kingdom
4 Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska Hosptial, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: Marcus.Ehrstrom{at}kids.ki.se.
Orexin-positive neurons are found in the lateral hypothalamic area and the enteric nervous system. The aim of this study was to investigate the mechanism of OXA action on small bowel motility. Electrodes were implanted in the serosa of the rat small intestine for recordings of myoelectric activity during infusion of saline or OXA in naive rats, vagotomized rats, rats pre-treated with guanethidine (3 mg kg-1) or N
-nitro-L-arginine (L-NNA; 1 mg kg-1). Naive rats were given a bolus of the orexin receptor-1 (OX1R) antagonist (SB-334867-A) (10 mg kg-1) and the effect of both OXA and SB-334867-A on fasting motility was studied. Double label immunocytochemistry with primary antibodies against OXA, nNOS, OX1R was performed. OXA induced a dose-dependent prolongation of the cycle length of the migrating myoelectric complex (MMC) and in the higher doses replaced the activity fronts with an irregular spiking pattern. Vagotomy or pre-treatment with guanethidine failed to prevent the response to OXA. The OXA-induced effect on the MMC cycle length was completely inhibited by pre-treatment with L-NNA (p<0.05), as did SB-334867-A. The OX1R antagonist shortened the MMC cycle length from 14.1 (12.0-23.5) to 11.0 (9.5-14.7) min (p<0.05) during control and treatment periods, respectively. Co-localization of OXA and nNOS was observed in myenteric neurons of the duodenum and nerve fibers in the circular muscle. Our results indicate that OXA inhibition of the MMC involves the OX1R and that activation of a L-arginine/nitric oxide pathway possibly originating from OX1R/nNOS-containing neurons in the myenteric plexus may mediate this effect. Endogenous OXA may have a physiological role in regulating the MMC.
