Studies on the effect of orexin on upper gastrointestinal function in rats and man

Aims: To define the morphological localisation of orexin A (OXA) in the gut, and study the effect of endogenous and peripherally administered OXA on fasting small bowel motility, gastric emptying and acid secretion, hormones involved in glucose homeostasis and pharmacokinetic profile of OXA in rats and humans.

Methods: The distribution of OXA, orexin receptors 1 and 2 (OX1 R, OX2R), neuronal nitric oxide synthase (nNOS) and various peptides were studied with immunocytochemistry in rat and human gut. In rats, the migrating myoelectric complex (MMC) was studied during intravenous (IV) infusion of OXA or the selective OX1 R-antagonist SB-334867-A. In separate sets of experiments, the rats were pretreated with vagotomy or the NOS-antagonist Nomeganitro-L-arginine (L-NNA). Gastric acid secretion and emptying of a 51Cr-labelled liquid nutrient or non-nutrient were studied in rats equipped with a gastric fistula and subjected to IV infusion of OXA or SB-334867-A. In humans, gastric emptying was studied of a 99mTclabelled omelette during IV infusion of OXA. Simultaneously, appetite ratings were measured using visual analogue scale (VAS) ratings. Plasma concentrations of OXA, leptin, insulin, glucagon, gastrin and glucose were analysed with radioimmunoassay (RIA).

Results: OXA- and OXRs-like immunoreactivity were found in nerve fibres and neurones in myenteric and submucosal ganglia, the circular muscle, the mucosa and endocrine cells in the stomach, duodenum and pancreas in both rats and humans. OXA was co-expressed with nNOS in myenteric neurons and circular muscle in rats and humans. IV OXA inhibited fasting small bowel motility in rats through OX1 R and nitric oxide (NO), independent of the vagus nerve. SB-334867-A inhibited gastric emptying and acid secretion independent of gastrin in rats. Gastric retention in humans increased during IV infusion of OXA without affecting appetite ratings. Plasma levels of leptin decreased and insulin increased in humans and OXA has a half-life in plasma of 27.1 min in rats.

Conclusions: Peripheral IV OXA affects upper gastrointestinal function in rats and humans. The activity of peripheral OXA may involve several pathways, including the central nervous system (CNS), intrinsic circuits of the enteric nervous system (ENS), vago-vagal reflexes or interactions with other gut hormones and NO. In humans, IV OXA affects hormones implicated in the regulation of glucose and energy homeostasis. The long half-life of OXA in plasma needs to be taken into account when interpreting results on metabolic and gut function after peripheral administration of OXA. Antagonists against OXRs may become a target in the treatment of obesity, diabetes and motility disorders of the gut.

List of scientific papers

I. Naslund E, Ehrstrom M, Ma J, Hellstrom PM, Kirchgessner AL (2002). "Localization and effects of orexin on fasting motility in the rat duodenum. " Am J Physiol Gastrointest Liver Physiol 282(3): G470-9
https://pubmed.ncbi.nlm.nih.gov/11841997

II. Ehrstrom M, Naslund E, Ma J, Kirchgessner AL, Hellstrom PM (2003). "Physiological regulation and NO-dependent inhibition of migrating myoelectric complex in the rat small bowel by OXA. " Am J Physiol Gastrointest Liver Physiol 285(4): G688-95. Epub 2003 Jun 19
https://pubmed.ncbi.nlm.nih.gov/12816759

III. Ehrstrom M, Naslund E, Levin F, Kaur R, Kirchgessner AL, Theodorsson E, Hellstrom PM (2004). "Pharmacokinetic profile of orexin A and effects on plasma insulin and glucagon in the rat. " Regul Pept 119(3): 209-12
https://pubmed.ncbi.nlm.nih.gov/15120482

IV. Ehrstrom M, Levin F, Kirchgessner AL, Schmidt PT, Hilsted LM, Gryback P, Jacobsson H, Hellstrom PM, Naslund E (2004). "Stimulatory effect of endogenous orexin A on gastric emptying and acid secretion independent of gastrin." (Manuscript)

V. Ehrstrom M, Gustafsson T, Kirchgessner AL, Gryback P, Jacobsson H, Hellstrom PM, Naslund E (2004). "Localization in the gut and effect of orexin A on gastric emptying, appetite and glucose metabolism in man." (Manuscript)