Studies on the effect of orexin on upper gastrointestinal function in rats and man
2004
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.
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