Central Exogenous Neuropeptide‐S Ameliorates Stress‐induced Impaired Gastric Emptying through Orexin‐mediated Pathway in Rats

Abstract

Stress is widely believed to play a major role in developing functional gastrointestinal (GI) disorders. Acute restraint stress (ARS) stimulates corticotrophin releasing factor (CRF) in the amygdala and paraventricular nucleus (PVN) of the hypothalamus which in turn plays a dominant role to delay gastric emptying (GE) via peripheral autonomic neural pathways in rats. Neuropeptide‐S (NPS), composed of 20 amino acids, is the endogenous ligand for the NPS receptor (NPSR) which is highly conserved in vertebrates including human. Within central nervous system (CNS), the NPS‐producing neurons are found mainly in locus coeruleus (LC) and amygdala which is involved in coping with fear and stress. Activation of the hypothalamus by stress is likely to be mediated in part by amygdala, the key limbic structure involved in the stress‐induced effects on the GI functions. Furthermore, CRF has been shown to excite NPS neurons in LC through the CRF‐1 receptor. In rodents, centrally administered NPS has been shown to inhibit anxiety, stress behaviors and stress‐stimulated fecal output in the rats. Orexin‐A (OXA), a hypothalamic neuropeptide, regulates feeding activity, energy homeostasis and arousal. Orexin receptor type‐1 (OXR1) is highly expressed in the dorsal vagal motor nucleus and OXA was shown to stimulate postprandial gastric motor functions via central vagal pathways. On the other hand, it has been shown that centrally administered NPS activates orexin‐containing neurons in hypothalamus in rats suggesting that OXA may contribute to the NPS‐mediated alterations in gastric motor functions under stressed conditions. To perform neuropeptide microdialysis, a microdialysis probe with large pore membrane was unilaterally placed into the central amygdala and LC. Central administrations of the drugs were performed through an injection cannula stereotaxically placed in the right lateral ventricle. NPS concentrations in microdialysates were assayed using EIA method. Solid GE was measured following an overnight fasting. Compared to their basal levels, ARS significantly reduced the NPS concentrations both in LC (5564.8 ± 186.8 ng/ml vs 562.9 ± 86.8 ng/ml, p<0.01) and amygdala (5197.7 ± 217.1 ng/ml vs 91.8 ± 12.18 ng/ml, p<0.01). In control rats, GE was 61.2 ± 3.4%. ARS significantly delayed gastric emptying 24.4 ± 3.2%; whereas, central administration of NPS (8 nmol, icv) completely restored the delayed GE induced by ARS (62.5 ± 5.7%, p<0.01). Pretreatment of selective OXA antagonist SB‐334867 (40 μg, icv) significantly (p<0.05) abolished the NPS‐induced restoration of delayed GE (38.9 ± 2.7%, p<0.05). It is suggested that stress may alter NPS expression within CNS. Exogenous administration of NPS restores stress‐induced gastric dysmotility which was abolished by OXA antagonist, suggesting that the effect of NPS on stress‐induced gastric motility is partly OXA‐dependent. Central NPS may be a novel candidate for the treatment of stress‐induced gastric motility disorders.