Centrally Administered Neuropeptide-S Alleviates Gastrointestinal Dysmotility Induced by Neonatal Maternal Separation

Background Neuropeptide-S (NPS) regulates autonomic outflow, stress response, and gastrointestinal (GI) motor functions. This study aimed to investigate the effects of NPS on GI dysmotility induced by neonatal maternal separation (MS). Methods MS was conducted by isolating newborn pups from dams from postnatal day 1 to day 14. In adulthood, rats were also exposed to chronic homotypic stress (CHS). Visceral sensitivity was assessed by colorectal distension-induced abdominal contractions. Gastric emptying (GE) was measured following CHS, whereas fecal output was monitored daily. NPS or NPS receptor (NPSR) antagonist was centrally applied simultaneously with electrocardiography and gastric motility recording. Immunoreactivities for NPS, NPSR, corticotropin-releasing factor (CRF), choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), and c-Fos were assessed by immunohistochemistry. Key results NPS alleviated the MS-induced visceral hypersensitivity. Under basal conditions, central exogenous or endogenous NPS had no effect on GE and gastric motility. NPS restored CHS-induced gastric and colonic dysmotility in MS rats while increasing sympatho-vagal balance without affecting vagal outflow. NPSR expression was detected in CRF-producing cells of hypothalamic paraventricular nucleus, and central amygdala, but not in Barrington's nucleus. Moreover, NPSR was present in ChAT-expressing neurons in dorsal motor nucleus of the vagus (DMV), and nucleus ambiguus (NAmb) in addition to the TH-positive neurons in C1/A1, and locus coeruleus (LC). Neurons adjacent to the adrenergic cells in LC were found to produce NPS. NPS administration caused c-Fos expression in C1/A1 cells, while no immunoreactivity was detected in DMV or NAmb. Conclusions NPS/NPSR system might be a novel target for the treatment of stress-related GI dysmotility.