Central apelin mediates stress - induced 1 gastrointestinal motor dysfunction in rats

34 35 Apelin, an endogenous ligand for APJ receptor, has been reported to be upregulated in 36 paraventricular nucleus (PVN) following stress. Central apelin is known to stimulate release 37 of corticotropin-releasing factor (CRF) via APJ receptor. We tested the hypothesis that stress38 induced gastrointestinal (GI) dysfunction is mediated by central apelin. We also assessed the 39 effect of exogenous apelin on GI motility under non-stressed (NS) conditions in conscious 40 rats. Prior to solid gastric emptying and colon transit measurements, APJ receptor antagonist 41 F13A was centrally (icv) administered under NS conditions and following AS (acute stress), 42 CHS (chronic homotypic stress) and CHeS (chronic heterotypic stress). Plasma corticosterone 43 was assayed. Strain gage transducers were implanted on serosal surfaces of antrum and distal 44 colon to record postprandial motility. Stress exposure induced coexpression of c-Fos and 45 apelin in hypothalamic PVN. Enhanced hypothalamic apelin and CRF levels in 46 microdialysates were detected following AS and CHeS which were negatively and positively 47 correlated with GE and CT, respectively. Central F13A administration abolished delayed GE 48 and accelerated CT induced by AS and CHeS. Central apelin-13 administration increased the 49 plasma corticosterone and inhibited GE and CT by attenuating antral and colonic contractions. 50 The inhibitory effect elicited by apelin-13 was abolished by central pretreatment of CRF 51 antagonist CRF9-41 in antrum, but not in distal colon. Central endogenous apelin mediates 52 stress-induced changes in gastric and colonic motor functions through APJ receptor. The 53 inhibitory effects of central exogenous apelin-13 on GI motility seem like partly CRF54 dependent. Apelin-13 inhibits colon motor functions through a CRF-independent pathway. 55