Central Actions of Thyrotrophin Releasing Hormone (TRH) Agonist, RX-77368 to Exert Analgesic Effect on Nociception Induced by Colorectal Distension and to Stimulate Colonic Propulsive Motor Function in Conscious Rat

Abstract

the effect of CCK and leptin interaction on intragastric pressure, suggesting CCK acts on low affinity CCKAR to enhance leptin action on gastric motility. CART is present in the nodose ganglia (NG). Immunostaining of NG obtained from fasting rats showed little or no CART immunoreactivities. A marked increase in CART staining in 19+3% of NG neurons was observed 30” following CCK8 (0.5 μg/kg) administration. 95+3% of this group of neurons contained both CCKAR and leptin receptor. The inhibitory action of leptin/CCK on gastric motility was abolished by electroporation of the NG with CART siRNA. We have previously demonstrated that the synergistic interaction between leptin and CCK in the NG involves cross talk between CCK/SRC cascades and the leptin/JAK/PI3K/STAT3. We showed that electroporation of the NG with siRNA of SRC or PI3 kinase or STAT3 but not MAPK reduced >80% of the inhibitory action of leptin/CCK on gastric motility. We conclude that CCK potentiates leptin's ability to evoke gastric relaxation. This is mediated by NG release of CART which acts via the vago-vagal pathway to evoke gastric relaxation. Leptin interacts with CCK via a CCK/SRC cascade and leptin/PI3K/STAT3 signaling pathway to stimulate increased CART transcription and its release. Hence acting in concert with CCK, leptin not only is an important mediator of satiety but also regulates the entry of nutrients into the intestine through its action on gastric motility.