Central administration of pan-somatostatin agonist ODT8-SST prevents abdominal surgery-induced inhibition of circulating ghrelin, food intake and gastric emptying in rats

Abstract

Background Activation of brain somatostatin receptors (sst1-5) with the stable pan-sst1-5 somatostatin agonist, ODT8-SST blocks acute stress and central corticotropin-releasing factor (CRF)-mediated activation of endocrine adrenal sympathetic responses. Brain CRF signaling is involved in delaying gastric emptying (GE) immediately post surgery. We investigated whether activation of brain sst signaling pathways modulates surgical stress-induced inhibition of gastric emptying and food intake. Methods Fasted rats were injected intracisternally (i.c.) with somatostatin agonists and underwent laparotomy and 1-min cecal palpation. GE of a non-nutrient solution and circulating acyl and desacyl ghrelin levels were assessed 50 min post surgery. Food intake was monitored for 24h. Key results The abdominal surgery-induced inhibition of GE (65%), food intake (73% at 2h) and plasma acyl ghrelin levels (67%) was completely prevented by ODT8-SST (1μg/rat, i.c.). The selective sst5 agonist, BIM-23052 prevented surgery-induced delayed GE, whereas selective sst1, sst2 or sst4 agonists had no effect. However, the selective sst2 agonist, S-346-011 (1μg/rat, i.c.) counteracted the abdominal surgery-induced inhibition of acyl ghrelin and food intake but not the delayed GE. The ghrelin receptor antagonist, [D-Lys3]-GHRP-6 (0.93 mg/kg, intraperitoneal, i.p.) blocked i.p. ghrelin-induced increased GE, while not influencing i.c. ODT8-SST-induced prevention of delayed GE and reduced food intake after surgery. Conclusions & Inferences ODT8-SST acts in the brain to prevent surgery-induced delayed GE likely via activating sst5. ODT8-SST and the sst2 agonist prevent the abdominal surgery-induced decrease in food intake and plasma acyl ghrelin indicating dissociation between brain somatostatin signaling involved in preventing surgery-induced suppression of GE and feeding response.

Brain peptides and the modulation of postoperative gastric ileus

“…However, the blockade of sst 2 signaling under conditions of abdominal surgery did not modulate the surgery-induced gastric ileus [29]. This observation is in line with a study showing that brain activation of sst 2 signaling does not alter the surgery-induced delay of gastric emptying, whereas the inhibition of food intake was restored [59]. This was associated with a restoration of circulating ghrelin levels to physiological concentrations observed under conditions of fasting [59] giving rise to a dissociation of ghrelin’s orexigenic and prokinetic actions under conditions of abdominal surgery when modulated by sst 2 signaling (Table 1).…”

Orexigenic response to tail pinch: role of brain NPY1 and corticotropin releasing factor receptors

“…Procedures for implanting the guide cannula into the right lateral cerebroventricle, intracerebroventricular injections of 10 l and assessment of correct guide cannula placement were as detailed previously (55). Stereotaxic coordinates were based on Paxinos and Watson's brain atlas (41).…”

“…For instance, we previously reported that acute intraperitoneal (ip) injection of the immune stressor lipopolysaccharide at a low dose (100 g/kg) reduced the food intake response to a fast in rats (7). Similarly, a visceral stressor (abdominal surgery) or psychological stressors (restraint or novel environment) reduced the refeeding response to an overnight fast in rats (8,45,55). The underlying mechanisms of acute stress-related reduction of food intake are largely linked to the activation of corticotropin releasing factor (CRF) signaling pathways.…”

Brain somatostatin receptor 2 mediates the dipsogenic effect of central somatostatin and cortistatin in rats: role in drinking behavior

“…Water intake was measured at 10 and 60 min after the intracerebroventricular injection. The peptide doses were based on our previous studies on food intake with water in rats (55,57,58).…”

“…Intracerebroventricular cannulation and injection were performed as previously described (58). Rats were anesthetized by an intramuscular injection of ketamine hydrochloride (75 mg/kg im, Ketanest; Fort Dodge Laboratories, Fort Dodge, IA) and xylazine (5 mg/kg im, Rompun; Mobay, Shawnee, KS).…”