Central Injection of the Stable Somatostatin Analog ODT8-SST Induces a Somatostatin2 Receptor-Mediated Orexigenic Effect: Role of Neuropeptide Y and Opioid Signaling Pathways in Rats

Abstract

Somatostatin and octreotide injected into the brain have been reported to modulate food intake. However, little is known regarding the underlying mechanisms. The stable oligosomatostatin analog, des-AA 1,2,4,5,12, ]-somatostatin (ODT8-SST), like somatostatin, binds to all five somatostatin receptors (sst 1-5 ). We characterized the effects of ODT8-SST injected intracerebroventricularly (icv) on food consumption and related mechanisms of action in freely fed rats. ODT8-SST (0.3 and 1 g per rat, icv) injected during the light or dark phase induced an early onset (within 1 h) and long-lasting (4 h) increase in food intake in nonfasted rats. By contrast, ip injection (0.3-3 mg/kg) or icv injection of selective sst 1 or sst 4 agonists (1 g per rat) had no effect. The 2 h food intake response during the light phase was blocked by icv injection of a sst 2 antagonist, the neuropeptide Y (NPY) Y 1 receptor antagonist, BIBP-3226, and ip injection of the -opioid receptor antagonist, naloxone, and not associated with changes in plasma ghrelin levels. ODT8-SST (1 g per rat, icv) stimulated gastric emptying of a solid meal which was also blocked by naloxone. The increased food intake was accompanied by a sustained increase in respiratory quotient, energy expenditure, and drinking as well as -opioid receptor-independent grooming behavior and hyperthermia, while ambulatory movements were not altered after ODT8-SST (1 g per rat, icv). These data show that ODT8-SST acts primarily through brain sst 2 receptors to induce a long-lasting orexigenic effect that involves the activation of Y 1 and opiate-receptors, accompanied by enhanced gastric transit and energy expenditure suggesting a modulation of NPYergic and opioidergic orexigenic systems by brain sst 2 receptors. (Endocrinology 151: 4224 -4235, 2010)

CCK-8 and CCK-58 differ in their effects on nocturnal solid meal pattern in undisturbed rats

“…Rats had free access to food and water before and during the experiment. Behavior was assessed manually and simultaneously in 4 rats/investigator, as described in our previous studies (50,51,53). This method requires a time-sampling technique by two investigators, who performed all experiments.…”

“…This has been used in rats before (15,31,39,49) and was established recently for the use in mice (21,52). To investigate the specificity of the observed effects on feeding behavior, other behavioral parameters, such as grooming and locomotor activity, were assessed as established originally by Antin et al (1) and in our previous studies (50,53).…”

“…Therefore, behavioral analyses were performed as established in our previous studies (50,53). Both forms of CCK reduced food intake during the early dark phase due to a reduction in eating behavior (eating, as well as food approach, and sniffing the food).…”

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

“…Other investigations on the influence of brain CRF signaling pathways in the tail-pinch feeding response have led to contradictory results (21,46). By contrast, the possible involvement of interconnected brain orexigenic signalings namely those involving neuropeptide Y (NPY)/Y 1 receptors (49,54) or recently demonstrated somatostatin receptor 2 (sst 2 )/NPY 1 (57) have not been explored. With regard to the sst 2 , we recently showed that intracerebroventricular (icv) injection of a sst 2 agonist in satiated rats induces a rapid and robust food intake response through activation of NPY 1 receptors (57).…”

“…In the present study, we first investigated the molecular substrates and neurocircuits involved in the acute 5-min mild tail pinch-induced feeding response focusing on the orexigenic pathways, namely, the ghrelin-NPY-opioid circuit and sst 2 pathways (54,57,66). This was achieved using selective antagonists of NPY 1 , BIBP-3226 (38), and sst 2 receptor S-406-028 (9) injected intracerebroventricularly and the -opiate receptor antagonist naloxone along with the measurement of circulating ghrelin levels and blood glucose.…”