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-AA1,2,4,5,12,13-[DTrp8]-somatostatin (ODT8-SST), like somatostatin, binds to all five somatostatin receptors (sst1–5). 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 μg 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 sst1 or sst4 agonists (1 μg per rat) had no effect. The 2 h food intake response during the light phase was blocked by icv injection of a sst2 antagonist, the neuropeptide Y (NPY) Y1 receptor antagonist, BIBP-3226, and ip injection of the μ-opioid receptor antagonist, naloxone, and not associated with changes in plasma ghrelin levels. ODT8-SST (1 μg 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 μ-opioid receptor-independent grooming behavior and hyperthermia, while ambulatory movements were not altered after ODT8-SST (1 μg per rat, icv). These data show that ODT8-SST acts primarily through brain sst2 receptors to induce a long-lasting orexigenic effect that involves the activation of Y1 and opiate-receptors, accompanied by enhanced gastric transit and energy expenditure suggesting a modulation of NPYergic and opioidergic orexigenic systems by brain sst2 receptors.