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.
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(1,2,4,5,12,13)-[DTrp(8)]-somatostatin (ODT8-SST), like somatostatin, binds to all five somatostatin receptors (sst(1-5)). We characterized the effects of ODT8-SST injected intracerebroventricularly (i.c.v.) on food consumption and related mechanisms of action in freely fed rats. ODT8-SST (0.3 and 1 microg per rat, i.c.v.) 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, i.p. injection (0.3-3 mg/kg) or i.c.v. injection of selective sst(1) or sst(4) agonists (1 microg per rat) had no effect. The 2 h food intake response during the light phase was blocked by i.c.v. injection of a sst(2) antagonist, the neuropeptide Y (NPY) Y(1) receptor antagonist, BIBP-3226, and ip injection of the mu-opioid receptor antagonist, naloxone, and not associated with changes in plasma ghrelin levels. ODT8-SST (1 microg per rat, i.c.v.) 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 mu-opioid receptor-independent grooming behavior and hyperthermia, while ambulatory movements were not altered after ODT8-SST (1 microg per rat, i.c.v.). 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.
Stengel
Andreas
A
Department of Medicine, Center for Ulcer Research and Education, Digestive Diseases Division, University of California Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
Coskun
Tamer
T
Goebel
Miriam
M
Wang
Lixin
L
Craft
Libbey
L
Alsina-Fernandez
Jorge
J
Rivier
Jean
J
Taché
Yvette
Y
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D006120:Grooming / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000502:physiology; D017481:Receptors, Somatostatin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D014151:Anti-Anxiety Agents; C092926:BIBP 3226; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; D009270:Naloxone; D013004:Somatostatin; C017583:somatostatin, octapeptide-Trp(8)-; D001120:Arginine