Central injection of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks CRF- and stress-related alterations of gastric and colonic motor function.
The influence of central injection of a new corticotropin releasing factor (CRF) antagonist, astressin, [cyclo(30-33)[D-Phe12,Nle21,38,Glu30,Lys33]r/ hCRF12-41)], on exogenous and endogenous CRF-induced gastric ileus and stimulation of bowel discharges was investigated in conscious rats. Intracisternal (ic) CRF (0.6 microg) reduced gastric emptying of a noncaloric solution to 17.1 +/- 4.9% compared with 50.1 +/- 4.6% in control group injected i.c. with vehicle. Astressin (1,3 and 10 microg, i.c.) dose dependently prevented ic CRF-induced delayed gastric emptying by 33, 100 and 100%, respectively, and had no effect on basal gastric emptying. Abdominal surgery with cecal manipulation (1 min) reduced gastric emptying to 19.8 +/- 5.5% 3 hr postsurgery compared with 59.9 +/- 5.2% after anesthesia alone plus i.c. vehicle. Astressin (1,3 and 10 microg, i.c.) prevented postoperative gastric ileus by 56, 93 and 92%, respectively. Intracerebroventricular CRF (0.6 microg) and water-avoidance stress stimulated pellet output (number/60 min) to 5 +/- 1 and 11 +/- 2, respectively, compared with no fecal pellet output after i.c.v. vehicle and no exposure to stress. Astressin (3 and 10 microg, i.c.v.) blocked exogenous CRF action by 47 and 63%, respectively, and colonic response to stress by 0 and 54%, respectively. These data indicate that astressin injected into the CSF at low doses (1-10 microg) has an antagonistic action against CRF and stress-related alterations of gastrointestinal motor function, without an intrinsic effect in these in vivo systems. Astressin may be a useful tool to explore functional CRF-dependent physiological pathways in specific brain nuclei.
Martínez
V
V
CURE: Digestive Diseases Research Center, West Los Angeles VA Medical Center, California 90073, USA.
Rivier
J
J
Wang
L
L
Taché
Y
Y
D000818:Animals; D001362:Avoidance Learning; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological
D010446:Peptide Fragments; C104416:astressin; D003346:Corticotropin-Releasing Hormone