Adrenergic mediation of the intestinal antisecretory action of opiates administered into the central nervous system

The antisecretory effects of the stable enkephalin analogs, [D-Ala²-Met⁵]enkephalinamide (DAMA) and [D-Ala²-D-Leu⁵]enkephalin, and the opiate drug morphine were evaluated on fluid secretion induced by cholera toxin in isolated loops of the jejunum and proximal and distal ileum in anesthetized rats. Intracerebroventricular administration of DAMA (0.03-3 μg) or [D-Ala²-D-Leu⁵] enkephalin (1.0-10 μg) dose-dependently reduced secretion in the jejunum without affecting fluid movement in the other small intestinal segments. Morphine in doses up to 30 μg i.c.v. had no significant antisecretory effects. Intravenous administration of DAMA, at doses up to 3000 μg/kg, had little effect on intestinal fluid accumulation. The antisecretory action of DAMA (3 μg i.c.v.) was completely blocked by pretreatment with the alpha adrenergic antagonist phentolamine and after peripheral sympathectomy induced by guanethidine. In contrast, DAMA activity was preserved in adrenal demedullated rats. DAMA had no significant effects upon mean arterial blood pressure or on blood acid-base balance. These results suggest that the antisecretory effects of opiates are, at least partly, mediated at sites within the central nervous system. These actions are probably a consequence of increased activity in sympathetic nerve fibers innervating the upper small intestine.