Growth Hormone-Releasing Effect of an Enkephalin Analog in the Dog: Evidence for Cholinergic Mediation*

Abstract

The GH-releasing effect of a potent enkephalin analog, [d-Ala², MePhe⁴, Met(o)⁵-ol]enkephalin (DAMME) and its possible mechanism(s) of action were investigated in unanesthetized dogs. DAMME injected iv into 14 male and female beagles (34 tests) at doses of 2.0, 4.0, 8.0, and 16.0 μg/kg induced clear-cut and dose-related rises in canine GH (cGH) levels. Peak cGH levels occurred 15–30 min post injection and cGH levels were still elevated at 120–180 min. Prior administration of the opiate antagonist naloxone (0.5 mg/kg iv) completely suppressed the hormonal response to DAMME (8 μg/kg) without significantly altering baseline cGH levels. Blockade of serotonin receptors by metergoline (1 mg/kg, orally 60 min before) induced a slight increase in cGH levels but did not modify the GH-releasing effect of DAMME. Subchronic administration of pimozide (1 mg, orally three times daily for 2 days and 3.0 mg orally 120 min before), a blocker of dopamine receptors, significantly reduced the peak cGH rise induced by DAMME. Complete suppression of the GH-releasing effect of DAMME was induced by blockade of cholinergic muscarinic receptors by atropine (80 μg/kg, sc 30 min before) but not by butyl-scopolamine (0.5 mg/dog, iv 30 min before), an anticholinergic drug which does not cross the bloodbrain barrier. Pretreatment with eserine (0.5 mg/dog, iv 15 min before), a reversible inhibitor of cholinesterase, was unable to potentiate the GH-releasing effect of a threshold dose of DAMME but induced a rise in plasma cGH levels per se. These results indicate that enkephalins are potent GH releasers in the dog and that cholinergic mediation plays an essential role in this effect. (Endocrinology 106: 1239, 1980)