Differential involvement of calcium in acute and chronic opioid action in the guinea-pig ileum in vitro.

The role of calcium in acute and chronic opioid action was studied by measuring the inhibitory response of electrically stimulated (0.1 Hz) myenteric plexus-longitudinal muscle strips of guinea-pig ileum in vitro subsequent to a test dose of morphine or to high frequency stimulation (10 Hz for 1 min) in the presence of graded concentrations of calcium in the buffer surrounding the strips. The inhibitory response induced by both procedures was enhanced in low calcium and diminished in high calcium medium. After the inhibitory response was established, an increase of the exogenous calcium concentration completely antagonized the inhibition. Additional experiments, in which the magnesium content of the medium was varied or the calcium-chelator [ethylenebis(oxyethylenenitrilo)tetraacetate] was used, pointed to an important role of endogenous calcium in the action of morphine and of opioid material released by high frequency stimulation. The degree of tolerance induced in vitro by incubating strips with morphine for 20 hr was not affected by omitting calcium in the incubation medium. It is suggested that endogenous calcium plays a modulatory role in processes which are intermediary between opioid receptor activation and the subsequent effect on neurotransmission (i.e., acetylcholine in the guinea-pig ileum). In contrast to the acute action of opioids, calcium seems to be less important for the development of tolerance in vitro.