The significance of mu- and delta-receptors in rat pancreatic islets for the opioid-mediated insulin release.
The binding and the insulinotropic effects of enkephalin analogs and of morphine were investigated in rat pancreatic islets. Binding of [3H]Met-enkephalin was saturable, specific and reversible; the rank order for inhibition competition of [3H]Met-enkephalin binding by various compounds was Met-enkephalin = D-Ala2-MePhe4, Met(0)ol enkephalin) greater than Leu-enkephalin greater than morphine with half-maximal inhibitory constants (IC50) of approx. 0.3, 0.3, 100 and greater than 100 nM, respectively. Both the natural enkephalins exerted their insulinotropic effect only at stimulatory glucose concentrations. They had a dual action; whereas insulin secretion was increased at low enkephalin concentration, this effect was reversed at higher concentrations. However, the various enkephalins exerted this effect at different concentrations; only the EC50 values (half-maximal effective concentrations) of their insulinotropic effect were in the same range as the IC50 values of inhibition of [3H]met-enkephalin binding. Cysteamine pretreatment of rats (depletion of somatostatin containing D-cells and decrease in somatostatin secretion) did not change the Met-enkephalin effect on insulin secretion. In contrast to Met-enkephalin, binding of [3H]morphine to islets was not saturable, and morphine had no effect on insulin secretion unless at unphysiologically high concentrations. The data, therefore, indicate that: mu-receptors (affinity for morphine) do not play a role in rat pancreatic islets; delta-receptors (binding site for Met-enkephalin when mu-receptors are not present) mediate the insulinotropic effect of low Met-enkephalin concentrations; and the insulinotropic action of Met-enkephalin is not mediated indirectly via the paracrine effect of an inhibition of somatostatin secretion.
D000818:Animals; D003543:Cysteamine / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013004:Somatostatin / Q000378:metabolism
D007328:Insulin; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013004:Somatostatin; D004744:Enkephalin, Methionine; D003543:Cysteamine; D009020:Morphine; D005947:Glucose