Modulation of the antinociceptive effect of morphine by casomorphin derivatives

Some D-amino acid-substituted derivatives of bovine beta-casomorphin1-5 (CM) were found to share a particular affinity to central opioid receptors. As far as the antinociceptive potency of CM derivatives and their ability to produce tolerance is concerned, possible interactions of two selected CMs (Tyr-Pro-Phe-D-Pro-Gly, D-Pro4 and Tyr-Pro-D-Phe-Pro-Gly, D-Phe3) with morphine and, moreover, the doses necessary to induce tolerance were studied. Antinociception was tested by using the hot-plate test in experiments with mice. It was found that both CMs injected in doses up to 1 mumol/kg were not able to produce any sign of antinociception. It is all the more so interesting since such non-antinociceptive doses of D-Phe3 decreased analgesia induced by 15 mumol/kg morphine significantly. This could be regarded as a consequence of delta-receptor occupation by D-Phe3 and a resulting shift in the mu-receptor-mediated signal transduction. Finally, we found that repeated applications (once daily over a period of 20 days) induced a detectable tolerance to morphine. This suggests that opioid analgesia and tolerance must not be mediated by the same mechanisms and, moreover, that the mechanisms responsible for the development of tolerance are able to react more sensitive to an opioid.