Differential effects of divalent cations, cation chelators and an ionophore (A23187) on morphine and dibutyryl guanosine 3': 5'-cyclic monophosphate antinociception.

The effects of intraventricularly (i.c.v.) administered divalent cations, cation chelators and an ionophore (A23187) on antinociception produced by i.c.v. administration of morphine or dibutyryl guanosine 3':5'-cyclic monophosphate (db c-GMP) were quantitated in the mouse tail-flick procedure. Ca++ pretreatment produced a dose-related potentiation (> 10-fold) of db c-GMP and a dose-related antagonism (> 20-fold) of morphine antinociception. Mg++ pretreatment antagonized db c-GMP, whereas morphine antinociception was unaffected. Ba++ and Sr++ were observed to possess intrinsic antinociceptive activity. Administration of Ba++ or Sr++ had greater than additive effects on db c-GMP and morphine antinociception. EDTA pretreatment did not affect db c-GMP or morphine antinociception. Ethylene glycol bis(beta-aminoethyl ether)N,N-tetraacetic acid had no effect on db c-GMP but potentiated the morphine response. The ionophore A23187 had no effect on db c-GMP or morphine in the tail-flick test. However, A23187 potentiated the effect of high doses of Ca++ on db c-GMP and increased the antagonistic effect of a low dose of Ca++ on morphine antinociception. The results provide further evidence that the mechanism of db c-GMP antinociception is different from that of morphine.