Effects of Morphine, Clonidine and Papaverine on Synaptosomal ⁴⁵Ca Uptake and Antinociceptive Action in Rats

Abstract

We studied the relationship between the inhibition of extracellular ⁴⁵Ca²⁺ uptake into synaptosomes and the antinociceptive action induced by morphine, clonidine and papaverine in rats. The antinociceptive action induced by clonidine was as potent as that by morphine, but that by papaverine was less potent than those by morphine and clonidine. Antinociceptive action by morphine was considerably potentiated by the simultaneous administration of clonidine. However, the antinociceptive actions induced by morphine and clonidine were found to be mediated through different receptor mechanisms. Although the pretreatment by papaverine blocked the morphine-induced antinociception, the inhibition induced by papaverine was not found to be mediated through the opiate receptor because papaverine did not displace [³H]-dihydromorphine binding to the membrane fraction from rat brain. Papaverine also inhibited the antinociceptive action induced by clonidine. Morphine inhibited the veratrine-stimulated synaptosomal ⁴⁵Ca²⁺ uptake by a naloxone-reversible process. Papaverine also strongly inhibited the veratrine-stimulated synaptosomal ⁴⁵Ca²⁺ uptake, while clonidine had virtually no effect. The inhibition of synaptosomal ⁴⁵Ca²⁺ uptake induced by morphine was not increased by simultaneous addition of clonidine. The strong inhibitions of synaptosomal ⁴⁵Ca²⁺ uptake were still observed by simultaneous addition of papaverine with morphine and clonidine. These results suggest that it is difficult to account for the drugs-induced antinociception by the inhibition of extracellular Ca²⁺ uptake into the synaptosomes only because papaverine inhibits the manifestation of the antiociceptive actions induced by morphine and clonidine mediated through mechanisms other than the inhibition of extracellular ⁴⁵Ca²⁺ uptake into the synaptosomes.