Commentary: Brain calcium and morphine action.

Although it was shown as long ago as the late 1930s and early 1940s that a high calcium diet prevented or delayed the development of tolerance and dependence to morphine in guinea pigs and rats [6,7], no further studies on the effect of calcium on opiate action were reported until 1966. Intracisternal or subcutaneous administration of calcium prevented the analgesic effect of morphine and meperidine in mice and guinea pigs respectively [S, 91. However, the action of opiates in vim on calcium metabolism in the nervous system was not investigated until recently, except for one report which showed that nonpharm~cological doses of morphine caused a slight decrease in whole brain calcium levels [IO]. The acute administration of morphine produced a decrease of tissue calcium in discrete regions of rat brain [ll]. Moreover, this decrease was linear, dose dependent, time dependent and occurred to an equal degree in eight discrete regions of the brain. This morphine action was antagonized by naloxone and was stereospecific. Harris et a[. [I21 have demonstrated that prior administration of calcium (as well as magnesium or manganese) to mice prevented the analgesic effect of a single dose of morphine and also that calcium was a more effective antagonist in morphinetolerant mice than in nontolerant animals. These reports prompted us to examine the effect of chronic morphine on brain calcium levels and the antagonism of concurrent administration of calcium on the naloxone-induced abstinence syndrome in morphinedependent rats [13]. As in acute experiments, morphine decreased calcium levels in the brain of morphine-dependent animals. Concurrent administration of calcium not only prevented the lowering of calcium but significantly blocked the precipitated abstinence syndrome. Earlier, Kakunaga and Kaneto Cl43 had