Morphine inhibits glutamate exocytosis from rat cerebral cortex nerve terminals (synaptosomes) by reducing Ca2+ influx

Morphine, a mu-opioid agonist, suppressed the Ca2+-dependent release of glutamate that was evoked by exposing cerebrocortical synaptosomes to the potassium channel blocker 4-aminopyridine. The presynaptic inhibition produced by morphine was concentration-dependent and blocked by the nonselective opioid receptor antagonist naloxone. As determined by examining the mechanism of mu-opioid receptor-mediated inhibition of glutamate release, morphine caused a significant reduction in 4-aminopyridine-evoked increase in the cytoplasmic free Ca2+ concentration ([Ca2+](c)), but failed to alter both 4-aminopyridine-evoked depolarization of the synaptosomal plasma membrane potential and Ca2+ ionophore (ionomycin)-induced glutamate release. In addition, morphine was not capable of producing further inhibition on 4AP-evoked glutamate release in synaptosomes pretreated with the cannabinoid CB, receptor agonist WIN 55212-2, which has been shown to depress glutamate release through a suppression of presynaptic voltage-dependent Ca2+ channel activity. These data suggest that morphine exerts its inhibitory effect presynaptically, likely through the reduction of Ca2+ influx into nerve terminals, and thereby inhibits the release of glutamate in the cerebral cortex. This may therefore indicate that mu-opioid receptor agonists have neuroprotective properties, especially in the excessive glutamate release that occurs under certain pathological conditions. (C) 2003 Wiley-Liss, Inc.