Opioids, NSAIDs and 5-lipoxygenase inhibitors act synergistically in brainvia arachidonic acid metabolism

We have established that mu-opioid receptor activation causes a presynaptic inhibition of neurotransmitter release that is mediated by 12-lipoxygenase metabolites of arachidonic acid in midbrain neurons [1]. We further demons trated that the efficacy of opioids was enhanced synergistically by treatme nt of brain neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism; cyclooxygenase (COX-1) and 5-lipoxygenase. These findings explain a mechanism of analgesic action of NSAIDs in the ce ntral nervous system that is both independent of prostanoid release and inh ibited by opioid antagonists, as well as the synergistic interaction of opi oids with NSAIDs. These findings also suggest new avenues for development o f centrally active medications involving combinations of lowered doses of o pioids and specific 5-lipoxygenase inhibitors.