Cellular actions of opioids and other analgesics: Implications for synergism in pain relief

1. mu-Opioid receptor agonists mediate their central analgesic effects by a ctions on neurons within brain regions such as the mid-brain periaqueductal grey (PAG). Within the PAG, mu-opioid receptor-mediated analgesia results from inhibition of GABAergic influences on output projection neurons. We ha ve established that mu-opioid receptor activation in the PAG causes a presy naptic inhibition of GABA release that is mediated by activation of a volta ge-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidoni c acid. 2. At a cellular level, mu-opioid agonists have also been shown to open inw ardly rectifying K+ channels, close voltage-gated Ca2+ channels and presyna ptically inhibit glutamatergic synaptic transmission in the PAG. 3. The mu-opioid receptor-mediated presynaptic inhibition of GABAergic tran smission was abolished by phospholipase A(2) inhibitors and non-specific LO X and specific 12-LOX inhibitors. Cyclo-oxygenase (COX) and specific 5-LOX inhibitors did not reduce the inhibitory effects of mu-opioid agonists. 4. The opioid actions on GABAergic transmission were mimicked by arachidoni c acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of m u-opioids was enhanced synergistically by treatment of PAG neurons with inh ibitors of the other major enzymes responsible for arachidonic acid metabol ism, COX and 5-LOX. 5. These results explain a previously described analgesic action of COX inh ibitors in the central nervous system that was both independent of prostano id release and inhibited by opioid receptor antagonists and they also expla in the synergistic interaction of opioids with COX inhibitors. These findin gs also suggest new avenues for the development of centrally active analges ic agents involving combinations of lowered doses of opioids and specific 5 -LOX inhibitors.