HOW OPIOIDS INHIBIT GABA-MEDIATED NEUROTRANSMISSION

The midbrain region periaqueductal grey (FAG) is rich in opioid recept ors and endogenous opioids and is a major target of analgesic action i n the central nervous system(1). It has been proposed that the analges ic effect of opioids on the FAG works by suppressing the inhibitory in fluence of the neurotransmitter GABA (gamma-aminobutyric acid) on neur ons that form part of a descending antinociceptive pathway(2). Opioids inhibit GABA-mediated (GABAergic) synaptic transmission in the FAG an d other brain regions by reducing the probability of presynaptic neuro transmitter release(3,4), but the mechanisms involved remain uncertain . Here we report that opioid inhibition of GABAergic synaptic currents in the FAG is controlled by a presynaptic voltage-dependent potassium conductance, Opioid receptors of the mu type in GABAergic presynaptic terminals are specifically coupled to this potassium conductance by a pathway involving phospholipase A(2), arachidonic acid and 12-lipoxyg enase. Furthermore, opioid inhibition of GABAergic synaptic transmissi on is potentiated by inhibitors of the enzymes cyclooxygenase and 5-li poxygenase, presumably because more arachidonic acid is available for conversion to IZ-lipoxygenase products, These mechanisms account for t he analgesic action of cyclooxygenase inhibitors in the PAG(5) and the ir synergism with opioids(6).