ENHANCEMENT OF OPIOID INHIBITION OF GABAERGIC SYNAPTIC TRANSMISSION BY CYCLOOXYGENASE INHIBITORS IN RAT PERIAQUEDUCTAL GREY NEURONS

Cyclo-oxygenase (COX) inhibitors potentiate opioid inhibition of GABAe rgic synaptic transmission in rat periaqueductal grey (PAG) (Vaughan e t al., 1997). In the present study, the relative contribution of cyclo -oxygenase-1 (COX-1) and COX-2 inhibition to this phenomenon was exami ned by use of whole-cell patch clamp recordings in brain slices. The m u-receptor partial agonist morphine (10 mu M) had little effect on GAB Aergic synaptic transmission. Morphine reduced the frequency of sponta neous miniature inhibitory postsynaptic currents (m.i.p.s.cs) by 13%. The nonselective COX inhibitor, indomethacin, produced a dose-dependen t potentiation of the morphine inhibition of m.i.p.s.c. frequency (max imum inhibition 42%, IC50=6 nM). More selective COX-2 inhibitors produ ced a similar potentiation of the morphine inhibition of m.i.p.s.c. fr equency; however, at greater concentrations (IC50 = 57 nM piroxicam, 1 .7 mu M DFU). Maintaining slices in the protein synthesis inhibitor cy cloheximide (1 mu M), to prevent COX-2 induction, had no effect on the potentiation action of DFU (10 mu M). These results demonstrate that the potentiation of opioid inhibition of GABAergic synaptic transmissi on in FAG is largely a result of inhibition of COX-1 activity. These f indings suggest that COX-1, rather than COX-2 inhibition, mediates the synergistic analgesic actions of opioids and non-steroidal anti-infla mmatory drugs (NSAIDs) in the midbrain FAG.