Enhancement of opioid inhibition of GABAergic synaptic transmission by cyclo-oxygenase inhibitors in rat periaqueductal grey neurones.
Cyclo-oxygenase (COX) inhibitors potentiate opioid inhibition of GABAergic synaptic transmission in rat periaqueductal grey (PAG) (Vaughan et al., 1997). In the present study, the relative contribution of cyclo-oxygenase-1 (COX-1) and COX-2 inhibition to this phenomenon was examined by use of whole-cell patch clamp recordings in brain slices. The mu-receptor partial agonist morphine (10 microM) had little effect on GABAergic synaptic transmission. Morphine reduced the frequency of spontaneous miniature inhibitory postsynaptic currents (m.i.p.s.cs) by 13%. The nonselective COX inhibitor, indomethacin, produced a dose-dependent potentiation of the morpine inhibition of m.i.p.s.c. frequency (maximum inhibition 42%, IC50=6 nM). More selective COX-2 inhibitors produced a similar potentiation of the morphine inhibition of m.i.p.s.c. frequency; however, at greater concentrations (IC50=57 nM piroxicam, 1.7 microM DFU). Maintaining slices in the protein synthesis inhibitor cycloheximide (1 microM), to prevent COX-2 induction, had no effect on the potentiation action of DFU (10 microM). These results demonstrate that the potentiation of opioid inhibition of GABAergic synaptic transmission in PAG is largely a result of inhibition of COX-1 activity. These findings suggest that COX-1, rather than COX-2 inhibition, mediates the synergistic analgesic actions of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in the midbrain PAG.
Vaughan
C W
CW
Department of Pharmacology, The University of Sydney, NSW, Australia.
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010487:Periaqueductal Gray / Q000166:cytology* / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000701:Analgesics, Opioid; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009294:Narcotics; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat