Vaughan C W
Department of Pharmacology, The University of Sydney, NSW, Australia.
Br J Pharmacol. 1998 Apr;123(8):1479-81. doi: 10.1038/sj.bjp.0701818.
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.
环氧化酶（COX）抑制剂可增强阿片类药物对大鼠中脑导水管周围灰质（PAG）中γ-氨基丁酸能（GABAergic）突触传递的抑制作用（Vaughan等人，1997年）。在本研究中，通过在脑片上使用全细胞膜片钳记录来检测环氧化酶-1（COX-1）和COX-2抑制对此现象的相对贡献。μ-受体部分激动剂吗啡（10μM）对GABAergic突触传递几乎没有影响。吗啡使自发性微小抑制性突触后电流（m.i.p.s.cs）的频率降低了13%。非选择性COX抑制剂吲哚美辛产生了剂量依赖性的增强吗啡对m.i.p.s.c频率的抑制作用（最大抑制率42%，IC50 = 6 nM）。更具选择性的COX-2抑制剂对吗啡抑制m.i.p.s.c频率产生了类似的增强作用；然而，在更高浓度下（IC50 = 57 nM吡罗昔康，1.7μM DFU）。将脑片置于蛋白质合成抑制剂放线菌酮（1μM）中以防止COX-2诱导，对DFU（10μM）的增强作用没有影响。这些结果表明，阿片类药物对PAG中GABAergic突触传递抑制作用的增强主要是抑制COX-1活性的结果。这些发现表明，介导阿片类药物和非甾体抗炎药（NSAIDs）在中脑PAG中协同镇痛作用的是COX-1，而非COX-2的抑制。
