Cellular actions of opioids and other analgesics: Implications for synergism in pain relief
Cellular actions of opioids and other analgesics: Implications for synergism in pain relief
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DOI：
10.1046/j.1440-1681.2000.03291.x
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发表时间：
2000-07-01
影响因子：
2.9
通讯作者：
Bagley, EE
中科院分区：
文献类型：
--
作者：
Christie, MJ;Connor, M;Bagley, EE
1.μ-阿片样物质受体激动剂通过作用于脑区域如中脑导水管周围灰质（PAG）内的神经元来介导其中枢镇痛作用。在PAG内，μ-阿片受体介导的镇痛作用是由于抑制GABA能对输出投射神经元的影响。我们已经确定PAG中的μ阿片受体激活引起GABA释放的突触前抑制，其通过花生四烯酸的12-脂氧合酶（LOX）代谢物激活电压依赖性K+通道介导。在细胞水平上，μ-阿片激动剂还显示打开内向整流K+通道，关闭电压门控Ca 2+通道，并在突触前抑制PAG中的突触能突触传递。μ阿片受体介导的GABA能传递突触前抑制可被磷脂酶A（2）抑制剂和非特异性LOX及特异性12-LOX抑制剂所消除。环氧合酶（考克斯）和特异性5-LOX抑制剂不能降低μ阿片激动剂的抑制作用.阿片对GABA能传递的作用被花生四烯酸和12-LOX代谢物所模拟，而不是5-LOX代谢物。通过用负责花生四烯酸代谢的其他主要酶考克斯和5-LOX的抑制剂处理PAG神经元，μ-阿片类药物的功效协同增强。这些结果解释了先前描述的考克斯抑制剂在中枢神经系统中的镇痛作用，其既独立于前列腺素释放又被阿片受体拮抗剂抑制，并且它们还解释了阿片类药物与考克斯抑制剂的协同相互作用。这些发现也为开发中枢活性镇痛剂提供了新的途径，这些镇痛剂涉及降低剂量的阿片类药物和特异性5-LOX抑制剂的组合。
1. mu-Opioid receptor agonists mediate their central analgesic effects by actions 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 have established that mu-opioid receptor activation in the PAG causes a presynaptic inhibition of GABA release that is mediated by activation of a voltage-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidonic acid.2. At a cellular level, mu-opioid agonists have also been shown to open inwardly rectifying K+ channels, close voltage-gated Ca2+ channels and presynaptically inhibit glutamatergic synaptic transmission in the PAG.3. The mu-opioid receptor-mediated presynaptic inhibition of GABAergic transmission was abolished by phospholipase A(2) inhibitors and non-specific LOX 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 arachidonic acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of mu-opioids was enhanced synergistically by treatment of PAG neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism, COX and 5-LOX.5. These results explain a previously described analgesic action of COX inhibitors in the central nervous system that was both independent of prostanoid release and inhibited by opioid receptor antagonists and they also explain the synergistic interaction of opioids with COX inhibitors. These findings also suggest new avenues for the development of centrally active analgesic agents involving combinations of lowered doses of opioids and specific 5-LOX inhibitors.