Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain
Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain
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DOI：
10.1124/jpet.103.060582
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发表时间：
2004-04-01
影响因子：
3.5
通讯作者：
Ueda, H
中科院分区：
文献类型：
--
作者：
Rashid, MH;Inoue, M;Ueda, H
众所周知，在神经病理性疼痛中，吗啡的止痛效力会降低。在这项研究中，我们证明了全身吗啡对神经病理性疼痛的有效性降低可能是由于外周失去吗啡止痛作用所致。当给定S.C.时在Hargreaves热实验中，与假手术对照组相比，部分坐骨神经损伤小鼠的吗啡镇痛量效曲线右移。静脉注射的剂量-反应曲线。然而，在神经损伤的小鼠中，吗啡的止痛作用没有变化，表明脊髓上水平的吗啡效力没有降低。另一方面，足底内(i.pl.)假手术小鼠的吗啡在神经损伤小鼠中几乎完全消失。用更灵敏的致敏性痛觉屈曲实验，观察到全身吗啡对神经损伤小鼠缓激肽(BK)伤害性痛觉的镇痛作用显著降低，并观察到i.pl的镇痛作用。吗啡对假手术小鼠BK伤害性感受的抑制作用在神经损伤小鼠中消失。免疫组织化学实验发现，在正常状态下，mU-阿片受体主要表达于小直径无髓背根神经节(DRG)神经元，并与缓激肽B2受体共存。当我们检测神经损伤小鼠背根神经节中MOP的表达时，我们观察到MOP的表达急剧下降。综上所述，这些数据表明，全身吗啡对神经病理性疼痛的效力降低可能至少部分是由于背根节内MOP表达的减少以及随后在这种情况下外周吗啡镇痛的丧失所致。
It is well known that the analgesic potency of morphine is reduced in neuropathic pain. In this study, we demonstrate that the decreased effectiveness of systemic morphine in neuropathic pain might be caused by the loss of morphine analgesia at the periphery. When given s.c. or i.t., the dose-response curves for morphine analgesia in Hargreaves thermal test were shifted rightward in partial sciatic nerve-injured mice compared with control sham-operated mice. The dose-response curves for i.c.v. morphine analgesia, however, were unchanged in nerve-injured mice, indicating no decrease in morphine potency at the supraspinal level. On the other hand, the dose-dependent analgesia produced by intraplantar (i.pl.) morphine in sham-operated mice almost completely disappeared in nerve-injured mice. With the more sensitive algogenic-induced nociceptive flexion test, significant reduction in the analgesic potency of systemic morphine was observed for bradykinin (BK) nociception in nerve-injured mice, and the analgesic effect of i.pl. morphine against BK nociception in sham-operated mice disappeared in nerve-injured mice. In immunohistochemical experiments, we found that, under normal state, mu-opioid receptors (MOPs) were mainly expressed in small-diameter unmyelinated dorsal root ganglion (DRG) neurons and colocalized with bradykinin B2 receptors. When we examined MOP expression in the DRG of nerve-injured mice, we observed a drastic decrease in MOP expression. Altogether, these data suggest that the lower potency of systemic morphine in neuropathic pain could be at least partly caused by the decreased MOP expression in DRG and subsequent loss of peripheral morphine analgesia in such a condition.