Mao Jianren, Price Donald D, Mayer David J
Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0516, USA.
Pain. 1995 Jun;61(3):353-364. doi: 10.1016/0304-3959(95)00022-K.
Recent evidence suggests that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, have in common certain neural substrates such as activation of the N-methyl-D-aspartate (NMDA) receptor and the subsequent intracellular activation of protein kinase C and nitric oxide. Should common cellular elements be involved in hyperalgesia and morphine tolerance, these cellular and intracellular commonalities might be expected to result in interactions between these two phenomena. Indeed, our previous studies have shown that thermal hyperalgesia develops when animals are made tolerant to the antinociceptive effects of morphine. In this study, we examined the hypothesis that reduction of morphine antinociception occurs following unilateral ligation of the rats's sciatic nerve, a procedure which produces symptoms of a neuropathic pain syndrome including thermal hyperalgesia. When tested using the paw-withdrawal test on day 8 (D8) after either nerve ligation or sham operation, a single intrathecal treatment with 10 micrograms morphine sulfate (30 min after administration) produced significant antinociception in sham-operated rats but not in nerve-injured ones. These results also were obtained when thermal hyperalgesia was reversed in nerve-injured rats by the non-competitive NMDA receptor antagonist MK-801. Consistently, 8 days after sciatic nerve ligation but not after a sham operation, an approximately 6-fold rightward shift occurred in the morphine antinociceptive dose-response curve. This rightward shift of the morphine antinociceptive dose-response curve did not occur at 24 h after either nerve ligation or sham operation. In addition, once daily treatment with 10 nmol MK-801 from D2 to D7 after nerve ligation prevented both the development of thermal hyperalgesia and the rightward shift of the morphine antinociceptive dose-response curve on D8. The results indicate that the antinociceptive effects of morphine are reduced in nerve-injured rats in the absence of daily exposure to morphine and that the NMDA receptor activation may have a critical role in mechanisms of this phenomenon. These data provide further evidence indicating that interactions do occur between neural mechanisms underlying thermal hyperalgesia and morphine tolerance.
最近的证据表明，痛觉过敏和吗啡耐受性这两种看似不相关的现象，具有某些共同的神经基质，如N-甲基-D-天冬氨酸（NMDA）受体的激活以及随后蛋白激酶C和一氧化氮的细胞内激活。如果痛觉过敏和吗啡耐受性涉及共同的细胞成分，那么这些细胞和细胞内的共性可能会导致这两种现象之间的相互作用。事实上，我们之前的研究表明，当动物对吗啡的镇痛作用产生耐受性时，热痛觉过敏就会出现。在本研究中，我们检验了这样一个假设：大鼠坐骨神经单侧结扎后，吗啡镇痛作用会减弱，该手术会产生包括热痛觉过敏在内的神经性疼痛综合征症状。在神经结扎或假手术后第8天（D8）使用爪部撤离试验进行测试时，鞘内单次注射10微克硫酸吗啡（给药后30分钟）在假手术大鼠中产生了显著的镇痛作用，但在神经损伤大鼠中则没有。当通过非竞争性NMDA受体拮抗剂MK-801逆转神经损伤大鼠的热痛觉过敏时，也得到了这些结果。同样，坐骨神经结扎后8天而非假手术后，吗啡镇痛剂量-反应曲线出现了约6倍的右移。在神经结扎或假手术后24小时，吗啡镇痛剂量-反应曲线并未出现这种右移。此外，在神经结扎后从D2到D7每天一次用10 nmol MK-801治疗，可防止热痛觉过敏的发展以及D8时吗啡镇痛剂量-反应曲线的右移。结果表明，在未每日接触吗啡的情况下，神经损伤大鼠中吗啡的镇痛作用减弱，并且NMDA受体激活可能在这一现象的机制中起关键作用。这些数据提供了进一步的证据，表明热痛觉过敏和吗啡耐受性的神经机制之间确实存在相互作用。
