Comparative pharmacological profiles of morphine and oxycodone under a neuropathic pain-like state in mice: Evidence for less sensitivity to morphine
Comparative pharmacological profiles of morphine and oxycodone under a neuropathic pain-like state in mice: Evidence for less sensitivity to morphine
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DOI：
10.1038/sj.npp.1301471
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发表时间：
2008-04-01
影响因子：
7.6
通讯作者：
Suzuki, Tsutomu
中科院分区：
文献类型：
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作者：
Narita, Minoru;Nakamura, Atsushi;Suzuki, Tsutomu
本研究旨在探讨吗啡和羟考酮在神经性疼痛样状态下的药理作用。在m-阿片受体（MOR）结合研究和g蛋白激活研究中，我们证实吗啡和羟考酮均表现出MOR激动作用。坐骨神经结扎小鼠表现出明显的神经性疼痛样行为。在此条件下，经坐骨神经结扎后，皮下注射吗啡对小鼠的抗痛觉作用明显减弱，而经坐骨神经结扎后，皮下注射羟考酮对小鼠的抗痛觉作用明显增强。假手术与神经结扎术后脊髓及椎管上吗啡、羟考酮抗痛觉作用差异无统计学意义。此外，吗啡或羟考酮诱导的坐骨神经结扎小鼠脊髓、导水管周围灰质和丘脑中鸟苷-5′-o-（3-硫代）三磷酸（[S-35] GTP γ S）结合的增加与假手术小鼠相似。经坐骨神经结扎后，sc、鞘内或脑室内注射吗啡代谢物吗啡-6-葡糖苷（M-6-G）诱导的抗痛觉性明显降低。此外，M-6-G诱导的g蛋白活化增加在坐骨神经结扎中被消除。此外，吗啡或羟考酮诱导的奖赏效应在神经性疼痛样状态下被显著抑制。在坐骨神经结扎小鼠中脑下部，吗啡或羟考酮增加的[35 S] GTPgS结合量明显低于对照组。这些发现提供了进一步的证据，证明羟考酮在神经性疼痛样状态下具有深刻的抗伤害感受作用，而奖励作用较少。此外，在神经性疼痛样状态下，M-6-G诱导的g蛋白激活的降低可能（至少在一定程度上）有助于抑制吗啡产生的抗痛觉作用。
The present study was undertaken to investigate pharmacological actions induced by morphine and oxycodone under a neuropathic pain-like state. In the m-opioid receptor (MOR) binding study and G-protein activation, we confirmed that both morphine and oxycodone showed MOR agonistic activities. Mice with sciatic nerve ligation exhibited the marked neuropathic pain-like behavior. Under these conditions, antinociception induced by subcutaneously (s.c.) injected morphine was significantly decreased by sciatic nerve ligation, whereas s.c. injection of oxycodone produced a profound antinociception in sciatic nerve-ligated mice. There were no significant differences in spinal or supraspinal antinociception of morphine and oxycodone between sham operation and nerve ligation. Moreover, either morphine-or oxycodone-induced increase in guanosine-5'-o-(3-thio) triphosphate ([S-35] GTP gamma S) binding in the spinal cord, periaqueductal gray matter and thalamus in sciatic nerve-ligated mice was similar to that in sham-operated mice. Antinociception induced by s.c., intrathecal, or intracerebroventricular injection of the morphine metabolite morphine-6-glucuronide (M-6-G) was significantly decreased by sciatic nerve ligation. Furthermore, the increase in the G-protein activation induced by M-6-G was eliminated in sciatic nerve ligation. In addition, either morphine-or oxycodone-induced rewarding effect was dramatically suppressed under a neuropathic pain-like state. The increased [ 35 S] GTPgS binding by morphine or oxycodone was significantly lower in the lower midbrain of mice with sciatic nerve ligation compared with that in control mice. These findings provide further evidence that oxycodone shows a profound antinociceptive effect under a neuropathic pain-like state with less of a rewarding effect. Furthermore, the reduction in G-protein activation induced by M-6-G may, at least in part, contribute to the suppression of the antinociceptive effect produced by morphine under a neuropathic pain-like state.