Changes in the rewarding effects induced by tramadol and its active metabolite M1 after sciatic nerve injury in mice
Changes in the rewarding effects induced by tramadol and its active metabolite M1 after sciatic nerve injury in mice
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DOI：
10.1007/s00213-008-1180-1
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发表时间：
2008-08
影响因子：
3.4
通讯作者：
A. Nakamura;M. Narita;K. Miyoshi;Keiko Shindo;Daiki Okutsu;Masami Suzuki;K. Higashiyama;Tsutomu Suzuki
中科院分区：
文献类型：
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作者：
A. Nakamura;M. Narita;K. Miyoshi;Keiko Shindo;Daiki Okutsu;Masami Suzuki;K. Higashiyama;Tsutomu Suzuki
本研究旨在探讨在神经病理性疼痛状态下曲马多及其活性代谢物O-脱甲基曲马多(M_1)的奖赏效应。结果在阿片受体结合和G蛋白激活中，我们证实M_1具有μ-阿片受体(MOR)激动剂活性，而不是曲马多。此外，我们还发现，皮下(S.C.)注射曲马多和M1在小鼠中均产生显著的位置偏爱，这种作用可被吗啡受体拮抗剂β-Funaltrexamine预先抑制。S.C.能显著提高小鼠伏隔核内的多巴胺水平。注射曲马多或M1。坐骨神经结扎的小鼠仅在同侧表现出对热刺激反应的爪子收缩潜伏期显著减少。在这些神经病理性疼痛的条件下，S.C.坐骨神经结扎后，曲马多或M1的注射均受到明显抑制。此外，坐骨神经结扎后，M1诱导的下中脑区G蛋白的激活受到抑制。讨论我们目前的数据支持曲马多的奖赏效应主要是通过MOR代谢到其活性代谢物M1。此外，坐骨神经结扎对M1诱导的下部中脑区G蛋白激活的抑制可能是抑制S.C.在神经病理性疼痛样状态下注射曲马多和M1。
IntroductionThe present study was designed to investigate the rewarding effects induced by tramadol and its active metaboliteO-desmethyltramadol (M1) under a neuropathic pain-like state.ResultsIn opioid receptor binding and G protein activation, we confirmed that M1, but not tramadol, showed μ-opioid receptor (MOR) agonistic activity. Furthermore, we found that the subcutaneous (s.c.) injection of tramadol and M1 each produced a significant place preference in mice, and these effects were significantly suppressed by pretreatment with the MOR antagonist β-funaltrexamine. The dopamine level in the mouse nucleus accumbens was significantly increased by s.c. injection of either tramadol or M1. Mice with sciatic nerve ligation exhibited a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under these neuropathic pain-like conditions, the rewarding effect induced by s.c. injection of either tramadol or M1 was dramatically inhibited after sciatic nerve ligation. Furthermore, the M1-induced G protein activation in the lower midbrain area was suppressed after sciatic nerve ligation.DiscussionOur present data support the notion that the rewarding effect induced by tramadol is mediated mainly through metabolism to its active metabolite M1 via MOR. Furthermore, the suppression of the M1-induced G protein activation in the lower midbrain area caused by sciatic nerve ligation may be responsible for inhibiting the rewarding effects induced by s.c. injection of tramadol and M1 under a neuropathic pain-like state.