Intrathecal rapamycin attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain.
Intrathecal rapamycin attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain.
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DOI：
10.31480/2330-4871/027
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发表时间：
2015
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影响因子：
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通讯作者：
Ji-Tian Xu;Linlin Sun;B. Lutz;A. Bekker;Y. Tao
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作者：
Ji-Tian Xu;Linlin Sun;B. Lutz;A. Bekker;Y. Tao
在慢性疼痛患者中，重复和长期使用阿片类药物往往伴随着阿片类药物诱导的镇痛耐受和痛觉过敏的开始。我们以前的研究表明，鞘内反复注射吗啡激活了脊髓背角神经元中哺乳动物雷帕霉素复合体1靶分子(MTORC1)，阻断这一激活可以阻止吗啡诱导的健康大鼠耐受和痛敏的启动。然而，在神经病理性疼痛条件下，脊髓mTORC1是否是吗啡诱导的耐受和痛敏所必需的，仍然难以捉摸。我们观察了鞘内注射mTORC1特异性抑制剂雷帕霉素对吗啡诱导的耐受和痛觉过敏的影响。从SNL后第8天开始鞘内持续注射吗啡1周后，SNL大鼠对尾部热刺激的最大可能镇痛效应(MPAE)和对机械刺激的同侧缩足阈值(PWT)均明显降低。这种减少可通过联合输注雷帕霉素来减弱。联合注射雷帕霉素也可抑制吗啡耐受，表现为减弱吗啡诱导的假手术大鼠MPAE降低，以及吗啡诱导的痛敏反应，表现为逆转吗啡诱导的假手术大鼠双侧和对侧SNL大鼠的PWT降低。这些结果表明，mTORC1抑制剂可以作为阿片类药物的佐剂用于临床神经病理性疼痛的治疗。
Repeated and long-term administration of opioids is often accompanied by the initiation of opioid-induced analgesic tolerance and hyperalgesia in chronic pain patients. Our previous studies showed that repeated intrathecal morphine injection activated the mammalian target of rapamycin complex 1 (mTORC1) in spinal dorsal horn neurons and that blocking this activation prevented the initiation of morphine-induced tolerance and hyperalgesia in healthy rats. However, whether spinal mTORC1 is required for morphine-induced tolerance and hyperalgesia under neuropathic pain conditions remains elusive. We here observed the effect of intrathecal infusion of rapamycin, a specific mTORC1 inhibitor, on morphine-induced tolerance and hyperalgesia in a neuropathic pain model in rats induced by the fifth lumbar spinal nerve ligation (SNL). Continuous intrathecal infusion of morphine for one week starting on day 8 post-SNL led to morphine tolerance demonstrated by morphine-induced reduction in maximal possible analgesic effect (MPAE) to tail heat stimuli and ipsilateral paw withdrawal threshold (PWT) to mechanical stimuli in SNL rats. Such reduction was attenuated by co-infusion of rapamycin. Co-infusion of rapamycin also blocked morphine tolerance demonstrated by attenuation of morphine-induced reduction in MPAE in sham rats and morphine-induced hyperalgesia demonstrated by the reverse of morphine-induced reduction in PWT on both sides of sham rats and on the contralateral side of SNL rats. The results suggest that mTORC1 inhibitors could serve as promising medications for use as adjuvants with opioids in clinical neuropathic pain management.