In reply to “Is intrathecal lidocaine administration risk‐free in rats with neuropathic pain?”
In reply to “Is intrathecal lidocaine administration risk‐free in rats with neuropathic pain?”
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DOI：
10.1016/j.ejpain.2009.04.001
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发表时间：
2009-09
影响因子：
3.6
通讯作者：
Jie Tian;Yiwen Gu;D. Su;Xiangrui Wang
中科院分区：
文献类型：
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作者：
Jie Tian;Yiwen Gu;D. Su;Xiangrui Wang
与Umbrain博士等人的观点一致，利多卡因可能的神经毒性也是我们在报告中考虑和讨论的一个问题。我们根据神经功能和形态学结果进行评估，包括行走能力、感觉阈值（另一组正常大鼠）和组织病理学评估。我们完全同意Umbrain博士等人的观点，即更详细地探索局部神经毒性效应将是有趣和有益的，可能包括神经元线粒体功能，这将包括在我们未来的研究中。在此，我们要强调的是，我们从未打算暗示利多卡因治疗神经性疼痛是无风险的。如论文中所述，在应用利多卡因后，特别是高剂量利多卡因后，在大鼠中均观察到严重的呼吸抑制、低血压和神经毒性作用（Tian等人，2009年）。这种方法的临床应用应基于对风险-受益比的非常仔细的评估。根据我们在CCI大鼠中的发现，我们推荐15 mg/kg的利多卡因，其临床价值可能相当于人体中刚好达到引起全脊髓麻醉的剂量范围的剂量。在外推到临床实践之前，需要进一步的研究在其他神经病理性疼痛模型中探索这个问题。Dr. Umbrain等人提到，在他们的研究结果中，注射400或1000 μg利多卡因可增加脑脊液（CSF）中前列腺素E2（PGE 2）水平90-120分钟，沿着自由活动大鼠的短暂机械和热痛觉过敏。因此，他们得出结论，利多卡因诱导了脊髓致敏的暂时状态（Umbrain等人，2008年）。他们的研究与我们的研究之间的一个关键区别是，他们专注于它在正常身体中的作用，而我们的目的是研究它在神经性疼痛状态中的作用。在不同的生理状态下，一种药物对同一系统的作用可能会完全改变。事实上，Ma等人先前报道，在外周神经损伤后，利多卡因可以下调脊髓中的前列腺素（PG）系统（Ma等人，2003年）。最近，我们的小组发现利多卡因减少了神经病大鼠脊髓中小胶质细胞中p38丝裂原活化蛋白激酶（MAPK）的活化（Gu et al.，2008年）。已知小胶质细胞中的活性p38 MAPK在细胞因子（包括PGE 2）的脊髓释放中起关键作用（Ajmone-Cat等人，2003; Svensson等人，2003年）。因此，我们的研究结果也表明，利多卡因可能会降低神经病大鼠脊髓中的PGE 2水平。除了其在脊髓中过度活跃的小胶质细胞和PG系统中的作用外，电生理学检查还显示利多卡因在选择性神经根结扎后减少大鼠脊髓中自发和外周诱发的神经元活动（Chapman等人，1998年）。与这些机制研究一致，在动物以及临床患者中的许多行为研究清楚地表明，鞘内给予利多卡因确实可以减轻神经性疼痛（Yamashiro和Hirano，1987; Mao和Chen，2000; Yokoyama等人，2002; Ma等人，2003年）。在日本，有意的全脊髓麻醉是由卫生和福利部批准的疼痛缓解疗法（Yokoyama等人，2002年）。总之，这些报告以及我们的发现（Gu等人，2008年; Tian等人，2009）支持利多卡因有效缓解某些类型的神经性疼痛的假设，并表明潜在的机制可能是复杂的。但同样，这种方法应该只适用于那些受益于...
In concurrence with Dr. Umbrain et al., the possible neurotoxicity of it lidocaine was also an issue that we considered and discussed in our report. We assessed this based on neurofunctional and morphologic findings, including walking ability, sensory threshold (in another set of normal rats), and histopathologic evaluations. We completely agree with Dr. Umbrain et al. that it would be interesting and informative to explore the local neurotoxic effects in more detail, perhaps including neuronal mitochondrial functions, which will be included in our future studies. We want to emphasize here that we never intended to imply that it lidocaine therapy for neuropathic pain was risk-free. As mentioned in the paper, severe respiratory depression, hypotension, and neurotoxic effects were all observed in rats after application of it lidocaine, especially with high doses (Tian et al., 2009). Clinical use of this method should be based on very careful assessment of the risk-benefit ratio. We recommended 15 mg/kg it lidocaine based on our findings in CCI rats, the clinical value of which may correspond to a dose in human beings that just reaches the dose range causing total spinal anesthesia. Future studies are required to explore this issue in other neuropathic pain models before extrapolation to clinical practice. Dr. Umbrain et al. mentioned that in their findings, 400 or 1000 μg it lidocaine injection increased prostaglandin E2 (PGE2) levels in the cerebrospinal fluid (CSF) for 90–120 min, along with a transient period of mechanical and thermal hyperalgesia in free moving rats. They therefore concluded that it lidocaine induced a temporary state of spinal cord sensitization (Umbrain et al., 2008). One key difference between their study and ours is that they focused on the effects of it lidocaine in normal bodies, while our purpose was to investigate the role of it lidocaine in neuropathic pain states. The effects of a given drug on the same system might be entirely altered in different physiological states. Indeed, Ma et al. previously reported that it lidocaine could down-regulate prostaglandin (PG) systems in the spinal cord following peripheral nerve injury (Ma et al., 2003). Recently, our group found that it lidocaine reduced p38 mitogen-activated protein kinase (MAPK) activation in microglia in the spinal cord of neuropathic rats (Gu et al., 2008). Active p38 MAPK in the microglia is known to play a pivotal role in the spinal release of cytokines, including PGE2 (Ajmone-Cat et al., 2003; Svensson et al., 2003). Thus, our results also suggested that it lidocaine might reduce PGE2 levels in the spinal cord of neuropathic rats. In addition to its role in hyperactive microglia and the PG system in the spinal cord, it lidocaine has also been shown by electrophysiological examinations to reduce spontaneous and peripherallyevoked neuronal activity in the spinal cord of rats following selective nerve root ligation (Chapman et al., 1998). Consistent with these mechanistic studies, numerous behavioral studies in animals as well as in clinical patients clearly indicate that lidocaine given intrathecally can indeed reduce neuropathic pain (Yamashiro and Hirano, 1987; Mao and Chen, 2000; Yokoyama et al., 2002; Ma et al., 2003). In Japan, intentional total spinal anesthesia is a pain-relief therapy approved by the Ministry of Health and Welfare (Yokoyama et al., 2002). Taken together, these reports as well as our findings (Gu et al., 2008; Tian et al., 2009) support the hypothesis that it lidocaine is effective in relieving certain types of neuropathic pain, and indicate that the underlying mechanisms are likely to be complicated. But again, this method should only be an option for those patients where the benefits from …