Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
PLoS One. 2013 Aug 1;8(8):e71326. doi: 10.1371/journal.pone.0071326. Print 2013.
Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine's analgesic and side effects.
神经病理性疼痛（NP）是一种与创伤、代谢、自身免疫和神经病因相关的使人虚弱的病症。尽管 NP 的触发因素多种多样，但存在共同的潜在途径，包括脊髓中免疫细胞的激活和 N-甲基-D-天冬氨酸受体（NMDAR）的上调。氯胺酮，一种众所周知的 NMDAR 拮抗剂，以持续的方式减轻神经病理性疼痛。最近的研究表明，新型 11 个氨基酸肽促红细胞生成素衍生物 ARA290 产生类似的、持久的 NP 缓解作用。在这里，我们表明这两种药物对 NMDAR 的 mRNA 表达以及小胶质细胞、星形胶质细胞和趋化因子（C-C 基序）配体 2 的表达也有类似的影响，这些都是 NP 发展的重要贡献者。尽管氯胺酮和 ARA 290 对 NP 及其分子介质的作用表明它们具有共同的作用机制，但 ARA 290 对 NMDAR 没有亲和力，而是通过参与组织保护的先天修复受体（IRR）特异性作用。因此，我们推测 IRR 可能在氯胺酮治疗神经病理性疼痛中起关键作用。为了评估这一点，我们研究了氯胺酮和 ARA 290 在缺乏β-共同受体（βcR）的小鼠 spared 神经损伤模型中对急性疼痛、副作用和痛觉过敏的影响，βcR 是 IRR 的结构组成部分。氯胺酮（50mg/kg）和 ARA 290（30μg/kg）对急性疼痛产生了不同的影响：氯胺酮产生了深刻的镇痛作用，并伴有精神运动副作用，但 ARA290 在正常和敲除小鼠中均没有。相反，虽然两种药物在 WT 小鼠中均具有抗痛觉过敏作用，但在缺乏βcR 的小鼠中对 NP 没有作用。总之，这些结果表明，IRR 的完整对于氯胺酮或 ARA 290 有效治疗 NP 是必需的，但与氯胺酮的镇痛和副作用无关。
