Intrathecal Injection of the σ1 Receptor Antagonist BD1047 Blocks Both Mechanical Allodynia and Increases in Spinal NR1 Expression during the Induction Phase of Rodent Neuropathic Pain
Intrathecal Injection of the σ1 Receptor Antagonist BD1047 Blocks Both Mechanical Allodynia and Increases in Spinal NR1 Expression during the Induction Phase of Rodent Neuropathic Pain
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DOI：
10.1097/aln.0b013e3181895a83
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发表时间：
2008-11-01
期刊：
影响因子：
8.8
通讯作者：
Lee, Jang-Hern
中科院分区：
文献类型：
--
作者：
Roh, Dae-Hyun;Kim, Hyun-Woo;Lee, Jang-Hern
背景选择性阻断脊髓受体（Sig-1 R）抑制小鼠福尔马林试验中的伤害性行为。本研究旨在验证鞘内注射Sig-1 R拮抗剂是否也能抑制慢性神经病理性pain.Methods：大鼠右侧坐骨神经慢性压迫性损伤（CCI）引起的神经病理性疼痛。从术后第0天至第5天（神经性疼痛的诱导期）或第15天至第20天（维持期）鞘内给予Sig-1 R拮抗剂BD 1047，每日两次。通过Western blot和免疫组化检测神经病理大鼠脊髓背角中Sig-1 R表达的变化，并检测BD 1047对N-甲基-D-天冬氨酸受体亚单位I表达和磷酸化的影响。术后第0-5天给予BD 1047可显著减轻CCI诱导的机械性异常性疼痛，但不能减轻热痛觉过敏，并且这种抑制被鞘内施用Sig-1 R激动剂PRE 084阻断。相比之下，在神经性疼痛的维持阶段进行BD 1047治疗对机械性异常性疼痛没有影响。CCI后1 ~ 3d，同侧脊髓背角的Sig-1 R表达显著增加。重要的是，在诱导期鞘内给予BD 1047（30 nmol），但不给予维持期，阻断了CCI诱导的N-甲基-D-天冬氨酸受体亚单位I表达和磷酸化的增加。这些结果表明，脊髓Sig-1 Rs在机械性异常性疼痛的诱导和脊髓N-甲基-D-乙酰基-D-乙酰基-门冬氨酸受体的CCI大鼠，并提出了一个潜在的治疗作用，使用Sig-1 R拮抗剂在神经性疼痛的临床管理。
Background Selective blockade of spinal receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain.Methods: Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-D-aspartate receptor subunit I expression and phosphorylation in spinal cord dorsal horn from neuropathic rats.Results: BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-D-aspartate receptor subunit I expression and phosphorylation.Conclusions: These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-D-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.