Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea.
Exp Neurol. 2013 Sep;247:383-91. doi: 10.1016/j.expneurol.2013.01.004. Epub 2013 Jan 15.
The direct activation of the spinal sigma-1 receptor (Sig-1R) produces mechanical allodynia (MA) and thermal hyperalgesia (TH) in mice. In addition, the blockade of the spinal Sig-1R prevents the induction of MA, but not TH in chronic constriction injury (CCI)-induced neuropathic rats. The present study was designed to investigate whether the increase in spinal p38 MAPK phosphorylation (p-p38 MAPK) mediates Sig-1R-induced MA or TH in mice and the induction of MA in neuropathic rats. MA and TH were evaluated using von Frey filaments and a hot-plate apparatus, respectively. Neuropathic pain was produced by CCI of the right sciatic nerve in rats. Western blot assay and immunohistochemistry were performed to determine the changes of p-p38 MAPK expression in the spinal cord. Intrathecal (i.t.) injection of PRE084, a selective Sig-1R agonist, into naïve mice time-dependently increased the expression of p-p38 MAPK, which was blocked by pretreatment with BD1047, a Sig-1R antagonist. I.t. pretreatment with SB203580, a p38 MAPK inhibitor also dose-dependently inhibited PRE084-induced MA, whereas TH induction was not affected. In CCI rats, i.t. injection of BD1047 during the induction phase (postoperative days 0 to 5) reduced the CCI-induced increase in p-p38 MAPK. In addition, i.t. SB203580 treatment during the induction phase also suppressed the development of CCI-induced MA, but not TH. Conversely, i.t. SB203580 treatment during the maintenance phase (postoperative days 15 to 20) had no effect on CCI-induced MA or TH. These results demonstrate that the increase in spinal p-p38 MAPK is closely associated with the induction of Sig-1R mediated MA, but not TH. Sigma-1 receptor modulation of p-p38 MAPK also plays an important role in the induction, but not the maintenance, of MA in neuropathic pain.
直接激活脊髓 sigma-1 受体（Sig-1R）可在小鼠中产生机械性痛觉过敏（MA）和热痛觉过敏（TH）。此外，脊髓 Sig-1R 阻断可防止慢性缩窄性损伤（CCI）诱导的神经病理性大鼠 MA 的诱导，但不能防止 TH 的诱导。本研究旨在探讨脊髓 p38 MAPK 磷酸化（p-p38 MAPK）的增加是否介导 Sig-1R 诱导的小鼠 MA 或 TH 以及神经病理性大鼠 MA 的诱导。使用 von Frey 纤维和热板仪分别评估 MA 和 TH。通过对大鼠右侧坐骨神经进行 CCI 产生神经病理性疼痛。进行 Western blot 检测和免疫组织化学分析以确定脊髓中 p-p38 MAPK 表达的变化。将选择性 Sig-1R 激动剂 PRE084 鞘内（i.t.）注射到未处理的小鼠中，可使 p-p38 MAPK 的表达呈时间依赖性增加，该增加可被 Sig-1R 拮抗剂 BD1047 预处理所阻断。p38 MAPK 抑制剂 SB203580 的 i.t. 预处理也呈剂量依赖性地抑制 PRE084 诱导的 MA，而对 TH 诱导没有影响。在 CCI 大鼠中，在诱导阶段（术后第 0 至 5 天）将 BD1047 鞘内注射可减少 CCI 诱导的 p-p38 MAPK 增加。此外，在诱导阶段进行 i.t. SB203580 治疗也可抑制 CCI 诱导的 MA 的发展，但不能抑制 TH。相反，在维持阶段（术后第 15 至 20 天）进行 i.t. SB203580 治疗对 CCI 诱导的 MA 或 TH 没有影响。这些结果表明，脊髓中 p-p38 MAPK 的增加与 Sig-1R 介导的 MA 的诱导密切相关，但与 TH 无关。Sigma-1 受体对 p-p38 MAPK 的调节在神经病理性疼痛中 MA 的诱导中起重要作用，但在维持中不起作用。
