Moon J Y, Roh D H, Yoon S Y, Choi S R, Kwon S G, Choi H S, Kang S Y, Han H J, Beitz A J, Oh S B, Lee J H
Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea.
Br J Pharmacol. 2014 Dec;171(24):5881-97. doi: 10.1111/bph.12893. Epub 2014 Nov 24.
Spinal astrocytes have emerged as important mechanistic contributors to the genesis of mechanical allodynia (MA) in neuropathic pain. We recently demonstrated that the spinal sigma non-opioid intracellular receptor 1 (σ1 receptor) modulates p38 MAPK phosphorylation (p-p38), which plays a critical role in the induction of MA in neuropathic rats. However, the histological and physiological relationships among σ1, p-p38 and astrocyte activation is unclear.
We investigated: (i) the precise location of σ1 receptors and p-p38 in spinal dorsal horn; (ii) whether the inhibition of σ1 receptors or p38 modulates chronic constriction injury (CCI)-induced astrocyte activation; and (iii) whether this modulation of astrocyte activity is associated with MA development in CCI mice.
The expression of σ1 receptors was significantly increased in astrocytes on day 3 following CCI surgery. Sustained intrathecal treatment with the σ1 antagonist, BD-1047, attenuated CCI-induced increase in GFAP-immunoreactive astrocytes, and the treatment combined with fluorocitrate, an astrocyte metabolic inhibitor, synergistically reduced the development of MA, but not thermal hyperalgesia. The number of p-p38-ir astrocytes and neurons, but not microglia was significantly increased. Interestingly, intrathecal BD-1047 attenuated the expression of p-p38 selectively in astrocytes but not in neurons. Moreover, intrathecal treatment with a p38 inhibitor attenuated the GFAP expression, and this treatment combined with fluorocitrate synergistically blocked the induction of MA.
Spinal σ1 receptors are localized in astrocytes and blockade of σ1 receptors inhibits the pathological activation of astrocytes via modulation of p-p38, which ultimately prevents the development of MA in neuropathic mice.
脊髓星形胶质细胞已成为神经性疼痛中机械性异常性疼痛（MA）发生机制的重要促成因素。我们最近证明，脊髓σ1非阿片类细胞内受体1（σ1受体）调节p38丝裂原活化蛋白激酶磷酸化（p-p38），这在神经性大鼠MA的诱导中起关键作用。然而，σ1、p-p38与星形胶质细胞活化之间的组织学和生理学关系尚不清楚。
我们研究了：（i）σ1受体和p-p38在脊髓背角的精确位置；（ii）抑制σ1受体或p38是否调节慢性压迫性损伤（CCI）诱导的星形胶质细胞活化；以及（iii）这种对星形胶质细胞活性的调节是否与CCI小鼠MA的发展有关。
CCI手术后第3天，星形胶质细胞中σ1受体的表达显著增加。用σ1拮抗剂BD-1047持续鞘内给药可减轻CCI诱导的GFAP免疫反应性星形胶质细胞的增加，并且该治疗与星形胶质细胞代谢抑制剂氟柠檬酸联合使用可协同减少MA的发展，但对热痛觉过敏无影响。p-p38免疫反应性星形胶质细胞和神经元的数量显著增加，但小胶质细胞未增加。有趣的是，鞘内注射BD-1047可选择性地降低星形胶质细胞而非神经元中p-p38的表达。此外，用p38抑制剂进行鞘内治疗可减弱GFAP的表达，并且该治疗与氟柠檬酸联合使用可协同阻断MA的诱导。
脊髓σ1受体定位于星形胶质细胞，阻断σ1受体可通过调节p-p38抑制星形胶质细胞的病理性活化，这最终可防止神经性小鼠MA的发展。
