Xu Mei, Bruchas Michael R, Ippolito Danielle L, Gendron Louis, Chavkin Charles
Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
J Neurosci. 2007 Mar 7;27(10):2570-81. doi: 10.1523/JNEUROSCI.3728-06.2007.
Partial sciatic nerve ligation (pSNL) markedly increased glial fibrillary acidic protein immunoreactivity (GFAP-IR) 1 week after lesion in the L4-L5 spinal dorsal horn of wild-type, but not in dynorphin knock-out, mice lacking kappa opioid receptors (KOR-/-) or in wild-type mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). A direct effect of KOR on glial cell proliferation was suggested by the findings that primary cultures of type II GFAP-immunoreactive astrocytes isolated from mouse spinal cord express KOR. Sustained treatment with the kappa agonist U50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolytinil)-cyclohexyl]-benzeneacetamide methane sulfonate) significantly increased the proliferation rate of GFAP-immunoreactive astrocytes isolated from wild-type mice, and this effect was blocked by norBNI pretreatment. Proliferation of cultured type II astrocytes may have been stimulated by mitogen-activated protein kinase (MAPK) activation by KOR because (1) U50,488 treatment increased phospho-p38 MAPK-immunoreactivity 247 +/- 44% over untreated cells, (2) the increase in phospho-p38 induced by U50,488 was blocked by norBNI and not evident in KOR-/- cultures, and (3) GFAP-immunoreactive astrocyte proliferation induced by U50,488 was blocked by the p38 MAPK inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Similar mechanisms of astrocyte activation may also be responsible in vivo because intrathecal injection of SB 203580 blocked the increased GFAP-IR in lumbar spinal cord induced by pSNL. Although the relationship between kappa-stimulated astrocyte proliferation and neuropathic pain mechanisms was not directly established in these studies, the results support the hypothesis that KOR activation induces spinal astrocyte proliferation, which may contribute to cellular reorganization after sciatic nerve damage.
部分坐骨神经结扎（pSNL）在野生型小鼠L4 - L5脊髓背角损伤后1周显著增加了胶质纤维酸性蛋白免疫反应性（GFAP - IR），但在强啡肽基因敲除小鼠、缺乏κ阿片受体（KOR - / -）的小鼠或用KOR拮抗剂去甲二氢吗啡酮（norBNI）预处理的野生型小鼠中未出现这种情况。从鼠脊髓分离的II型GFAP免疫反应性星形胶质细胞的原代培养物表达KOR这一发现提示了KOR对胶质细胞增殖有直接作用。用κ激动剂U50,488（反式 - 3,4 - 二氯 - N - 甲基 - N - [2 - (1 - 吡咯烷基) - 环己基] - 苯乙酰胺甲磺酸盐）持续处理显著增加了从野生型小鼠分离的GFAP免疫反应性星形胶质细胞的增殖率，且这种作用被norBNI预处理所阻断。培养的II型星形胶质细胞的增殖可能是由KOR激活丝裂原活化蛋白激酶（MAPK）所刺激，因为（1）U50,488处理使磷酸化p38 MAPK免疫反应性比未处理细胞增加了247±44%，（2）U50,488诱导的磷酸化p38增加被norBNI阻断，且在KOR - / -培养物中不明显，（3）U50,488诱导的GFAP免疫反应性星形胶质细胞增殖被p38 MAPK抑制剂SB 203580 [4 - (4 - 氟苯基) - 2 - (4 - 甲亚磺酰基苯基) - 5 - (4 - 吡啶基) - 1H - 咪唑]所阻断。类似的星形胶质细胞激活机制在体内可能也起作用，因为鞘内注射SB 203580阻断了pSNL诱导的腰段脊髓GFAP - IR增加。尽管在这些研究中未直接确定κ刺激的星形胶质细胞增殖与神经性疼痛机制之间的关系，但结果支持这样的假说，即KOR激活诱导脊髓星形胶质细胞增殖，这可能有助于坐骨神经损伤后的细胞重组。
