脊髓集落刺激因子1在大鼠吗啡镇痛耐受中的作用

赵昱; 吴军; 安扬; 常青

doi:10.13898/j.cnki.issn.1000-2200.2021.05.003

脊髓集落刺激因子1在大鼠吗啡镇痛耐受中的作用

Role of spinal colony-stimulating factor 1 in rats in morphine tolerance to analgesia

摘要

摘要:
目的观察脊髓集落刺激因子1（CSF1）在大鼠吗啡镇痛耐受过程中的作用。
方法成功鞘内置管SD大鼠随机分为0.9%氯化钠溶液组（NS组）、吗啡组（MOR组）、CSF1R抑制剂组（PLX3397组）、CSF1R抑制剂+吗啡组（PLX3397+MOR组），各15只。MOR组和PLX3397+MOR组连续7 d鞘内注射吗啡15 μg建立吗啡耐受动物模型，PLX3397+MOR组同时灌胃给予CSF1R抑制剂PLX3397（290 mg/kg）；NS组鞘内注射及灌胃给予0.9%氯化钠溶液，PLX3397组鞘内注射0.9%氯化钠溶液，灌胃给予CSF1R抑制剂PLX3397。采用50 ℃热水甩尾潜伏期法和机械反射阈值法观察CSF1在吗啡的镇痛耐受中作用；应用免疫组织荧光染色法检测脊髓背角小胶质细胞激活标志物IBA1表达变化；Western blotting法检测吗啡对腰段脊髓CSF1表达的影响。
结果连续7 d鞘内注射吗啡，MOR组大鼠最大镇痛效应百分率（percent of maximal possible potential effect，%MPE）进行性降低（P < 0.05）；而与MOR组比较，PLX3397+MOR组大鼠注射吗啡3、5、7 d时%MPE均增加（P < 0.05）；PLX3397组与NS组各时点%MPE差异均无统计学意义（P>0.05）。注射吗啡7 d后，MOR组小胶质细胞标志物IBA-1在大鼠腰段脊髓背角表达较NS组增加（P < 0.05），MOR+PLX3397组大鼠IBA-1表达较MOR组减少（P < 0.05）；MOR组和MOR+PLX3397组大鼠腰段脊髓CSF1表达均较NS组增加（P < 0.05），2组CSF1表达差异无统计学意义（P>0.05）。
结论脊髓CSF1参与吗啡耐受形成，抑制脊髓CSF1表达可能为临床治疗吗啡镇痛耐受提供一种新的作用靶点。

Abstract:
ObjectiveTo investigate the role of spinal colony-stimulating factor 1(CSF1) in morphine tolerance to analgesia.
MethodsMale Sprague-Dawley rats with successful intrathecal catheter were randomly divided into four groups(n=15): 0.9% sodium chloride solution group(NS), morphine group(MOR), CSF1R inhibitor PLX3397 group(PLX3397) and morphine plus PLX3397 group(MOR+ PLX3397).A morphine tolerance model of rats was induced by intrathecal injection of 15 μg morphine once daily for 7 consecutive days in MOR and MOR+PLX3397 group.PLX3397 was administered intragastrically in PLX3397 and MOR+PLX3397 group, 0.9% sodium chloride solution was administered intrathecally in NS and PLX3397 group.The role of CSF1 on morphine antinociceptive tolerance was explored by %MPE^TFL and %MPE^MWT.Immunohistochemistry assay was applied to detect the expression of IBA-1.Western blotting was used to evaluate the change of spinal CSF1 expression.
ResultsIntrathecal injection of morphine for 7 days, %MPE in MOR group showed progressive decrease, while %MPE in MOR+PLX3397 group were significantly increased as compared with MOR group on day 3, 5, 7 after chronic morphine(P < 0.05);There was no significant difference in %MPE between PLX3397 and NS group(P>0.05).on day 7 after chronic morphine, the expression of IBA-1 in MOR group was significantly up-regulated as compared with NS group(P < 0.05), while the expression of IBA-1 in MOR+PLX3397 group was significantly down-regulated as compared with MOR group(P < 0.05);the expression of CSF1 in MOR and MOR+PLX3397 group was significantly up-regulated as compared with NS group(P < 0.05).
ConclusionsCSF1 in the spinal cord can be involved in the development of tolerance to morphine-induced analgesia.Inhibition of CSF1 may provide a new therapeutic target for morphine tolerance to analgesia.

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