高压氧对化疗相关外周神经痛的预防作用及其机制

目的探讨高压氧可否预防化疗相关外周神经痛(CIPNP),同时,以脊髓大麻素受体(CBRs)为主要靶点,探讨其作用机制。方法 75只雄性SD大鼠按随机数字表法分为5组,即空白对照组、模型对照组、高压氧干预组、高压氧+AM630组及高压氧+AM251组,每组15只。CIPNP模型采取紫杉醇腹腔注射法建立,所有干预组从第1次紫杉醇注射开始,隔日应用高压氧干预,共5次。高压氧+AM630组和高压氧+AM251组于每次高压氧干预前分别给予大麻素Ⅱ型受体(CBR2)阻滞剂AM630和大麻素Ⅰ型受体(CBR1)阻滞剂AM251腹腔注射。行为学测试使用von fery纤维毛分别于实验开始前及实验期间每隔7 d测试大鼠机械缩足阈值(MWT);应用Western blotting检测脊髓CBR1、CBR2的表达;应用免疫组化及Western blotting检测脊髓星形胶质细胞标志物胶质纤维酸性蛋白(GFAP)的表达;应用酶联免疫吸附法(ELISA)检测脊髓炎性细胞因子白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)的表达。结果与空白对照组相比,模型对照组MWT明显降低,差异有统计学意义(P<0.01),实验第21天差异最明显(15.46±2.83)gvs.( 4.33±3.53)g],差异有统计学意义(P<0.01);脊髓GFAP、IL-1β、TNF-α表达均明显升高,差异有统计学意义(P<0.05或P<0.01)。与模型对照组相比,高压氧干预组MWT及脊髓CBR2均明显升高,差异有统计学意义(P<0.05);脊髓GFAP、IL-1β、TNF-α表达均明显降低,差异有统计学意义(P<0.05);腹腔注射AM630可逆转上述作用,而腹腔注射AM251无类似作用。结论高压氧可以预防紫杉醇诱导的CIPNP,其机制可能与高压氧激活脊髓CBR2,并进一步阻断脊髓胶质细胞活化及炎性细胞因子表达有关。

Preventive effect and mechanism of hyperbaric oxygen on chemotherapy-induced peripheral neuropathic pain

Objective To investigate the effect of hyperbaric oxygen(HBO)on the prevention of chemotherapy-induced peripheral neuropathic pain(CIPNP),and to observe its mechanism by targeting spinal cannabinoid receptors(CBRs).Methods A total of 75 male Sprague-Dawley(SD)rats were randomly divided into 5 groups(15 rats in each group),i.e.blank control group,CIPNP control group,CIPNP+HBO group,CIPNP+HBO+AM630 group,and CIPNP+HBO+AM251 group.The model rats with CIPNP were established by injecting paclitaxel(i.p.).Each group with HBO intervention received the HBO treatment on the second day after each of the 5 times of paclitaxel injection.The CIPNP+HBO+AM630 and CIPNP+HBO+AM251 groups were administered with AM630(an antagonist of CBR2)and AM251(an antagonist of CBR1)respectively before each HBO treatment.The behavioral test was carried out to measure the mechanical withdrawal threshold(MWT)of rats by von fery filaments before the experiment and every 7 days during the experiment.The expressions of CBR1 and CBR2 were tested by Western blotting.The expression of glial fibrillary acidic protein(GFAP)was tested by immunohistochemistry(ICH)and Western blotting.And the expressions of inflammatory cytokines in the spinal cord,i.e.Interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α),were detected by enzyme-linked immunosorbent assay(ELISA).Results Compared with that of the blank control group,the MWT of the CIPNP control group was significantly decreased(P<0.01),and the difference was most significant(15.46±2.83)g vs.(4.33±3.53)g;P<0.01]especially on the 21st day of the experiment.The expressions of spinal GFAP,IL-1β,and TNF-αwere significantly increased,and the differences were statistically significant(P<0.05).Compared with those of the CIPNP control group,the MWT and spinal CBR2 of the CIPNP+HBO group were significantly increased(P<0.05),the GFAP,IL-1β,and TNF-αin the spinal cord were significantly decreased(P<0.05),and the above-mentioned effects could be blocked by intraperitoneal injection of AM630,while there was no such reverse effect after intraperitoneal injection of AM251.Conclusion HBO can prevent paclitaxel-induced CIPNP,and its mechanism may be related to the activation of spinal CBR2 and then the blocking of the activation of GFAP and the expression of inflammatory cytokines in the spinal cord.