咖啡因对大鼠神经病理性疼痛及加巴喷丁止痛的作用及相关机制

发布时间：2018-06-21 19:10

本文选题：咖啡因 + 加巴喷丁　；参考：《北京协和医学院》2014年博士论文

【摘要】：研究目的咖啡因可以显著增强急性疼痛的药物疗效,但对神经疼痛药物疗效的影响尚不明确。已有研究提示咖啡因会减弱神经病理性疼痛的药物疗效。这可能与咖啡因非选择性阻断腺苷受体(Adenosine receptor, AR)有关。加巴喷丁及其相应的衍生物是目前神经病理性疼痛的主要治疗药物。本研究拟在单侧大鼠坐骨神经压迫损伤(Chronic constriction injury, CCI)模型中通过单独咖啡因或加巴喷丁,以及二者联合应用,探讨咖啡因对神经病理性疼痛及对加巴喷丁镇痛效果的影响。同时,明确脊髓背角中腺苷A2A受体及蛋白激酶A(PKA)的表达。研究方法健康雄性SD大鼠60只,随机分为正常对照组(Naive)、假于术组(Sham)与坐骨神经慢性压迫损伤组(CCI), CCI组进一步分为：生理盐水(normal saline,NS)处理组、加巴喷丁(Gabapentin)100mg/kg处理组(GBP)、咖啡因(Caffeine)10、30、100mg/kg处理组(CAF10、CAF30、CAF100)及加巴喷丁100mg/kg分别与咖啡因10、30,100mg/kg联合应用处理组(GBP+CAF10、30、100),n=6。分别于CCI模型建模前及建模后3、7、14天监测各组大鼠体重、机械缩足阈值(Paw withdrawal threshold, PWT)及热缩足潜伏期(Paw withdrawal latency, PWL)。单侧CCI大鼠模型建立后7天给予腹腔注射给药,每天1次,连续7天。建模14天后处死大鼠,取L4-L6段腰膨大脊髓背角行Western Blotting检测腺苷A2A受体蛋白的表达情况,行Real-time PCR检测腺苷A2A受体及PKA的表达情况。研究结果咖啡因10mg/kg与30mg/kg对神经病理性无明显缓解作用,咖啡因1OOmg/kg X神经病理性疼痛有显著缓解作用,且有统计学意义(P0.05)。分子水平,在大鼠脊髓背角中,提示咖啡因组Real-time PCR基因的表达量较正Adora2a、Prkaca常对照组升高提示咖啡因1Western Blot组腺苷A2A受体蛋白表达增加；Omg/kg咖啡因10组腺苷A2A受体蛋白表达量降低。联合用药时,咖啡因Omg/kg与10mg/kg会部分抵消加巴喷丁30mg/kg勺镇痛效果。咖啡因100mg/kg对加100mg/kg巴喷丁的镇痛作用无显著影响。分子水平,在大鼠脊髓背角中,提示不同剂量咖啡因联合加巴喷丁组,Real-time PCR表达升高无显著性差异；Adora2a、Prkaca提示不同剂量咖啡因联合加巴喷丁组中腺苷A2A受体表达均下降,Western Blot但各组间均无显著性差异(P0.05)。研究结论在神经病理性疼痛的药物治疗中,大剂量咖啡因具有一定程度的镇痛作用。其分子机制与大剂量咖啡因抑制腺苷A2A受体进而抑制cAMP依赖信号通路引起。加巴喷丁可以有效缓解神经病理性疼痛,但中小剂量的咖啡因会减弱其疗效。其分子机制与cAMP依赖信号通路不相关。日常咖啡中咖啡因含量偏低,因此服用加巴喷丁治疗神经病理性疼痛的患者,用药期间应避免饮用咖啡或含有咖啡因的饮品。
[Abstract]:Objective caffeine can significantly enhance the drug efficacy of acute pain, but the effect on neuropathic drugs is unclear. Studies have shown that caffeine weakens the effects of drugs on neuropathic pain. This may be related to the nonselective blocking of adenosine receptor (ARR) by caffeine. Gabapentin and its derivatives are currently the main treatment for neuropathic pain. The purpose of this study was to investigate the effect of caffeine on neuropathic pain and the analgesic effect of gabapentin in unilateral rat sciatic nerve compression injury model by caffeine or gabapentine alone. At the same time, the expression of adenosine A 2A receptor and protein kinase A 2 A in the dorsal horn of spinal cord was determined. Methods Sixty healthy male Sprague-Dawley rats were randomly divided into normal control group, sham group and chronic compression group of sciatic nerve. The CCI group was further divided into two groups: normal saline group. GBP CAF1030100mg / kg, CAF10, CAF30, CAF100, and 100mg/kg combined with caffeine 1030mg / kg, GBP CAF1030100mgkg / kg, respectively. The body weight, paw withdrawal threshold and latent period of thermal contraction were monitored before and 3 days after modeling. Rats with unilateral CCI were given intraperitoneal injection once a day for 7 days after the establishment of CCI model. The rats were killed after 14 days of modeling. The expression of adenosine A2A receptor protein was detected by Western blotting, and the expression of adenosine A2A receptor and PKA was detected by Real-time PCR. Results caffeine 10mg/kg and 30mg/kg did not significantly relieve neuropathic pain, but caffeine 1OOmg / kg X neuropathic pain was significantly alleviated, and there was statistically significant difference between caffeine 1 OOmg / kg X neuropathic pain. At the molecular level, the expression of Real-time PCR gene in the dorsal horn of spinal cord in rats was higher than that in the normal control group. It suggested that the expression of adenosine A2A receptor protein in caffeine 1 Western Blot group was increased and the expression of adenosine A2A receptor protein in Omg / kg caffeine 10 group was lower than that in normal control group. In combination, caffeine Omg / kg and 10mg/kg partially counteracted the analgesic effect of gabapentin 30mg/kg spoons. Caffeine 100mg/kg had no significant effect on the analgesic effect of 100mg/kg. At the molecular level, in the spinal dorsal horn of rats, there was no significant difference in the expression of real-time PCR between different doses of caffeine and gabapentin. The expression of adenosine A2A receptor in different doses of caffeine combined with gabapentine group was decreased, but there was no significant difference in the expression of adenosine A2A receptor between the two groups. Conclusion in the treatment of neuropathic pain, large dose caffeine has a certain degree of analgesic effect. Its molecular mechanism is associated with the inhibition of adenosine A 2A receptor and camp dependent signaling pathway by high dose caffeine. Gabapentin is effective in relieving neuropathic pain, but moderate and low doses of caffeine attenuate it. Its molecular mechanism is not related to camp dependent signaling pathway. Caffeine in daily coffee is low, so patients who take gabapentin for neuropathic pain should avoid drinking coffee or caffeinated drinks.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R741

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