PDF(Pubmed)
Abstract：
The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin inhibits cyclooxygenase (COX) activity, and minocycline inhibits 5-lipoxygenase (5-LOX) activity. Male Sprague Dawley rats with paclitaxel-induced mechanical allodynia were treated with indomethacin, minocycline, IPM combination, licofelone (a dual COX/LOX inhibitor), or their vehicles. AM251, a CB1 receptor antagonist, and AM630, a CB2 receptor antagonist, were administered before the IPM combination or licofelone. Mechanical allodynia was measured using a dynamic plantar aesthesiometer. Molecular docking was performed using CB-Dock2. Licofelone and IPM combination had antiallodynic effects, which were significantly higher than either indomethacin or minocycline alone. AM251 and AM630 blocked the antiallodynic effects of IPM combination and licofelone. Molecular docking showed that licofelone binds to both CB1 and CB2 receptors with a high affinity similar to the phytocannabinoid 1-trans-delta-9-tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2. Licofelone inhibits COX and LOX and/or directly interacts with CB receptors to produce antiallodynic effects in a rat model of PINP. The findings further suggest that licofelone could be a therapeutic agent for managing PINP.
摘要：
紫杉醇作为化疗药物的用途受到剂量依赖性紫杉醇诱导的神经性疼痛(PINP)发展的限制。最近,我们观察到,吲哚美辛联合米诺环素(IPM)以大麻素(CB)受体依赖性方式减弱小鼠模型中的PINP.吲哚美辛抑制环氧合酶（COX）活性，二甲胺四环素抑制5-脂氧合酶(5-LOX)活性。用吲哚美辛治疗紫杉醇引起的机械性异常性疼痛的雄性SpragueDawley大鼠，米诺环素,IPM组合，licofelone（一种双重COX/LOX抑制剂），或他们的车辆。AM251，CB1受体拮抗剂，和AM630，一种CB2受体拮抗剂，在IPM组合或利科非酮之前给药。使用动态足底美学计测量机械异常性疼痛。使用CB-Dock2进行分子对接。Licofelone和IPM组合具有抗痛觉过敏作用，显着高于单独的吲哚美辛或米诺环素。AM251和AM630阻断了IPM组合和利科非酮的抗痛觉过敏作用。分子对接表明，与植物大麻素1-反式-δ-9-四氢大麻酚和合成大麻素WIN55,212-2相似，利科芬酮与CB1和CB2受体均具有高亲和力。Licofelone在PINP大鼠模型中抑制COX和LOX和/或直接与CB受体相互作用以产生抗痛觉异常作用。研究结果进一步表明，licofelone可能是管理PINP的治疗剂。
