Masocha Willias, Aly Esraa, Albaloushi Aisha, Al-Romaiyan Altaf
Department of Pharmacology and Therapeutics, College of Pharmacy, Kuwait University, Safat 13110, Kuwait.
Biomedicines. 2024 Jul 11;12(7):1545. doi: 10.3390/biomedicines12071545.
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.
紫杉醇作为一种化疗药物的应用受到剂量依赖性紫杉醇诱导的神经性疼痛（PINP）的限制。最近，我们观察到吲哚美辛加米诺环素（IPM）的组合以大麻素（CB）受体依赖性方式减轻小鼠模型中的PINP。吲哚美辛抑制环氧化酶（COX）活性，米诺环素抑制5-脂氧合酶（5-LOX）活性。对患有紫杉醇诱导的机械性异常性疼痛的雄性Sprague Dawley大鼠用吲哚美辛、米诺环素、IPM组合、利考昔芬（一种COX/LOX双重抑制剂）或它们的赋形剂进行治疗。在给予IPM组合或利考昔芬之前，给予CB1受体拮抗剂AM251和CB2受体拮抗剂AM630。使用动态足底触觉测量仪测量机械性异常性疼痛。使用CB-Dock2进行分子对接。利考昔芬和IPM组合具有抗异常性疼痛作用，显著高于单独使用吲哚美辛或米诺环素。AM251和AM630阻断了IPM组合和利考昔芬的抗异常性疼痛作用。分子对接显示，利考昔芬以与植物大麻素1-反式-δ-9-四氢大麻酚和合成大麻素WIN 55,212-2相似的高亲和力与CB1和CB2受体结合。利考昔芬抑制COX和LOX和/或直接与CB受体相互作用，在PINP大鼠模型中产生抗异常性疼痛作用。这些发现进一步表明利考昔芬可能是一种治疗PINP的药物。
