Abstract:
Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose. Administration of Cris-104 and donepezil combination (3 μmol/kg) successfully reversed hyperalgesia and mechanical allodynia observed in rats subjected to spinal nerve ligation (SNL). The combination also modulated neuroinflammation by reducing astrocyte activation, evident in the decreased expression of glial fibrillary acidic protein (GFAP) in the spinal cord. The observed synergism in combining a nicotinic receptor agonist with an anticholinesterase agent underscores its potential for treating chronic pain. This alternative therapeutic distinct advantage, including dose reduction and high selectivity for the receptor, contribute to a more favorable profile with minimized adverse effects.
摘要:
慢性疼痛是当代医学的一大挑战。鉴于疗效有限和与可用治疗相关的许多不良反应。认识到胆碱能途径作为治疗靶点的潜力,本工作评估了新型α4β2*受体激动剂Cris-104的组合的抗伤害感受活性,和多奈哌齐,一种中枢抗胆碱酯酶药.等值线分析显示,等摩尔组合比理论计算的等效添加剂剂量有效约10倍。给予Cris-104和多奈哌齐组合(3μmol/kg)成功逆转了在进行脊神经结扎(SNL)的大鼠中观察到的痛觉过敏和机械性异常性疼痛。该组合还通过减少星形胶质细胞激活来调节神经炎症,脊髓胶质纤维酸性蛋白(GFAP)表达降低。观察到的烟碱受体激动剂与抗胆碱酯酶剂组合的协同作用强调了其治疗慢性疼痛的潜力。这种替代治疗的独特优势,包括减少剂量和对受体的高选择性,有助于一个更有利的配置文件与最小的不利影响。