Di Cesare Mannelli Lorenzo, Ghelardini Carla, Calvani Menotti, Nicolai Raffaella, Mosconi Luigi, Toscano Annarita, Pacini Alessandra, Bartolini Alessandro
University of Florence, Department of Preclinical and Clinical Pharmacology, Florence, Italy.
J Neurosci Res. 2009 Jan;87(1):200-7. doi: 10.1002/jnr.21815.
Several pathologies related to nervous tissue alterations are characterized by a chronic pain syndrome defined by persistent or paroxysmal pain independent or dependent on a stimulus. Pathophysiological mechanisms related to neuropathic disease are associated with mitochondrial dysfunctions that lead to an activation of the apoptotic cascade. In a model of peripheral neuropathy obtained by the loose ligation of the rat sciatic nerve, acetyl-L-Carnitine (ALCAR; 100 mg/kg intraperitoneally [i.p.] twice daily for 14 days) was able to reduce hyperalgesia and apoptosis. In the present study, different mechanisms for the analgesic and the antineuropathic effect of ALCAR are described. The muscarinic blocker atropine (5 mg/kg i.p.) injected simultaneously with ALCAR did not antagonize the ALCAR antihyperalgesic effect on the paw-pressure test but significantly reduced the analgesic effect of ALCAR. Conversely, the antineuropathic effect of ALCAR was prevented by cotreatment with the nicotinic antagonist mecamylamine (2 mg/kg i.p. twice daily for 14 days). A pharmacological silencing of the nicotinic receptors significantly reduced the X-linked inhibitor of apoptosis protein-related protective effect of ALCAR on the apoptosis induced by ligation of the sciatic nerve. Taken together, these data highlight the relevance of nicotinic modulation in neuropathy treatment.
几种与神经组织改变相关的病理状况的特征是一种慢性疼痛综合征，其定义为持续或阵发性疼痛，独立于或依赖于刺激。与神经病变相关的病理生理机制与线粒体功能障碍有关，线粒体功能障碍会导致凋亡级联反应的激活。在通过大鼠坐骨神经松弛结扎获得的周围神经病变模型中，乙酰-L-肉碱（ALCAR；100mg/kg腹腔注射[i.p.]，每日两次，共14天）能够减轻痛觉过敏和细胞凋亡。在本研究中，描述了ALCAR镇痛和抗神经病变作用的不同机制。与ALCAR同时注射的毒蕈碱拮抗剂阿托品（5mg/kg i.p.）并未拮抗ALCAR对 paw-pressure试验的抗痛觉过敏作用，但显著降低了ALCAR的镇痛作用。相反，与烟碱拮抗剂美加明（2mg/kg i.p.，每日两次，共14天）联合治疗可预防ALCAR的抗神经病变作用。烟碱受体的药理学沉默显著降低了ALCAR对坐骨神经结扎诱导的细胞凋亡的X连锁凋亡抑制蛋白相关保护作用。综上所述，这些数据突出了烟碱调节在神经病变治疗中的相关性。
