Costa Barbara, Siniscalco Dario, Trovato Anna Elisa, Comelli Francesca, Sotgiu Maria Luisa, Colleoni Mariapia, Maione Sabatino, Rossi Francesco, Giagnoni Gabriella
Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
Br J Pharmacol. 2006 Aug;148(7):1022-32. doi: 10.1038/sj.bjp.0706798. Epub 2006 Jun 12.
An attractive alternative to the use of direct agonists at the cannabinoid receptor type 1 (CB1) in the control of neuropathic pain may be to potentiate the actions of endogenous cannabinoids. Thus, the effects of AM404, an inhibitor of anandamide uptake, were assessed in an experimental model of neuropathic pain in rats. Daily treatment with AM404 prevented, time- and dose-dependently, the development of thermal hyperalgesia and mechanical allodynia in neuropathic rats. Antagonists at cannabinoid CB1 or CB2 receptors, or at the transient receptor potential vanilloid type 1 receptor, each partially reversed effects induced by AM404. A complete reversal was obtained when the three antagonists were given together, suggesting that all three receptors are involved. AM404 treatment affected two pathways involved in the generation and maintenance of neuropathic pain, one mediated by nitric oxide (NO) and the other by cytokines. AM404 completely prevented the overproduction of NO and the overexpression of nNOS, inhibited the increase in tumour necrosis factor alpha (TNFalpha) and enhanced the production of interleukin-10. Both NO and TNFalpha are known to contribute to the apoptotic process, which plays an important role in the establishment of chronic pain states. AM404 treatment prevented the increase in the ratio between pro- and anti-apoptotic gene bax/bcl-2 expression observed in the spinal cord of neuropathic rats. Taken together, these findings suggest that inhibition of endocannabinoid uptake, by blocking the putative anandamide carrier, results in the relief of neuropathic pain and may represent a novel strategy for treating chronic pain.
在控制神经性疼痛方面，一种比使用大麻素1型（CB1）受体直接激动剂更具吸引力的替代方法可能是增强内源性大麻素的作用。因此，在大鼠神经性疼痛的实验模型中评估了阿南达胺摄取抑制剂AM404的效果。每天用AM404治疗可时间和剂量依赖性地预防神经性大鼠热痛觉过敏和机械性异常性疼痛的发展。大麻素CB1或CB2受体拮抗剂，或瞬时受体电位香草酸亚型1受体拮抗剂，各自部分逆转了AM404诱导的效应。当三种拮抗剂一起给药时可获得完全逆转，表明所有三种受体都参与其中。AM404治疗影响了参与神经性疼痛产生和维持的两条途径，一条由一氧化氮（NO）介导，另一条由细胞因子介导。AM404完全阻止了NO的过量产生和nNOS的过表达，抑制了肿瘤坏死因子α（TNFα）的增加并增强了白细胞介素-10的产生。已知NO和TNFα都有助于凋亡过程，而凋亡过程在慢性疼痛状态的建立中起重要作用。AM404治疗阻止了神经性大鼠脊髓中促凋亡基因与抗凋亡基因bax/bcl-2表达比值的增加。综上所述，这些发现表明，通过阻断假定的阿南达胺载体来抑制内源性大麻素摄取，可缓解神经性疼痛，可能代表一种治疗慢性疼痛的新策略。
