La Rana G, Russo R, Campolongo P, Bortolato M, Mangieri R A, Cuomo V, Iacono A, Raso G Mattace, Meli R, Piomelli D, Calignano A
Department of Experimental Pharmacology, 3101 Gillespie NRF, University of California, Irvine, CA 92697-4625, USA.
J Pharmacol Exp Ther. 2006 Jun;317(3):1365-71. doi: 10.1124/jpet.105.100792. Epub 2006 Mar 1.
The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat), and inflammatory pain (complete Freund's adjuvant injection in the rat). In the formalin model, administration of AM404 (1-10 mg/kg i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB(1) cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg/kg i.p.) but not by the CB2 antagonist SR144528 (1 mg/kg i.p.) or the vanilloid antagonist capsazepine (30 mg/kg i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury and complete Freund's adjuvant model, daily treatment with AM404 (1-10 mg/kg s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg/kg i.p.) and was accompanied by decreased expression of cyclooxygenase-2 and inducible nitric-oxide synthase in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.
内源性大麻素系统可能在疼痛的中枢和外周调节中发挥重要作用。在本研究中，我们研究了内源性大麻素转运抑制剂AM404 [N-(4-羟基苯基)-二十碳-5,8,11,14-四烯酰胺] 对急性和持续性伤害感受的啮齿动物模型（小鼠足底注射福尔马林）、神经性疼痛（大鼠坐骨神经结扎）和炎性疼痛（大鼠注射完全弗氏佐剂）的影响。在福尔马林模型中，腹腔注射AM404（1-10 mg/kg）可产生剂量依赖性的镇痛作用，CB(1) 大麻素受体拮抗剂利莫那班（SR141716A；腹腔注射1 mg/kg）可阻断该作用，但CB2拮抗剂SR144528（腹腔注射1 mg/kg）或香草酸拮抗剂辣椒素（腹腔注射30 mg/kg）则不能。另一种花生四烯乙醇胺转运抑制剂UCM707 [N-(3-呋喃甲基)-二十碳-5,8,11,14-四烯酰胺] 也观察到了类似的效果。在慢性压迫损伤和完全弗氏佐剂模型中，连续14天皮下注射AM404（1-10 mg/kg）可使对热刺激和机械刺激的伤害性反应剂量依赖性降低，单次注射利莫那班（腹腔注射1 mg/kg）可阻断该作用，同时坐骨神经中环氧合酶-2和诱导型一氧化氮合酶的表达也降低。这些结果为内源性大麻素系统在疼痛调节中的作用提供了新的证据，并指出花生四烯乙醇胺转运作为镇痛药开发的潜在靶点。
