Lynch James J, Wade Carrie L, Mikusa Joseph P, Decker Michael W, Honore Prisca
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Department R4N5, Bldg. AP9A-LL, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA.
Eur J Pharmacol. 2005 Feb 10;509(1):43-8. doi: 10.1016/j.ejphar.2004.12.034.
ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.
ABT - 594（(R)-5-(2-氮杂环丁烷基甲氧基)-2-氯吡啶）代表了一类新型的广谱镇痛药，其主要作用机制是激活神经元烟碱型乙酰胆碱受体。本研究在大鼠化疗诱导的神经性疼痛模型中对ABT - 594的作用进行了表征，在该模型中它能减轻机械性异常性疼痛，其半数有效剂量（ED50）为40 nmol/kg（腹腔注射）。这种抗异常性疼痛作用未被纳洛酮全身（腹腔注射）预处理所阻断，但被美加明完全阻断。在较高测试剂量下，樟磺咪芬（0.2 - 5 μmol/kg，腹腔注射）预处理仅部分阻断了ABT - 594的作用。相比之下，樟磺咪芬中枢（脑室内）预处理完全阻断了ABT - 594的抗异常性疼痛作用。综上所述，数据表明ABT - 594在大鼠长春新碱模型中具有强大的抗异常性疼痛作用，并且在该化疗诱导的神经性疼痛动物模型中，除了其强大的中枢作用部位外，ABT - 594的作用还部分由外周烟碱型乙酰胆碱受体介导。
