Joshi S K, Honore Prisca, Hernandez Gricelda, Schmidt Robert, Gomtsyan Arthur, Scanio Marc, Kort Michael, Jarvis Michael F
Abbott Laboratories, Neuroscience Research, Abbott Park, Illinois, USA.
J Pain. 2009 Mar;10(3):306-15. doi: 10.1016/j.jpain.2008.09.007. Epub 2008 Dec 13.
Evidence implicating Nav1.8 and TRPV1 ion channels in various chronic pain states is extensive. In this study, we used isobolographic analysis to examine the in vivo effects of the combination of the Nav1.8 blocker A-803467 [5-(4-Chloro-phenyl)-furan-2-carboxylic acid (3,5-dimethoxy-phenyl)-amide] with 2 structurally distinct TRPV1 antagonists, A-840257 [1-(1H-Indazol-4-yl)-3-([R]-4-piperidin-1-yl-indan-1-yl)-urea] or A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea]. The antinociceptive effects of the Nav1.8 blocker alone and in combination with each TRPV1 antagonist were examined in an inflammatory (complete Freund's adjuvant, CFA) and a neuropathic (spinal nerve ligation, SNL) pain model after systemic (intraperitoneal) administration. Alone, A-803467 was efficacious in both CFA and SNL models with ED(50) values of 70 (54.2 to 95.8) mg/kg and 70 (38.1 to 111.9) mg/kg, respectively. The ED(50) values of the TRPV1 antagonists A-840257 and A-425619 alone in the CFA model were 10 (3.6 to 14.9) mg/kg and 43 (24.1 to 62.2) mg/kg, respectively; both were without significant effect in the SNL model. A series of experiments incorporating 1:1, 3:1, or 0.3:1 ED(50) dose-ratio combinations of A-840257 and A-803467, or A-425619 and A-803467 were performed in both pain models, and the effective doses of mixtures that produced 50% antinociception (ED(50, mix)) were determined by isobolographic analysis. The ED(50, mix) in each case was not found to be statistically different than ED(50, add), the theoretical ED(50) calculated assuming additive effects. These data demonstrate that Nav1.8 blockers and TRPV1 antagonists administered in combination produce an additive effect in rat pain models. Using such a combination strategy to produce analgesia may potentially provide an improved therapeutic separation from unwanted in vivo side effects associated with blockade of either Nav1.8 or TRPV1 alone.
In this report, effects of coadministration of TRPV1 antagonists and A-803467, a Nav1.8 blocker, were investigated in preclinical rodent models of neuropathic and inflammatory pain. The 2 classes of novel antinociceptive agents produced an additive interaction in attenuating CFA-induced thermal hyperalgesia, providing a rationale for their use as a combination strategy in the clinic for treating inflammatory pain.
有大量证据表明Nav1.8和TRPV1离子通道与多种慢性疼痛状态有关。在本研究中，我们采用等效线图分析法，研究Nav1.8阻滞剂A-803467[5-(4-氯苯基)-呋喃-2-羧酸(3,5-二甲氧基苯基)-酰胺]与2种结构不同的TRPV1拮抗剂A-840257[1-(1H-吲唑-4-基)-3-([R]-4-哌啶-1-基茚满-1-基)-脲]或A-425619[1-异喹啉-5-基-3-(4-三氟甲基苄基)-脲]联合使用的体内效应。在全身（腹腔内）给药后，在炎症（完全弗氏佐剂，CFA）和神经病理性（坐骨神经结扎，SNL）疼痛模型中，检测单独使用Nav1.8阻滞剂以及与每种TRPV1拮抗剂联合使用时的抗伤害感受作用。单独使用时，A-803467在CFA和SNL模型中均有效，其半数有效剂量（ED50）分别为70（54.2至95.8）mg/kg和70（38.1至111.9）mg/kg。TRPV1拮抗剂A-840257和A-425619在CFA模型中的ED50值分别为10（3.6至14.9）mg/kg和43（2,4.1至62.2）mg/kg；两者在SNL模型中均无显著作用。在两种疼痛模型中，进行了一系列包含A-840257与A-803467或A-425619与A-803467的1:1、3:1或0.3:1 ED50剂量比组合的实验，并通过等效线图分析法确定产生50%抗伤害感受作用（ED50,mix）的混合物有效剂量。在每种情况下，均未发现ED50,mix与ED50,add（假设为相加作用计算出的理论ED50）存在统计学差异。这些数据表明，联合使用Nav1.8阻滞剂和TRPV1拮抗剂在大鼠疼痛模型中产生相加作用。采用这种联合策略产生镇痛作用可能会潜在地改善与单独阻断Nav1.8或TRPV1相关的体内不良副作用的治疗分离。
在本报告中，研究了TRPV1拮抗剂与Nav1.8阻滞剂A-803467联合给药在神经病理性和炎症性疼痛的临床前啮齿动物模型中的作用。这两类新型抗伤害感受剂在减轻CFA诱导的热痛觉过敏方面产生相加相互作用，为它们在临床上作为联合策略用于治疗炎症性疼痛提供了理论依据。
