Jarvis Michael F, Honore Prisca, Shieh Char-Chang, Chapman Mark, Joshi Shailen, Zhang Xu-Feng, Kort Michael, Carroll William, Marron Brian, Atkinson Robert, Thomas James, Liu Dong, Krambis Michael, Liu Yi, McGaraughty Steve, Chu Katharine, Roeloffs Rosemarie, Zhong Chengmin, Mikusa Joseph P, Hernandez Gricelda, Gauvin Donna, Wade Carrie, Zhu Chang, Pai Madhavi, Scanio Marc, Shi Lei, Drizin Irene, Gregg Robert, Matulenko Mark, Hakeem Ahmed, Gross Michael, Johnson Matthew, Marsh Kennan, Wagoner P Kay, Sullivan James P, Faltynek Connie R, Krafte Douglas S
Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA.
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8520-5. doi: 10.1073/pnas.0611364104. Epub 2007 May 2.
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
河豚毒素抗性钠通道的激活有助于神经元动作电位的电发生。针对Na(v)1.8的反义寡核苷酸研究表明，该通道与实验性炎症性疼痛和神经性疼痛有关。我们在此报告A-803467的发现，这是一种钠通道阻滞剂，能有效阻断河豚毒素抗性电流（IC(50)=140 nM），并在体外抑制大鼠背根神经节神经元自发和电诱发动作电位的产生。在重组细胞系中，A-803467能有效阻断人Na(v)1.8（IC(50)=8 nM），对人Na(v)1.2、Na(v)1.3、Na(v)1.5和Na(v)1.7的选择性大于100倍（IC(50)值≥1 μM）。A-803467（20 mg/kg，静脉注射）可阻断大鼠脊髓背角中广动力范围神经元的机械诱发放电。A-803467还能剂量依赖性地减轻多种大鼠疼痛模型中的机械性异常性疼痛，包括：坐骨神经结扎（ED(50)=47 mg/kg，腹腔注射）、坐骨神经损伤（ED(50)=85 mg/kg，腹腔注射）、辣椒素诱导的继发性机械性异常性疼痛（ED(50)约为100 mg/kg，腹腔注射）以及足底注射完全弗氏佐剂后的热痛觉过敏（ED(50)=41 mg/kg，腹腔注射）。A-803467对福尔马林诱导的伤害感受以及急性热痛和术后疼痛无效。这些数据表明，体内急性和选择性药理阻断Na(v)1.8钠通道在神经性和炎症性疼痛的动物模型中产生显著的镇痛作用。
