A-803467, a potent and selective [Na.sub.v]1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against [Na.sub.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.sub.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.sub.v]1.8 ([IC.sub.50] = 8 nM) and was >100-fold selective vs. human [Na.sub.v]1.2, [Na.sub.v]1.3, [Na.sub.v]1.5, and [Na.sub.v]1.7 ([IC.sub.50] values [greater than or equal to]1 [micro]M). 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.sub.50] = 47 mg/kg, i.p.), sciatic nerve injury ([ED.sub.50] = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia ([ED.sub.50] [approximately equal to] 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection ([ED.sub.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.sub.v]1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain. allodynia | electrophysiology | hyperalgesia | sensory neurons