Reversal of neuropathic pain by α-hydroxyphenylamide: A novel sodium channel antagonist

Sodium (Na) channel blockers are known to possess antihyperalgesic properties. We have designed and synthesized a novel Na channel antagonist, α-hydroxyphenylamide, and determined its ability to inhibit both TTX-sensitive (TTX-s) and TTX-resistant (TTX-r) Na currents from small dorsal root ganglion (DRG) neurons. α-Hydroxyphenylamide tonically inhibited both TTX-s and TTX-r Na currents yielding an IC₅₀ of 8.2 ± 2.2 μM (n = 7) and 28.9 ± 1.8 μM (n = 8), respectively. In comparison, phenytoin was less potent inhibiting TTX-s and TTX-r currents by 26.2 ± 4.0% (n = 8) and 25.5 ± 2.0%, respectively, at 100 μM. α-Hydroxyphenylamide (10 μM) also shifted equilibrium gating parameters of TTX-s Na channels to greater hyperpolarized potentials, slowed recovery from inactivation, accelerated the development of inactivation and exhibited use-dependent block. In the chronic constriction injury (CCI) rat model of neuropathic pain, intraperitoneal administration of α-hydroxyphenylamide attenuated the hyperalgesia by 53% at 100 mg/kg, without affecting motor coordination in the Rotorod test. By contrast, the reduction in pain behavior produced by phenytoin (73%; 100 mg/kg) was associated with significant motor impairment. In summary, we report that α-hydroxyphenylamide, a sodium channel antagonist, exhibits antihyperalgesic properties in a rat model of neuropathic pain, with favorable sedative and ataxic side effects compared with phenytoin.