Future potential and status of selective sodium channel blockers for the treatment of pain

Abstract

Voltage-gated sodium (NaV1) channels in the peripheral nervous system and CNS play a critical role in pain signaling. Nociceptive neurons express several NaV1 channel subtypes that may contribute to the hyperexcitability characteristic of chronic pain states. The non-subtype selective, state-dependent NaV1 channel blockers lidocaine and carbamazepine are efficacious in the treatment of neuropathic pain; however, the target-driven development of novel sodium channel blocking analgesics has been generally unsuccessful. Recent human genetic data indicate an important role for the NaV1.7 channel subtype in pain signaling, and significant preclinical data identifies the NaV1.8 channel as a promising analgesic target, suggesting that the selective blockade of these subtypes may improve on the therapeutic index of sodium channel modulators. However, few subtype-selective small-molecule sodium channel blockers have been described. This review provides an overview of the NaV1 channel subtypes that are preferentially expressed in nociceptive neurons, the assay technologies used to develop NaV1 channel blockers, and a summary of recent advances in the development of subtype-selective and novel state-dependent NaV1 channel blockers.