Subtype-selective sodium channel blockers promise a new era of pain research

Abstract

Chronic pain affects ≈1.5 million patients worldwide. Despite several treatment options, successful pain management is difficult to achieve, and this area of therapy remains a major unmet medical need. Chronic pain is thought to originate from aberrant electrical signaling in the nervous system. Pain-sensing neurons of the peripheral nervous system express several sodium channel (Nav1) subtypes. Their relative contribution to pain signaling is the subject of intense research and debate, and they may vary depending on the cause, anatomical location, and sensory qualities of pain. Knockdown of individual sodium channel subtypes in rodents, either by genetic ablation or through treatment with antisense oligonucleotides, has provided important information on this subject. However, interpretation of the results may be confounded by compensatory mechanisms, in the case of genetic ablation, or residual protein expression and inflammation associated with the oligonucleotide administration, in the case of the antisense technology. Subtype-selective pharmacological agents are needed to identify unambiguously the roles of individual Nav1 subtypes, but, despite years of efforts, such agents have been difficult to identify. The manuscript by Jarvis et al. (1) in this issue of PNAS reveals the first reputed Nav1.8-selective small-molecule sodium channel blocker to be publicly disclosed. By providing a much-sought-after exciting new tool, this work represents a …