Equivalent excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Abstract

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel Na V 1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but efforts to treat pain by inhibiting Na V 1.7 pharmacologically have largely failed. This may reflect the variable contribution of Na V 1.7 to nociceptor excitability. Contrary to claims that Na V 1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve equivalent excitability using different combinations of Na V 1.3, Na V 1.7, and Na V 1.8. Selectively blocking one of those Na V subtypes reduces nociceptor excitability only if the other two subtypes are weakly expressed. For example, excitability relies on Na V 1.8 in acutely dissociated nociceptors but responsibility shifts to Na V 1.7 and Na V 1.3 by the fourth day in culture. A similar shift in Na V dependence occurs in vivo after inflammation, impacting ability of the Na V 1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different Na V subtypes exemplifies degeneracy – equivalent function using different components – and compromises the reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant Na V subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.Nociceptors can achieve equivalent excitability using different sodium channel subtypes. The analgesic efficacy of subtype-selective drugs hinges on which subtype controls excitability. This contingency likely contributes to poor clinical outcomes.