Similar 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_V1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting Na_V1.7 pharmacologically have struggled. This may reflect the variable contribution of Na_V1.7 to nociceptor excitability. Contrary to claims that Na_V1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of Na_V1.3, Na_V1.7, and Na_V1.8. Selectively blocking one of those Na_V subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on Na_V1.8 in acutely dissociated nociceptors but responsibility shifts to Na_V1.7 and Na_V1.3 by the fourth day in culture. A similar shift in Na_V dependence occurs in vivo after inflammation, impacting ability of the Na_V1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different Na_V subtypes exemplifies degeneracy - achieving similar function using different components - and compromises 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.