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

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 clinical trials seeking to treat pain by inhibiting Na V 1.7 pharmacologically have struggled. 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 similar 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 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 - 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.