Equivalent 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 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.