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 Na1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting Na1.7 pharmacologically have struggled. This may reflect the variable contribution of Na1.7 to nociceptor excitability. Contrary to claims that Na1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of Na1.3, Na1.7, and Na1.8. Selectively blocking one of those Na subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on Na1.8 in acutely dissociated nociceptors but responsibility shifts to Na1.7 and Na1.3 by the fourth day in culture. A similar shift in Na dependence occurs in vivo after inflammation, impacting ability of the Na1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different Na subtypes exemplifies degeneracy - achieving similar function using different components - and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant Na subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.