Equivalent excitability through different sodium channel subtypes and implications for analgesia by subtype-selective drugs

Abstract

ABSTRACTNociceptive sensory neurons convey pain signals to the CNS. Nociceptor hyperexcitability amplifies those signals, causing pain hypersensitivity. Reducing nociceptor excitability should mitigate that hypersensitivity, consistent with the effects of loss-of-function mutations in voltage-gated sodium (NaV) channels like NaV1.7. Yet efforts to phenocopy such mutations pharmacologically have failed in clinical trials. This failure may stem from the degenerate nature of nociceptor excitability. Here, we show that nociceptors can achieve equivalent excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. If NaV1.3 and/or NaV1.8 levels are high enough to maintain nociceptor excitability, selectively blocking NaV1.7 (e.g. with PF-05089771) becomes inconsequential. We demonstrate shifts in drug efficacy by comparing neurons tested after different numbers of days in vitro (DIV): Nociceptor excitability relies on NaV1.8 at DIV0 but that responsibility shifts to NaV1.7 and NaV1.3 on DIV4-7. A similar shift in NaV-dependence occurs in vivo, following inflammation, and impacts the ability of PF-05089771 to modulate pain sensitivity. These results demonstrate that nociceptors are surprisingly flexible in using different NaV isoforms to regulate excitability. This flexibility poses a serious problem for subtype-selective drugs whose efficacy hinges on such vagaries. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.