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

Abstract

Nociceptive 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.

Homeostatic regulation of neuronal function: importance of degeneracy and pleiotropy

“…For instance, the sodium channels Na V 1.7 and Na V 1.8 both activate during action potentials, but because it activates at voltages near threshold, Na V 1.7 is typically ascribed an important role in spike initiation whereas Na V 1.8, because it activates at suprathreshold voltages, is thought to contribute exclusively to the depolarizing upswing of the spike, only after initiation has occured (Bennett et al, 2019); in that sense, the two channels are functionally distinct. However, in the absence (or upon inactivation) of Na V 1.7, voltage threshold shifts into the range where Na V 1.8 activates, allowing Na V 1.8 to contribute to spike initiation (Xie et al, 2022), thus revealing greater functional overlap than comparison of their voltage-sensitivities suggests and, more generally, that functional overlap can be context-dependent.…”

“…Differences in activation (m) and inactivation (h) (bottom) explain differences in the spike waveform and energy efficiency. Na V 1.8 and Na V 1.7 models correspond to models for day in vitro 0 and 4-7, respectively, from Xie et al (2022). 2020).…”

“…This suggests that neurological disorders involving a chronic increase or decrease in neuronal excitability reflect a problem in homeostatic regulation rather than a problem with any one ion channel (Ratté and Prescott, 2016). Lossor gain-of-function mutations in channels like Na V 1.7, which cause congenital insensitivity to pain or painful neuropathies, respectively, seem to provide persuasive counterarguments, but when one digs deeper, the inconsistencies support rather than disprove the role of homeostatic regulation (Xie et al, 2022). Below, we discuss the different ways homeostatic regulation of excitability can fail.…”