Targeting the tamoxifen receptor within sodium channels to block osteoarthritic pain

Voltage-gated sodium channels (NaV) in nociceptive neurons initiate action potentials required for transmission of aberrant painful stimuli observed in osteoarthritis (OA). Targeting NaV subtypes with drugs to produce analgesic effects for OA pain management is a developing therapeutic area. Previously, we determined the receptor site for the tamoxifen analog N-desmethyltamoxifen (ND-Tam) within a prokaryotic NaV. Here, we report the pharmacology of ND-Tam against eukaryotic NaVs natively expressed in nociceptive neurons. ND-Tam and analogs occupy two conserved intracellular receptor sites in domains II and IV of NaV1.7 to block ion entry using a “bind and plug” mechanism. We find that ND-Tam inhibition of the sodium current is state dependent, conferring a potent frequency- and voltage-dependent block of hyperexcitable nociceptive neuron action potentials implicated in OA pain. When evaluated using a mouse OA pain model, ND-Tam has long-lasting efficacy, which supports the potential of repurposing ND-Tam analogs as NaV antagonists for OA pain management. [Display omitted] •Tamoxifen metabolites inhibit NaVs responsible for aberrant pain in OA•A “bind and plug” mechanism confers selective inhibition of NaVs in hyperexcitable neurons•Metabolites outperform conventional NaV antagonists in in vitro and in vivo OA pain assays•Targeting NaVs with prototypic analogs may be a viable strategy for OA pain management McCollum et al. explore the pharmacology of tamoxifen metabolites against NaVs—ion-conducting proteins responsible for aberrant pain signaling in neurons. These chemicals use a “bind and plug” mechanism that confers selective inhibition of NaVs in hyperexcitable neurons, which might be a viable strategy for osteoarthritis pain management.