Targeting the tamoxifen receptor within sodium channels to block osteoarthritic pain.

ABSTRACT: Voltage-gated sodium channels (Na_V) in nociceptive neurons initiate action potentials required for transmission of aberrant painful stimuli observed in osteoarthritis (OA). Targeting Na_V 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 Na_V. Here, we report the pharmacology of ND-Tam against eukaryotic Na_Vs natively expressed in nociceptive neurons. ND-Tam and analogs occupy two conserved intracellular receptor sites in domains II and IV of Na_V1.7 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 Na_V antagonists for OA pain management.

SUBMITTER: McCollum MM 

PROVIDER: S-EPMC9523973 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature