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Papers of the Week

Papers: 20 Aug 2022 - 26 Aug 2022

Animal Studies, Pharmacology/Drug Development

2022 Aug 23

Cell Rep



Editor's Pick

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


McCollum MM, Larmore M, Ishihara S, Ng LCT, Kimura LF, Guadarrama E, Ta MC, Vien TN, Frost GB, Scheidt KA, Miller RE, Decaen PG
Cell Rep. 2022 Aug 23; 40(8):111248.
PMID: 36001977.


Voltage-gated sodium channels (Na) in nociceptive neurons initiate action potentials required for transmission of aberrant painful stimuli observed in osteoarthritis (OA). Targeting Na 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. Here, we report the pharmacology of ND-Tam against eukaryotic Nas natively expressed in nociceptive neurons. ND-Tam and analogs occupy two conserved intracellular receptor sites in domains II and IV of Na1.7 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 antagonists for OA pain management.