Targeting the tamoxifen receptor within sodium channels to block osteoarthritic pain

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McCollum, Megan M. ; Larmore, Megan ; Ishihara, Shingo ; Ng, Leo C. T. ; Kimura, Louise F. ; Guadarrama, Eduardo ; Ta, My C. ; Vien, Thuy N. ; Frost, Grant B. ; Scheidt, Karl A. ; Miller, Rachel E. ; DeCaen, Paul G.

• Document type: Journal article
• Source: CELL REPORTS; v. 40, n. 8, p. 16-pg., 2022-08-23.

Abstract

Voltage-gated sodium channels (NaV) in nociceptive neurons initiate action potentials required for transmis-sion 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 nocicep-tive 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. (AU)

• FAPESP's process: 19/26414-2 - Electrophysiological characterization of primary cilium ionic currents of dorsal root ganglia neurons upon inflammatory stimulation and their modulation by crotalphine
• Grantee: Louise Faggionato Kimura Vieira
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor