Abstract
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.
Original language | English (US) |
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Article number | 111248 |
Journal | Cell reports |
Volume | 40 |
Issue number | 8 |
DOIs | |
State | Published - Aug 23 2022 |
Funding
We thank Dr. Christopher H. Thompson and Dr. Al George for their advice on analyzing current-clamp datasets. We thank Dongjun Ren from the laboratory of Dr. Daniela Menichella for demonstrating the DRG neuron isolation protocol. We thank all members of the DeCaen lab for their useful scientific discussions. The authors acknowledge their respective funding agencies: P.G.D. was supported by NIH NIDDK ( 1R01 DK123463-01 ). M.L. was supported by NU’s Molecular Biophysics Training Program through NIH NIGMS ( 5T32 GM008382 ). The R.E.M. group was supported by NIH NIAMS ( R01 AR077019 ). R.E.M. was supported by NIH grants R01AR077019 and P30AR079206 . K.A.S. was supported by Northwestern University , and L.F.K. was supported by a fellowship from the Sao Paulo Research Foundation (FAPESP-2019/26414-2).
Keywords
- CP: Neuroscience
- DRG neurons
- molecular pharmacology
- nociceptors
- osteoarthritis
- pain
- sodium channel
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology