| Texto completo | |
| Autor(es): Mostrar menos - |
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.
Número total de Autores: 12
|
| Tipo de documento: | Artigo Científico |
| Fonte: | CELL REPORTS; v. 40, n. 8, p. 16-pg., 2022-08-23. |
| Resumo | |
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) | |
| Processo FAPESP: | 19/26414-2 - Caracterização eletrofisiológica das correntes iônicas do cílio primário dos neurônios dos gânglios da raiz dorsal após estimulação inflamatória e sua modulação pela crotalfina |
| Beneficiário: | Louise Faggionato Kimura Vieira |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado |