Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Pharmacology ; 103(5-6): 257-262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30759446

RESUMO

Osteoarthritic pain has a strong impact on patients' quality of life. Understanding the pathogenic mechanisms underlying osteoarthritic pain will likely lead to the development of more effective treatments. In the present study of osteoarthritic model rats, we observed a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNAs in dorsal root ganglia (DRG) neurons, which were associated with hyperalgesic behaviors. The activation of KCNQ/M channels with flupirtine significantly increased the mechanical threshold and prolonged the withdrawal latency of osteoarthritic model rats at 3-14 days after model induction, and all effects of flupirtine were blocked by KCNQ/M-channel antagonist, XE-991. Together, these results indicate that suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of osteoarthritic pain.


Assuntos
Aminopiridinas/farmacologia , Artrite Experimental/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Analgésicos/farmacologia , Animais , Antracenos/farmacologia , Artrite Experimental/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Canal de Potássio KCNQ2/efeitos dos fármacos , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/efeitos dos fármacos , Canal de Potássio KCNQ3/metabolismo , Masculino , Osteoartrite/fisiopatologia , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley
2.
Pflugers Arch ; 455(1): 115-24, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17447081

RESUMO

The open state of M(Kv7.2/7.3) potassium channels is maintained by membrane phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)). They can be closed on stimulating receptors that induce PI(4,5)P(2) hydrolysis. In sympathetic neurons, closure induced by stimulating M1-muscarinic acetylcholine receptors (mAChRs) has been attributed to depletion of PI(4,5)P(2), whereas closure by bradykinin B(2)-receptors (B2-BKRs) appears to result from formation of IP(3) and release of Ca(2+), implying that BKR stimulation does not deplete PI(4,5)P(2). We have used a fluorescently tagged PI(4,5)P(2)-binding construct, the C-domain of the protein tubby, mutated to increase sensitivity to PI(4,5)P(2) changes (tubby-R332H-cYFP), to provide an on-line read-out of PI(4,5)P(2) changes in single living sympathetic neurons after receptor stimulation. We find that the mAChR agonist, oxotremorine-M (oxo-M), produces a near-complete translocation of tubby-R332H-cYFP into the cytoplasm, whereas bradykinin (BK) produced about one third as much translocation. However, translocation by BK was increased to equal that produced by oxo-M when synthesis of PI(4,5)P(2) was inhibited by wortmannin. Further, wortmannin 'rescued' M-current inhibition by BK after Ca(2+)-dependent inhibition was reduced by thapsigargin. These results provide the first direct support for the view that BK accelerates PI(4,5)P(2) synthesis in these neurons, and show that the mechanism of BKR-induced inhibition can be switched from Ca(2+) dependent to PI(4,5)P(2) dependent when PI(4,5)P(2) synthesis is inhibited.


Assuntos
Canal de Potássio KCNQ2/efeitos dos fármacos , Canal de Potássio KCNQ2/metabolismo , Neurônios/metabolismo , Fosfatidilinositol 4,5-Difosfato/fisiologia , Bloqueadores dos Canais de Potássio , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Animais , Bradicinina/farmacologia , Células CHO , Membrana Celular/metabolismo , Cricetinae , Cricetulus , DNA Complementar/biossíntese , DNA Complementar/genética , Agonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Fosfatidilinositol 4,5-Difosfato/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gânglio Cervical Superior/citologia , Gânglio Cervical Superior/efeitos dos fármacos , Translocação Genética
3.
Neuropharmacology ; 51(6): 1068-77, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16904708

RESUMO

The family of Kv7 (KCNQ) potassium channels consists of five members. Kv7.2 and 3 are the primary molecular correlates of the M-current, but also Kv7.4 and Kv7.5 display M-current characteristics. M-channel modulators include blockers (e.g., linopirdine) for cognition enhancement and openers (e.g., retigabine) for treatment of epilepsy and neuropathic pain. We investigated the effect of a Bristol-Myers Squibb compound (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide [(S)-1] on cloned human Kv7.1-5 potassium channels expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp recordings we found that (S)-1 blocks Kv7.1 and Kv7.1/KCNE1 currents. In contrast, (S)-1 produced a hyperpolarizing shift of the activation curve for Kv7.2, Kv7.2/Kv7.3, Kv7.4 and Kv7.5. Further, the compound enhanced the maximal current amplitude at all potentials for Kv7.4 and Kv7.5 whereas the combined activation/block of Kv7.2 and Kv7.2/3 was strongly voltage-dependent. The tryptophan residue 242 in S5, known to be crucial for the effect of retigabine, was also shown to be critical for the enhancing effect of (S)-1 and BMS204352. Furthermore, no additive effect on Kv7.4 current amplitude was observed when both retigabine and (S)-1 or BMS204352 were applied simultaneously. In conclusion, (S)-1 differentially affects the Kv7 channel subtypes and is dependent on a single tryptophan for the current enhancing effect in Kv7.4.


Assuntos
Acrilamidas/farmacologia , Canais de Potássio KCNQ/efeitos dos fármacos , Morfolinas/farmacologia , Neurônios/metabolismo , Acrilamidas/metabolismo , Algoritmos , Animais , Sítios de Ligação/efeitos dos fármacos , DNA Complementar/biossíntese , DNA Complementar/genética , Eletrofisiologia , Humanos , Canais de Potássio KCNQ/genética , Canal de Potássio KCNQ1/efeitos dos fármacos , Canal de Potássio KCNQ2/efeitos dos fármacos , Cinética , Morfolinas/metabolismo , Neurônios/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Mutação Puntual/efeitos dos fármacos , Triptofano/efeitos dos fármacos , Triptofano/metabolismo , Xenopus laevis
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA