Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance.
Pharmacol Res
; 165: 105482, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33549727
ABSTRACT
BACKGROUND AND PURPOSE:
The aim of this work was to investigate the role and signal transduction of toll-like receptor 4 (TLR4), TGF-ß-activated kinase 1 (TAK1) and nod-like receptor protein 3 (NLRP3) in microglial in the development of morphine-induced antinociceptive tolerance.METHODS:
TLR4 and NLRP3 knockout mice and 5Z-7-oxozeaeno (a selective inhibitor against TAK1 activity) were used to observe their effect on the development of morphine tolerance. Intrathecal injections of morphine (0.75 mg/kg once daily for 7 days) were used to establish anti-nociceptive tolerance, which was measured by the tail-flick test. Spinal TLR4, TAK1, and NLRP3 expression levels and phosphorylation of TAK1 were evaluated by Western blotting and immunofluorescence.RESULTS:
Repeated treatment with morphine increased total expression of spinal TLR4, TAK1, and NLRP3 and phosphorylation of TAK1 in wild-type mice. TLR4 knockout attenuated morphine-induced tolerance and inhibited the chronic morphine-induced increase in NLRP3 and phosphorylation of TAK1. Compared with controls, mice that received 5Z-7-oxozeaenol showed decreased development of morphine tolerance and inhibition on repeated morphine-induced increase of NLRP3 but not TLR4. NLRP3 knockout mice showed resistance to morphine-induced analgesic tolerance with no effect on chronic morphine-induced expression of TLR4 and TAK1. TLR4, TAK1, and NLRP3 were collectively co-localized together and with the microglia marker Iba1.CONCLUSIONS:
Microglial TLR4 regulates TAK1 expression and phosphorylation and results in NLRP3 activation contributes to the development of morphine tolerance through regulating neuroinflammation. Targeting TLR4-TAK1-NLRP3 signaling to regulate neuro-inflammation will be alternative therapeutics and strategies for chronic morphine-induced antinociceptive tolerance.Palavras-chave
5Z-7-oxozeaeno (PubChem CID: 9863776); DAPI dihydrochloride(PubChem CID:160166); Dimethyl sulfoxide (PubChem CID: 679); Formaldehyde (PubChem CID: 712); Morphine (PubChem CID: 5288826); Morphine tolerance; Neuroinflammation; Nod-like receptor protein 3, NLRP3; Pentobarbital (PubChem CID: 4737); TAK1, TGF-ß-activated kinase 1; TLR4, toll-like receptor 4
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Microglia
/
MAP Quinase Quinase Quinases
/
Tolerância a Medicamentos
/
Receptor 4 Toll-Like
/
Proteína 3 que Contém Domínio de Pirina da Família NLR
/
Morfina
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article