Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance

Wang, Haiyan; Huang, Min; Wang, Wenying; Zhang, Yu; Ma, Xiaqing; Luo, Limin; Xu, Xiaojun; Xu, Liang; Shi, Haibo; Xu, Yongming; Wang, Aizhong; Xu, Tan

doi:10.1016/j.phrs.2021.105482

Cited by 33 publications

(22 citation statements)

References 55 publications

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“…Then the CCI + M3 + CNO and CCI + Vector + CNO mice were intraperitoneally injected with a dose of 3 mg/kg CNO with a syringe, while the CCI + M3 + saline and CCI + Vector + Saline mice received the same amount of saline. CCI + M3 + CNO + Yohimbine mice were injected with CNO [ 31 ] and intrathecal injected 5 μl yohimbine [ 32 ] between the L4/L5 intervertebral space with an insulin syringe (BD, USA) [ 33 ]. CCI + M3 + CNO + Saline mice received the same amount of saline.…”

Section: Methodsmentioning

confidence: 99%

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

Wei

Zhou

et al. 2022

J Neuroinflammation

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Background The noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury. Methods The Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro–adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated. Results Activation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice. Conclusion These findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

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Section: Methodsmentioning

confidence: 99%

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

Wei

Zhou

et al. 2022

J Neuroinflammation

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“…Significant NLRP3 inflammasome activation was observed in the prefrontal cortex and peripheral blood of morphine-treated mice [ 132 ]. Repeated exposures to morphine in wild-type mice increased the level of inflammation-related signals including NLRP3 inflammasome via the TLR4/NF-κB/NLRP3 pathway [ 133 ]. Procyanidins inhibit the morphine-induced activation of NLRP3 inflammasome and inflammatory responses in the microglia [ 134 ].…”

Section: Roles Of Nlrp Inflammasome In Neuropsychiatric Disordersmentioning

confidence: 99%

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

et al. 2022

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The NLRP inflammasome is a multi-protein complex which mainly consists of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain. Its activation is linked to microglial-mediated neuroinflammation and partial neuronal degeneration. Many neuropsychiatric illnesses have increased inflammatory responses as both a primary cause and a defining feature. The NLRP inflammasome inhibition delays the progression and alleviates the deteriorating effects of neuroinflammation on several neuropsychiatric disorders. Evidence on the central effects of the NLRP inflammasome potentially provides the scientific base of a promising drug target for the treatment of neuropsychiatric disorders. This review elucidates the classification, composition, and functions of the NLRP inflammasomes. It also explores the underlying mechanisms of NLRP inflammasome activation and its divergent role in neuropsychiatric disorders, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, depression, drug use disorders, and anxiety. Furthermore, we explore the treatment potential of the NLRP inflammasome inhibitors against these disorders.

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“…According to previous studies (Usui et al, 2016;Wang et al, 2011Wang et al, , 2021, rats were anaesthetized by intraperitoneal injection of 50 mg/kg sodium pentobarbital. After making a shallow incision, the lower 1/3 of the left tibia of the rat was exposed, and a hole was drilled.…”

Section: Bone Cancer Pain Modelmentioning

confidence: 99%

Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

et al. 2021

Journal of Neurochemistry

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Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance

Cited by 33 publications

References 55 publications

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

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