Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

Bai, Liying; Zhai, Cai-Hong; Han, Kun; Li, Zhisong; Qian, Junliang; Jing, Ying; Zhang, Wei; Xu, Ji‐Tian

doi:10.1007/s12264-014-1483-7

Cited by 60 publications

(46 citation statements)

References 47 publications

(61 reference statements)

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“…MMP-9 has been proven to cleave IL-1β, which is one of the most important pro-inflammatory cytokines in nervous system and promotes the development of opioid-induced tolerance and hyperalgesia [33]. Our data demonstrated that intraoperative remifentanil infusion induced the up-regulation of mature active IL-1β in both DRG neurons and SGCs, and NAC decreased remifentanil-induced IL-1β activation via inhibiting MMP-9.…”

Section: Discussionmentioning

confidence: 61%

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

Liu

Zhang

et al. 2017

Oncotarget

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Treatment of remifentanil-induced postoperative hyperalgesia (RIH) remains a clinical challenge because the mechanisms are not fully understood. Matrix metalloproteinase-9 (MMP-9) is a key component in neuroinflammation because of its facilitation of pro-inflammatory cytokine maturation. Therefore, inhibition of MMP-9 may represent a novel therapeutic approach to the treatment of RIH. Sprague-Dawley rats were randomly divided into three groups: Control, Incision and Remifentanil. A right plantar surgical incision was performed in Group Incision, and intraoperative remifentanil (0.04 mg/kg, 0.4 ml) was infused subcutaneously for 30 min in Group Remifentanil. The results indicated that intraoperative remifentanil induced an up-regulation and activation of MMP-9 in DRGs but not spinal cords. MMP-9 was expressed primarily in DRG neurons co-expressing mu opioid receptors (MOR), and elicited interleukin-1β (IL-1β) cleavage in DRG neurons and satellite glial cells (SGCs). Intraperitoneal injection of N-acetyl-cysteine (NAC), a broadly used safe drug, significantly attenuated RIH via suppressing the activation of MMP-9 in DRGs. NAC inhibited the cleavage of IL-1β in DRGs, which is a critical substrate of MMP-9, and markedly suppressed glial activation and neuron excitability in spinal dorsal horn induced by remifentanil. These results demonstrated that NAC can effectively alleviate RIH via powerfully inhibiting MMP-9 activation in DRGs.

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Section: Discussionmentioning

confidence: 61%

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

Liu

Zhang

et al. 2017

Oncotarget

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“…Astrocytes and microglia are activated after chronic morphine treatment in mice spinal cord789, and the activated glias can increase the release of pro-inflammatory cytokines such as TNF-α and IL-1β101112 to further promote the development of morphine tolerance. The western blot results showed that the levels of GFAP (an astrocytic marker), IBA1 (a microglial marker) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Chronic morphine treatment can significantly increase the release of different neurotransmitters such as glutamate (Glu), which binds to the NMDA receptor to enhance the excitatory synaptic transmission56. It also activates the astrocytes and microglia789, leading to the release of the pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β)101112 to promote the morphine tolerance.…”

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confidence: 99%

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

Dai

Xiong

Yan

et al. 2016

Sci Rep

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Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Morphine is a highly efficacious agent against chronic severe pain. However, repeated morphine administration leads to antinociceptive tolerance which discontinues morphine therapy for chronic pain. The cellular and molecular mechanisms underlying morphine tolerance are still not fully understood. Morphine is known to exert analgesic effect mainly by activating MOR encoded by the MOR-1 gene. And in MOR-1 knockout mice, the analgesia and tolerance of morphine are absent 1,2 . These results suggested that morphine tolerance may be partly mediated by MOR and it has been reported that MOR desensitization 3,4 contributes to the development of morphine tolerance. In addition, central sensitization also promotes the development and maintenance of morphine tolerance. Chronic morphine treatment can significantly increase the release of different neurotransmitters such as glutamate (Glu), which binds to the NMDA receptor to enhance the excitatory synaptic transmission 5,6 . It also activates the astrocytes and microglia 7-9 , leading to the release of the pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα ) and interleukin-1β (IL-1β ) 10-12 to promote the morphine tolerance.D2DR, a dopamine receptor subtype which affects the locomotion, reward and abuse of opioids [13][14][15][16] has been reported to be involved in morphine-induced nociception modulation in rats. Activation of D2DR by quinpirole in hypothalamic A11 cell group 17 , ventrolateral orbital cortex (VLO) 18 and dorsal hippocampus (CA1) 19 of rats exerts antinociceptive effect. Intraperitoneal injection of quinpirole enhances the antinociceptive effect of morphine 20 . However, Michael A. King and colleagues reported that the effect of opioid analegesia is potentiated in D2DR knock-out mice 21 . Therefore, the apparent analgesia effect and mechanism of D2DR were still not clear. And the effect and mechanism of D2DR on morphine tolerance has also not been elucidated.The present study was performed to investigate the possible role of D2DR in morphine tolerance at spinal levels of mice. Our results indicated that chronic morphine treatment increased the neuronal D2DR expression

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“…Western blotting was performed according to our published procedures [30,31]. Briefly, the animals were sacrificed by decapitation and the L4-5 spinal dorsal horns were harvested and placed temporarily in liquid nitrogen.…”

Section: Western Blottingmentioning

confidence: 99%

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

Bai

Wang

et al. 2016

Neurosci. Bull.

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Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism. Here, we determined that spared nerve injury (SNI) increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia (DRG) neurons and satellite glial cells. SNI also induced longlasting upregulation of CXCL12 and CXCR4 in the ipsilateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNIinduced a sustained increase in TNF-a expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-a synthesis inhibitor thalidomide reduced the SNI-induced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection (i.t.) of the CXCR4 antagonist AMD3100, both 30 min before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. administration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the activation of ERK in the spinal cord. The mechanical hypersensitivity induced in naïve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-a might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL12/CXCR4 signaling via ERK activation contributes to the development and maintenance of neuropathic pain.

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Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

Cited by 60 publications

References 47 publications

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

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