Spinal Peroxynitrite Contributes to Remifentanil-induced Postoperative Hyperalgesia <i>via</i> Enhancement of Divalent Metal Transporter 1 without Iron-responsive Element–mediated Iron Accumulation in Rats

Shu, Ruichen; Zhang, Lin-Lin; Wang, Chunyan; Li, Nan; Wang, Haiyun; Xie, Keliang; Yu, Yonghao; Wang, Guolin

doi:10.1097/aln.0000000000000562

Cited by 38 publications

(30 citation statements)

References 57 publications

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“…To quantify mechanical and thermal allodynia, the mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) of one hind-limb paw were assessed using von Frey filaments (Stoelting Co., Wood Dale, IL, USA) [ 18 ] and a hot plate (7370, UgoBasile Biological Research Apparatus Co., Ltd., Italy), as previously described [ 19 ]. Tests were performed by an observer blind to the experimental procedures before the surgery (baseline) and at 6 h intervals during the 48 h after surgery.…”

Section: Methodsmentioning

confidence: 99%

Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord

Zhang

Tan

et al. 2016

PLoS ONE

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Toll-like receptor 4 (TLR4) is important for the pathogenesis of inflammatory reactions and the promotion of pain processing after ischemia/reperfusion (IR) in spinal cord. Recently, C-X-C chemokine ligand 12 (CXCL12) and its receptor, C-X-C chemokine receptor 4 (CXCR4), were demonstrated to be simultaneously critical for inflammatory reactions, thereby facilitating glial activation. However, whether CXCL12/CXCR4 expression can contribute to IR-induced inflammatory pain via spinal TLR4 remained unclear. A rat model was established by 8 min of aortic arch occlusion. The effects of CXCL12/CXCR4 expression and TLR4 activation on inflammatory hyperalgesia were investigated by pretreatments with CXCL12-neutralizing antibody, CXCR4 antagonist (AMD3100) and TLR4 antagonist (TAK-242) for 5 consecutive days before surgery. The results indicated that IR induced significant and sustained inflammatory pain, observed as decreases in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), throughout the post-injury period. The increased levels of TLR4 and proinflammatory chemokine CXCL12, as well as its receptor, CXCR4, were closely correlated with the PWT and PWL trends. Double immunostaining further suggested that TLR4, which is mainly expressed on astrocytes and microglia, was closely co-localized with CXCL12 and CXCR4 in spinal dorsal horn. As expected, intrathecal pretreatment with the TLR4 antagonist, TAK-242 markedly ameliorated pain by inhibiting astrocytic and microglial activation, as shown by decreases in TLR4 immunoreactivity and the percentage of double-labeled cells. These protective effects were likely due in part to the reduced production of the downstream cytokines IL-1β and TNF-α, as well as for the recruitment of CXCL12 and CXCR4. Additionally, intrathecal pretreatment with CXCL12-neutralizing antibody and AMD3100 resulted in similar analgesic and anti-inflammatory effects as those receiving TAK-242 pretreatment. These results suggest that intrathecal blockade of CXCL12/CXCR4 expression may attenuate IR-induced pain sensation and the release of inflammatory cytokines by limiting glial TLR4 activation in spinal cord.

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Section: Methodsmentioning

confidence: 99%

Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord

Zhang

Tan

et al. 2016

PLoS ONE

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“…Our previous study has identified the important role of aberrant iron accumulation in remifentanil-induced hyperalgesia in rats. 54 However, the cellular mechanism and signaling pathway involved in iron accumulation modulating pain hypersensitivity are unclear. In the present study, remifentanil was applied to the primary cultured SDH neurons to establish an in vitro model of OIH.…”

Section: Discussionmentioning

confidence: 99%

“…28,52,55 Our recent study in rats demonstrates the pathophysiological role of iron accumulation mediated by divalent metal transporter 1 without iron-responsive element [DMT1(-) IRE] in remifentanil-induced postoperative hyperalgesia due to abnormal peroxynitrite formation and subsequently mitochondria dysfunction. 54 However, current knowledge on the role of iron metabolism disorder in remifentanil-induced hyperalgesia is sparse. Thus, a hypothesis was proposed that NMDA receptor activation facilitates iron uptake via inducing Ca 2+ influx and ROS production in neurons, contributing to remifentanilinduced hyperalgesia.…”

mentioning

confidence: 99%

NMDA Receptor Modulates Spinal Iron Accumulation Via Activating DMT1(-)IRE in Remifentanil-Induced Hyperalgesia

Shu

Zhang

et al. 2021

The Journal of Pain

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“…Increasing clinical and experimental evidence has revealed that intraoperative infusion of remifentanil induced acute postoperative hyperalgesia (RIH) [25,26]. Recently, the role of ROS and inflammation in RIH has gained much attention and reducing spinal oxidative stress RIH effectively alleviated in rats [5][6][7]27]. BA, a plant-derived pentacyclic triterpene, potently reduces visceral pain accompanied by reducing lipid peroxidation and MMP-9, and activating SOD [14].…”

Section: Discussionmentioning

confidence: 99%

“…Al-Pharmacology 2018;102:300-306 DOI: 10.1159/000493144 though the activation of spinal N-methyl-D-aspartate (NMDA) receptor pathway is well known to play a key role in RIH, it is not feasible to attenuate RIH by inhibiting NMDA receptors owing to the inevitable side effects (e.g., psychogenia) [2][3][4]. Recently, the overproduction of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) by remifentanil is reported to directly activate neuronal NMDA receptors and matrix metalloproteinase-9 (MMP-9) and facilitate RIH [5][6][7]. Acute morphine induces a significant up-regulation of MMP-9 in dorsal root ganglion (DRG), mediating neuroinflammatory response and central hypersensitivity [8].…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

Mao

Shu

et al. 2018

Pharmacology

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Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 μg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (p < 0.01), and the significant increase in oxidative stress and inflammation evidenced by up-regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1β and tumour necrosis factor-α (p < 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (p < 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide dismutase activity (p < 0.01) compared with control and incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (p < 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down-regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn.

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Spinal Peroxynitrite Contributes to Remifentanil-induced Postoperative Hyperalgesia via Enhancement of Divalent Metal Transporter 1 without Iron-responsive Element–mediated Iron Accumulation in Rats

Abstract: Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and "iron-targeted" therapies.

Cited by 38 publications

References 57 publications

Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord

Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord

NMDA Receptor Modulates Spinal Iron Accumulation Via Activating DMT1(-)IRE in Remifentanil-Induced Hyperalgesia

Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

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