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

Shu, Ruichen; Zhang, Lin-Lin; Zhang, Hao; Li, Yuan; Wang, Chunyan; Su, Lin; Zhao, Hongwei; Wang, Guolin

doi:10.1016/j.jpain.2020.03.007

Cited by 14 publications

(9 citation statements)

References 60 publications

(57 reference statements)

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“…In addition, the mevalonate pathway produces antioxidants or activates selenocysteine transfer RNA, which enhances GPX4 expression [ 36 ]. Consistent with these findings, extracellular glutamate concentrations are markedly increased in MCAO rats, which accelerates neuronal iron uptake and results in excitotoxicity-related cell death [ 86 , 87 ].…”

Section: Ferroptosis and Cerebral Ischemiamentioning

confidence: 77%

“…Besides, glutaminase 2 is the p53 target gene, and upregulation of glutaminase 2 results in p53-dependent ferroptosis [ 85 ]. Glutaminolysis and the glutamine-fueled intracellular metabolic pathway [ 84 ] also contribute to cysteine deprivation and increase of glutamate levels, which activates glutamate N-methyl-D-aspartic acid receptors and accelerates neuronal iron uptake [ 86 ]. Because cysteine availability is the limiting factor for the biosynthesis of glutathione, some cells that are resistant to ferroptosis induced by system x c − inhibitors leverage the transsulfuration pathway to biosynthesize cysteine from methionine and subsequently bypass the requirement for cystine import via the cystine/glutamate antiporter system x c − [ 74 ].…”

Section: Ferroptosis and Cerebral Ischemiamentioning

confidence: 99%

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Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.

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Section: Ferroptosis and Cerebral Ischemiamentioning

confidence: 77%

Section: Ferroptosis and Cerebral Ischemiamentioning

confidence: 99%

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Neuronal iron accumulation is indispensable for the functional plasticity of excitatory glutaminergic synapses [ 15 , 30 , 31 ]. The tight interaction between neuroinflammation and iron overload has been revealed in several pathological conditions [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…One limitation is that we did not evaluate the distribution of CXCL1, CXCR2 and TfR1 proteins in the spinal dorsal horn using immunohistochemistry staining in our fracture pain models, which should be addressed in future. In addition, previous reports revealed that divalent metal transporter 1 (DMT1) is one of the most important regulators in neural iron overload during opioid-induced acute hyperalgesia and fracture-caused chronic allodynia [ 15 , 16 , 19 ]. Given that DMT1 is also a key target of hydrogen analgesia in remifentanil-caused hyperalgesia [ 19 ], it will be interesting to study whether DMT1 is implicated in hydrogen-rich saline antinociception in our mouse model of chronic fracture allodynia.…”

Section: Discussionmentioning

confidence: 99%

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Hydrogen-Rich Saline Attenuates Chronic Allodynia after Bone Fractures via Reducing Spinal CXCL1/CXCR2-Mediated Iron Accumulation in Mice

Wang

Liu

et al. 2022

Brain Sciences

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Purpose: Neuroinflammation often initiates iron overload in the pathogenesis of neurological disorders. Chemokine-driven neuroinflammation is required for central sensitization and chronic allodynia following fractures, but specific molecular modulations are elusive. This present study explored whether hydrogen-rich saline, as one potent anti-inflammatory pharmaceutical, could alleviate fracture-caused allodynia by suppressing chemokine CXCL1 expression and iron overload. Methods: A mouse model of tibial fracture with intramedullary pinning was employed for establishing chronic allodynia. Three applications of hydrogen-rich saline (1, 5 or 10 mL/kg) were administrated intraperitoneally on a daily basis from days 4 to 6 following fractures. Spinal CXCL1 and its receptor CXCR2 levels, transferrin receptor 1 (TfR1) expression and iron concentration were examined. Recombinant CXCL1, a selective CXCR2 antagonist and an iron chelator were used for verification of mechanisms. Results: Repetitive injections of hydrogen-rich saline (5 and 10 mL/kg but not 1 mL/kg) prevent fracture-caused mechanical allodynia and cold allodynia in a dose-dependent manner. Single exposure to hydrogen-rich saline (10 mL/kg) on day 14 after orthopedic surgeries controls the established persistent fracture allodynia. Furthermore, hydrogen-rich saline therapy reduces spinal CXCL1/CXCR2 over-expression and TfR1-mediated iron accumulation in fracture mice. Spinal CXCR2 antagonism impairs allodynia and iron overload following fracture surgery. Intrathecal delivery of recombinant CXCL1 induces acute allodynia and spinal iron overload, which is reversed by hydrogen-rich saline. Moreover, iron chelation alleviates exogenous CXCL1-induced acute pain behaviors. Conclusions: These findings identify that hydrogen-rich saline confers protection against fracture-caused chronic allodynia via spinal down-modulation of CXCL1-dependent TfR1-mediated iron accumulation in mice.

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Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial

et al. 2023

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Introduction Several factors may lead to increased postoperative pain sensitivity, of which remifentanil-induced hyperalgesia (RIH) is one of the main factors. High-dose remifentanil exposure during anesthesia may induce RIH. Esketamine may prevent RIH by antagonizing N -methyl- d -aspartate (NMDA) receptors, thereby reducing the postoperative pain sensitivity. This study examined the effects of different esketamine doses on pain sensitivity in patients undergoing thyroidectomy and determined the optimal dose. Methods This study included 117 patients who received elective thyroidectomy. They were randomized into four groups: saline group (group C), esketamine 0.2 mg·kg −1 group (group RK1), esketamine 0.4 mg·kg −1 group (group RK2), and esketamine 0.6 mg·kg −1 group (group RK3). Five minutes before anesthesia induction, the same volume of study drugs were injected respectively in groups C, RK1, RK2, and RK3. Remifentanil was pumped at the same rate of 0.3 µg·kg −1 ·min −1 during surgery to ensure uniformity. This study’s primary outcomes were the mechanical pain thresholds measured before surgery, as well as at 30 min, 6 h, 24 h, and 48 h after surgery. Hyperalgesia, rescue analgesia, numerical rating scale (NRS) score, and adverse reactions were recorded. Results Compared with baseline, the mechanical pain threshold was significantly decreased in group C [(94.67 ± 22.85) versus (112.00 ± 36.62) versus (161.33 ± 53.28) g, P < 0.001 at 30 min, P < 0.001 at 6 h] and group RK1 [(102.86 ± 24.17) versus (114.29 ± 41.05) versus (160.00 ± 54.98) g, P < 0.001 at 30 min, P < 0.001 at 6 h] around the surgical incision, and in group C [(112.00 ± 31.78) versus (170.67 ± 56.26) g, P < 0.001 at 30 min, (118.67 ± 34.42) versus (170.67 ± 56.26) g, P = 0.001 at 6 h] and group RK1 [(114.29 ± 45.17) versus (175.71 ± 54.80) g, P = 0.001 at 30 min, (121.43 ± 38.46) versus (175.71 ± 54.80) g, P = 0.002 at 6 h] on the forearm at 30 min and 6 h after surgery; compared with group C, the mechanical pain threshold was higher in group RK2 [(142.76 ± 50.06) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (145.52 ± 49.83) versus (112.00 ± 36.62) g, P < 0.001 at 6 h] and group RK3 [(140.00 ± 40.68) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (150.67 ± 56.50) versus (112.00 ± 36.62) g, P = 0.010 at 6 h] around the surgical incision, and in group RK2 [(149.66 ± 39.50) versus (112.00 ± 31.78) g, P = 0.006 at 30 min, (156.55 ± 47.23) versus...

show abstract

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

Cited by 14 publications

References 60 publications

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Hydrogen-Rich Saline Attenuates Chronic Allodynia after Bone Fractures via Reducing Spinal CXCL1/CXCR2-Mediated Iron Accumulation in Mice

Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial

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