Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain

Vincent, Kathleen; Wang, Shu Fan; Laferrière, André; Kumar, Naresh; Coderre, Terence J.

doi:10.1097/j.pain.0000000000000823

Cited by 35 publications

(24 citation statements)

References 37 publications

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“… 12 Accumulating evidence suggests that mGluR5 is a crucial mediator of glutamate-induced neuroplasticity underlying persistent pain. 46 – 50 Since blocking P2X4 or TrkB receptors prevents the upregulation of EAAT3 and trigeminal allodynia, pharmacological blockade of these receptors may represent a potential therapeutic approach for treating trigeminal allodynia, as seen in migraineurs. More studies are needed to further investigate the precise mechanisms underlying microglia-neuron interactions in the pathophysiology of chronic migraine.…”

Section: Discussionmentioning

confidence: 99%

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P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia

et al. 2018

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ObjectivePrevious studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model.MethodsP2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis.ResultsRepeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons.ConclusionsThese data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia–neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

“…Glutamate influx through EAAT3 may further activate intracellular metabotropic glutamate 5 receptor (mGluR5), which is essential for enhanced Ca 2+ -dependent Fos and plays a crucial role in the glutamate-induced neuroplasticity underlying persistent pain. 12 , 46 – 50 …”

Section: Discussionmentioning

confidence: 99%

P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia

et al. 2018

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“…Using permeable mGlu5 antagonists reaching the cytoplasm, the authors have demonstrated that blocking intracellular mGlu5 had a greater antinociceptive effect than by blocking cell membrane expressed mGlu5 (Vincent et al, 2016). Pre-treatment with an excitatory amino acid transporter (EAAT) inhibitor, which is meant to decrease intracellular glutamate levels, decreases pain-related behavior in an inflammatory pain model (Vincent et al, 2017).…”

Section: Role Of Mglur In Pain Transmission At the Spinal Cord Levelmentioning

confidence: 99%

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Pereira

Goudet

2019

Front. Mol. Neurosci.

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Pain is an essential protective mechanism meant to prevent tissue damages in organisms. On the other hand, chronic or persistent pain caused, for example, by inflammation or nerve injury is long lasting and responsible for long-term disability in patients. Therefore, chronic pain and its management represents a major public health problem. Hence, it is critical to better understand chronic pain molecular mechanisms to develop innovative and efficient drugs. Over the past decades, accumulating evidence has demonstrated a pivotal role of glutamate in pain sensation and transmission, supporting glutamate receptors as promising potential targets for pain relieving drug development. Glutamate is the most abundant excitatory neurotransmitter in the brain. Once released into the synapse, glutamate acts through ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels triggering fast excitatory neurotransmission, and metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors modulating synaptic transmission. Eight mGluRs subtypes have been identified and are divided into three classes based on their sequence similarities and their pharmacological and biochemical properties. Of note, all mGluR subtypes (except mGlu6 receptor) are expressed within the nociceptive pathways where they modulate pain transmission. This review will address the role of mGluRs in acute and persistent pain processing and emerging pharmacotherapies for pain management.

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“…An increasing body of evidence suggests that glutamatergic mechanisms and glutamate receptors are involved in the regulation of pain, i.e. pain transmission [16].…”

Section: Discussionmentioning

confidence: 99%

Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems

Erdinç

Uyar

Kelle

et al. 2019

Psychiatry and Clinical Psychopharmacology

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OBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that Nmethyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine is a non-competitive NMDA receptor antagonist drug and has well-known antinociceptive properties. The drug acts not only on NMDA receptors but also has effects on the monoaminergic system and non-NMDA glutamatergic receptors which have vital roles in the regulation of pain. This study was conducted to investigate the serotonergic and glutamatergic involvement in low-dose ketamine (20 mg/ kg) analgesia in mice. METHOD: The effects of serotonin were suppressed with two different ways; either the serotonin was depleted with p-chlorophenylalanine (pCPA, 150 mg/kg/d; 4 days) or the serotonin receptors were blocked with methiothepin (0.1 mg/kg), and α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) receptors were antagonized with GYKI-52466 (20 mg/kg). Fluoxetine (20 mg/kg; 7 days) was used to increase the serotoninergic activity. We used a hotplate (HP) test to measure pain reaction latencies. Furthermore, we tested sustained analgesic effects of ketamine for six consecutive times (1-hour break between each test). RESULTS: In our experiment, ketamine treatment increased pain reaction latencies, yet it failed to increase the latencies when combined with antiserotonergic drugs, e.g. pCPA and methiothepin. The latencies were increased with AMPA receptor blockade, yet ketamine did not increase the analgesic effect of the AMPA receptor antagonist, i.e. GYKI-52466. In consecutive tests, ketamine was effective for 5 h, and the peak effect was seen at the 3rd-hour test. CONCLUSION: Our data suggest that the activity of the serotonergic system and AMPA receptors are necessary for ketamine to produce antinociceptive effects. In pain management, ketamine can offer an alternative option to traditional analgesics and may be useful to reduce opioid tolerance.

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Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain

Cited by 35 publications

References 37 publications

P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia

P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems

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