The Role of N-Methyl-d-Aspartate (NMDA) Receptors in Pain: A Review

Petrenko, Andrei B.; Yamakura, Tomohiro; Baba, Hiroshi; Shimoji, Koki

doi:10.1213/01.ane.0000081061.12235.55

Cited by 577 publications

(468 citation statements)

References 78 publications

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“…The increase in NMDAR-mediated excitation in the superficial dorsal horn of the spinal cord certainly could contribute to a nociceptive sensitization that, in turn, produces a decrease in the antinociceptive efficacy of a given dose of opiate. How the role of NMDARs in opiate tolerance induction differs from their role in opiate tolerance expression requires more study and, perhaps, more pharmacological tools with an improved therapeutic window in vivo (Loftis and Janowsky, 2003;Petrenko et al, 2003). Particularly novel in our results is the demonstration that presynaptic rather than postsynaptic NMDARs are involved dynamically in regulating the increased excitation in spinal dorsal horn associated with opiate tolerance.…”

Section: Discussionmentioning

confidence: 80%

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Zeng¹,

Thomson²,

Aicher³

et al. 2006

J. Neurosci.

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EPSC (mEPSC) frequency in contrast to a decrease in mEPSC frequency produced by NMDA in opiate-naive slices. Finally, NMDAR antagonists inhibit the expression of opiate tolerance both in inhibiting EPSCs in spinal slices and in inhibiting behavioral nociceptive responses to heat.NMDAR antagonists have been reported in many studies to inhibit morphine analgesic tolerance. Our studies suggest that an increase in primary afferent NMDAR expression and activity mediates a hypersensitivity to noxious stimuli and causes the inhibition of opiate efficacy, which defines tolerance.

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Section: Discussionmentioning

confidence: 80%

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Zeng¹,

Thomson²,

Aicher³

et al. 2006

J. Neurosci.

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“…4 Two types of glutamate receptors, an ionotropic receptor and a metabotropic receptor, have been reported to be involved in pain perception. 5,6 Ionotropic glutamate receptors are classified into three subtypes; α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate receptors, whereas metabotropic glutamate receptors (mGluR) are classified into eight subtypes, mGluR1-8. The mGluRs are classified into three subgroups.…”

Section: Conclusion : Les Agonistes α-2 Produisent Un Effet Analgésiqmentioning

confidence: 99%

Regional Anesthesia and Pain

Saito

Aoe

Kozikowski

et al. 2006

Can J Anesth/J Can Anesth

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Purpose: Not all bone cancer pain can be effectively treated with current therapies. In the present study, the effects of ip administration of α-2 agonists (dexmedetomidine and clonidine), N-methyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), an N-acetylaspartylglutamate peptidase inhibitor (ZJ-43), and morphine were examined in a mouse bone cancer pain model. Methods:A bone cancer pain model was produced by injection of murine sarcoma cells into the medullary cavity of the distal femur. To estimate the level of bone cancer pain, the number of pain-related behaviours induced by repeated applications of a von Frey monofilament (0.166 g) to the site of tumour cells implantation was counted. Drugs were administered two weeks after the implantation.Results: Morphine produced a significant analgesic effect (P < 0.001). The α-2 agonists produced analgesic effects (P < 0.001) with an efficacy similar to that of morphine, but only at doses that produced severe sedation. MK-801 had only limited analgesic effects, while ketamine produced an analgesic effect (P < 0.001) with the same efficacy as morphine. ZJ-43 (100 mg·kg -1 ) had a significant analgesic effect (P < 0.05) and the effect of ZJ-43 was antagonized by the selective group II metabotropic glutamate receptor (mGluR) antagonist. Conclusion:These data suggest that α-2 agonists produce an analgesic effect only at a sedative dose and that ketamine, but not MK-801, is associated with an analgesic response without overt side effects. The effect of ZJ-43 is mediated by activating group II mGluRs. Objectif : Les douleurs du cancer des os ne sont pas toujours soulagées par les traitements habituels. Dans la présente étude, les effets de l'administration ip d'agonistes α-2 (dexmédétomi-dine et clonidine), d'antagonistes N-méthyl-D-aspartate (NMDA) (MK-801 et kétamine), d'un inhibiteur de N-acétylaspartylgluta-mate peptidase (ZJ-43) et de morphine ont été examinés dans un modèle de douleur du cancer des os chez la souris. Méthode : Un modèle de douleur du cancer des os a été produit en injectant des cellules de sarcome d'Ewing dans la cavité médul-laire distale du fémur. Pour évaluer le niveau de douleur, nous avons calculé le nombre de mouvements reliés à la douleur induite par l'application répétée d'un monofilament von Frey (0,166 g) au site de la tumeur implantée. Les médicaments ont été administrés deux semaines après l'implantation.Résultats : La morphine a produit une analgésie significative (P < 0,001). Les agonistes α-2 ont produit une analgésie (P < 0,001) similaire à celle de la morphine, mais seulement à des doses produisant une sédation importante. Le MK-801 a eu un effet limité et la kétamine a produit une analgésie aussi efficace que celle de la morphine (P < 0,001). ) a eu un effet analgésique significatif (P < 0,05)

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“…Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity [9][10][11] . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 .…”

mentioning

confidence: 99%

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Liu

Gingrich

Vargas‐Caballero

et al. 2008

Nat Med

196

205

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Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.Chronic pain is categorized as inflammatory or neuropathic, each involving neuroplastic changes leading to hypersensitivity in peripheral and central nociceptive systems 1,2 . Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity 9-11 . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.

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The Role of N-Methyl-d-Aspartate (NMDA) Receptors in Pain: A Review

Cited by 577 publications

References 78 publications

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Regional Anesthesia and Pain

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

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