Glutamate receptors and pain

Bleakman, David; Alt, Andrew; Nisenbaum, Eric S.

doi:10.1016/j.semcdb.2006.10.008

Cited by 257 publications

(197 citation statements)

References 156 publications

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“…Targeting the glutamatergic system facilitates the treatment of chronic pain (1)(2)(3)(4). In the brain, the majority of fast excitatory synaptic transmissions are mediated by AMPA-type glutamate receptors (5,6).…”

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confidence: 99%

Persistent Inflammation-induced Up-regulation of Brain-derived Neurotrophic Factor (BDNF) Promotes Synaptic Delivery of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor GluA1 Subunits in Descending Pain Modulatory Circuits

Tao

Chen

Zhou

et al. 2014

Journal of Biological Chemistry

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Background: AMPA-type glutamate receptor-mediated synaptic transmission is enhanced in descending pain modulatory circuits under pain conditions. Results: Epigenetic regulation of BDNF by persistent inflammation triggers AMPA receptor GluA1 phosphorylation. Conclusion: Synaptic delivery of GluA1 in the brain stem is initiated by BDNF/TrKB activation under pain conditions. Significance: We investigate how GluA1 is delivered to synapses to understand the molecular mechanisms underlying pain in descending pain modulatory circuits.

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mentioning

confidence: 99%

Persistent Inflammation-induced Up-regulation of Brain-derived Neurotrophic Factor (BDNF) Promotes Synaptic Delivery of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor GluA1 Subunits in Descending Pain Modulatory Circuits

Tao

Chen

Zhou

et al. 2014

Journal of Biological Chemistry

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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%

“…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 . 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 .…”

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

199

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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“…Activation of the NMDA receptor is associated with abnormalities in the sensory (peripheral and central) system, resulting in neuronal excitation and various pain manifestations like spontaneous pain, allodynia, hyperalgesia. [33,34,35,36] Blocking of these receptors by NMDA antagonists may be helpful in reversing the pain pathology and reducing the pain.…”

Section: Nmda Receptor Antagonistsmentioning

confidence: 99%