Roles of Phosphorylation of N-Methyl-d-Aspartate Receptor in Chronic Pain

Pan, Lijun; Li, Tiansheng; Wang, Rui; Deng, Weiheng; Pu, Huangsheng; Deng, Mei

doi:10.1007/s10571-022-01188-6

Cited by 9 publications

(5 citation statements)

References 214 publications

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“… 8 It is also possible that chronic morphine exposure differentially regulates GluN2B phosphorylation in the presence and absence of a pain state. Phosphorylation of NMDARs alters channel properties, including opening, conductance, and desensitization and synaptic localization, 41 and GluN2B possesses several phosphorylation sites and interacts with multiple kinases. A limitation of our study is that the synaptic localization of the changes in GluN2B expression and the phosphorylation state of this subunit were not determined, and probing these in future would be valuable.…”

Section: Discussionmentioning

confidence: 99%

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Gonçalves,

Woodhams,

et al. 2024

PR9

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Introduction: Sustained opioid use has long-term negative impacts on future pain experience, particularly in women. This study aimed to investigate the underlying spinal neurobiology of this clinical observation in an experimental model of joint pain. Objectives: In this study, we tested the hypothesis that sustained opioid treatment exacerbates chronic pain responses and alters spinal cord dorsal horn astrogliosis and the expression of GluN2B-containing N-methyl-d-aspartate receptors in female rats. Methods: Subcutaneous morphine (3 mg/kg) or saline was administered twice daily for 1 week before inducing a model of joint knee pain (intra-articular injection of 2 mg of monosodium iodoacetate [MIA]) in adult female Sprague-Dawley rats, with pain-free controls receiving 50 µL of saline. Pain behavior (weight-bearing and mechanical paw withdrawal thresholds) was measured at baseline and at intervals thereafter. Twice-daily morphine/saline treatment was continued for up to 3 weeks after intra-articular injections, and spinal cord tissue was collected for Western blot analyses. Results: Area under the curve analysis of weight-bearing asymmetry confirmed a significant exacerbation of pain behavior in the morphine/MIA group, compared with the saline/MIA group (F(3,18) = 46.3, P < 0.0001), despite comparable joint damage in both groups. Sustained morphine treatment was associated with significant elevations in dorsal horn expression of astrocytic glial fibrillary acidic protein (27 ± 5% increase) and neuronal GluN2B (80 ± 30% increase), but not microglial IBA1, irrespective of the model of joint pain. Conclusion: These data suggest that sustained morphine treatment in female rats drives spinal cord plasticity, including spinal astrogliosis and the expression of GluN2B-containing N-methyl-d-aspartate receptors, priming the dorsal horn to incoming sensory inputs and producing exacerbated pain responses.

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Section: Discussionmentioning

confidence: 99%

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Gonçalves,

Woodhams,

et al. 2024

PR9

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“…It has been reported that NMDAR phosphorylation is observed in both neuropathic and inflammatory pain (Pan et al, 2022 ; Zhang et al, 2022 ). NMDARs can be phosphorylated at different sites by a variety of kinases.…”

Section: The Regulation In the Expression And Activation Of Nmdarsmentioning

confidence: 99%

NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain

Liu

Fang

et al. 2022

Front. Cell. Neurosci.

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Peripheral and central sensitizations of the trigeminal nervous system are the main mechanisms to promote the development and maintenance of chronic orofacial pain characterized by allodynia, hyperalgesia, and ectopic pain after trigeminal nerve injury or inflammation. Although the pathomechanisms of chronic orofacial pain are complex and not well known, sufficient clinical and preclinical evidence supports the contribution of the N-methyl-D-aspartate receptors (NMDARs, a subclass of ionotropic glutamate receptors) to the trigeminal nociceptive signal processing pathway under various pathological conditions. NMDARs not only have been implicated as a potential mediator of pain-related neuroplasticity in the peripheral nervous system (PNS) but also mediate excitatory synaptic transmission and synaptic plasticity in the central nervous system (CNS). In this review, we focus on the pivotal roles and mechanisms of NMDARs in the trigeminal nervous system under orofacial neuropathic and inflammatory pain. In particular, we summarize the types, components, and distribution of NMDARs in the trigeminal nervous system. Besides, we discuss the regulatory roles of neuron-nonneuronal cell/neuron-neuron communication mediated by NMDARs in the peripheral mechanisms of chronic orofacial pain following neuropathic injury and inflammation. Furthermore, we review the functional roles and mechanisms of NMDARs in the ascending and descending circuits under orofacial neuropathic and inflammatory pain conditions, which contribute to the central sensitization. These findings are not only relevant to understanding the underlying mechanisms, but also shed new light on the targeted therapy of chronic orofacial pain.

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“…Indeed, spinal cord central sensitization is dependent on NMDAR‐mediated elevations of cytosolic Ca 2+ in the post synaptic neuron. Further, the long‐term synaptic plasticity associated with central sensitization is primarily expressed as phosphorylation‐induced alterations in the activity of NMDAR and/or promotion of receptor trafficking to the membrane 41 . In addition, GABA‐mediated inhibitory tone has been shown to be altered at dorsal horn level, resulting in disinhibition of specific spinal excitatory interneurons expressing PKCγ, activating an NMDAR‐dependent circuit and enabling innocuous stimuli to be perceived as painful (allodynia).…”

Section: A Brief Description Of the Main Spinal Mechanisms Involved I...mentioning

confidence: 99%

“…Phosphorylation is the predominant regulatory mechanism of NMDARs and many protein kinases as PKA, PKC, Src family protein tyrosine kinases, Ca 2+ / calmodulin‐dependent protein kinase II, casein kinase II and cyclin‐dependent kinase 5 can direct phosphorylate this receptor 73,87 . In fact, NMDAR phosphorylation has been established as a main process in central sensitization, 41,87 increasing the activity of this receptor and the delivery of NMDAR channels to the plasma membrane 88,89 . In particular, increased PKC‐dependent phosphorylation of the GluN1 subunit was correlated with pain behaviors in different models of chronic pain and hyperalgesia 90,91 .…”

Section: Brief Overview Of Spinal Nmdar Function and Activity In Chro...mentioning

confidence: 99%

Therapeutic potential of progesterone in spinal cord injury‐induced neuropathic pain: At the crossroads between neuroinflammation and N‐methyl‐D‐aspartate receptor

Ferreyra

González

2022

J Neuroendocrinology

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In recent decades, an area of active research has supported the notion that progesterone promotes a wide range of remarkable protective actions in experimental models of nervous system trauma or disease, and has also provided a strong basis for considering this steroid as a promising molecule for modulating the complex maladaptive changes that lead to neuropathic pain, especially after spinal cord injury. In this review, we intend to give the readers a brief appraisal of the main mechanisms underlying the increased excitability of the spinal circuit in the pain pathway after trauma, with particular emphasis on those mediated by the activation of resident glial cells, the subsequent release of proinflammatory cytokines and their impact on N‐methyl‐D‐aspartate receptor function. We then summarize the available preclinical data pointing to progesterone as a valuable repurposing molecule for blocking critical cellular and molecular events that occur in the dorsal horn of the injured spinal cord and are related to the development of chronic pain. Since the treatment and management of neuropathic pain after spinal injury remains challenging, the potential therapeutic value of progesterone opens new traslational perspectives to prevent central pain.

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Roles of Phosphorylation of N-Methyl-d-Aspartate Receptor in Chronic Pain

Cited by 9 publications

References 214 publications

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain

Therapeutic potential of progesterone in spinal cord injury‐induced neuropathic pain: At the crossroads between neuroinflammation and N‐methyl‐D‐aspartate receptor

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