GluN2B and GluN2D NMDARs dominate synaptic responses in the adult spinal cord

Hildebrand, Michael E.; Pitcher, Graham; Harding, Erika K.; Li, Hongbin; Beggs, Simon; Salter, Michael W.

doi:10.1038/srep04094

Cited by 66 publications

(135 citation statements)

References 68 publications

(118 reference statements)

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“…NR2b was chosen based both on our preliminary studies and on a recent study showing NR2b-containing receptor/ion channels to play a prominent role in synaptic transmission in the superficial lamina of the rodent spinal cord. 21 CaMK2 was included based on our ingenuity pathway analysis of our previously-published SC microarray data 4 and its known binding to, and activation by, stimulated NR2bs; synaptophysin was chosen as a proxy indicator of synaptic abundance; and BDNF was chosen because of its known involvement in pain and central sensitization.…”

Section: Resultsmentioning

confidence: 99%

“…34 Despite the fact that the exact role of NMDA receptors in this mechanism is unknown, it is generally felt that an important pathway through which peripheral noxious stimulation leads to persistent pain states is through central sensitization at the level of the SC, where, in concert with other systems, the co-release of peptides and glutamate from peripheral nerves induces the activation of NMDA receptors. 35 For our biochemical studies, the NR2b subunit was chosen based both on our preliminary data and on a recent study showing NR2b-containing receptors to play a predominant role in synaptic transmission in the superficial lamina of the rodent SC; 21 CaMK2 was included based on ingenuity pathway analysis of our previously-published SC microarray data 4 and its known binding to, and activation by, stimulated NR2bs; synaptophysin was chosen as a proxy indicator of synaptic abundance; BDNF was chosen because of its established involvement in pain and central sensitization. We show that persistent sensitization in our model is associated with decreased NR2b and increased CaMK2, with no changes in the spinal levels of synaptophysin and BDNF.…”

Section: Discussionmentioning

confidence: 99%

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Differential Efficacy of Ketamine in the AcuteversusChronic Stages of Complex Regional Pain Syndrome in Mice

et al. 2015

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Background Complex regional pain syndrome (CRPS) is a painful, disabling and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system (CNS) changes. Ketamine is a centrally-acting agent believed to work through blockade of N-methyl-D-aspartate (NMDA) receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug’s effects and efficacy at different stages of the syndrome remain unclear. Methods We used a mouse model of CRPS (n=8–12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg/kg/day; 7 days) or vehicle infusion during acute (3weeks [3w] post-fracture) and chronic (7w post-fracture) stages. Results Acute phase fracture mice displayed elevated limb temperature, edema and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks post-fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including NMDA receptor 2b (NR2b), Ca2+/calmodulin-dependent protein kinase ii (CaMK2), and brain-derived neurotrophic factor (BNDF). Conclusions Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute stages of CRPS, suggesting that the centrally-acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential Efficacy of Ketamine in the AcuteversusChronic Stages of Complex Regional Pain Syndrome in Mice

et al. 2015

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“…Central sensitization is a mechanism common to most chronic pain syndromes (Latremoliere & Woolf, 2009), including CRPS, where increased glutamate levels in the cerebrospinal fluid of patients are observed (Alexander, Perreault, Reichenberger, & Schwartzman, 2007). For our molecular and biochemical studies, the Nr2b subunit was chosen based on our preliminary data, on a recent study showing that NR2b-containing receptors play a predominant role in synaptic transmission in the superficial lamina of the rodent spinal cord (Hildebrand et al, 2014),on the observation that NMDA receptor antagonists can sometimes be effective CRPS treatments (Finch, Knudsen, & Drummond, 2009; Schwartzman et al, 2009; Sigtermans et al, 2009), and on our own study demonstrating that the NMDA receptor antagonist ketamine can reverse allodynia during the chronic phase of CRPS-like symptoms in the fracture mice (manuscript under review). We postulated that higher levels of Nr2b would be associated with greater levels of nociceptive sensitization.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in a Murine Model of Complex Regional Pain Syndrome

Tajerian

Sahbaie

Sun

et al. 2015

Neurobiology of Learning and Memory

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Complex Regional Pain Syndrome (CRPS) is a major cause of chronic pain after surgery or trauma to the limbs. Despite evidence showing that the prevalence and severity of many forms of chronic pain, including CRPS, differ between males and females, laboratory studies on sex-related differences in animal models of CRPS are not available, and the impact of sex on the transition from acute to chronic CRPS pain and disability are unexplored. Here we make use of a tibia fracture/cast mouse model that recapitulates the nociceptive, functional, vascular, trophic, inflammatory and immune aspects of CRPS. Our aim is to describe the chronic time course of nociceptive, motor and memory changes associated with fracture/cast in male and female mice, in addition to exploring their underlying spinal mechanisms. Our behavioral data shows that, compared to males, female mice display lower nociceptive thresholds following fracture in the absence of any differences in ongoing or spontaneous pain. Furthermore, female mice show exaggerated signs of motor dysfunction, deficits in fear memory, and latent sensitization that manifests long after the normalization of nociceptive thresholds. Our biochemical data show differences in the spinal cord levels of the glutamate receptor NR2b, suggesting sex differences in mechanisms of central sensitization that could account for differences in duration and severity of CRPS symptoms between the two groups.

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“…) and spinal cord (Hildebrand et al . ), based on biochemical data and observations of neuronal NMDA receptors with functional and pharmacological properties that appear to be intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Despite their prevalence in the CNS, there is a lack of quantitative data describing important properties of triheteromeric GluN1/2B/2D receptors, such as deactivation time course, blockade by extracellular Mg 2+ and subunit‐selective allosteric modulation (Stroebel et al .…”

Section: Introductionmentioning

confidence: 99%

Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors

Bhattacharya

Thompson

et al. 2019

The Journal of Physiology

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Key points Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS. Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+. GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors. Abstract Triheteromeric NMDA‐type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the triheteromeric GluN1/2B/2D NMDA receptor subtype that is expressed in distinct neuronal populations throughout the CNS. We show that neither GluN2B, nor GluN2D dominate the functional properties of GluN1/2B/2D receptors because agonist potencies, open probability and the glutamate deactivation time course of GluN1/2B/2D receptors are intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Furthermore, channel blockade of GluN1/2B/2D by extracellular Mg2+ is intermediate compared to GluN1/2B and GluN1/2D, although GluN1/2B/2D is more sensitive to blockade by ketamine and memantine compared to GluN1/2B in the presence of physiological Mg2+. Subunit‐selective allosteric modulators have distinct activity at GluN1/2B/2D receptors, including GluN2B‐selective antagonists, ifenprodil, EVT‐101 and CP‐101‐606, which inhibit with similar potencies but with different efficacies at GluN1/2B/2D (∼65% inhibition) compared to GluN1/2B (∼95% inhibition). Furthermore, the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. We show that these key features of allosteric modulation of recombinant GluN1/2B/2D receptors are also observed for NMDA receptors in hippocampal interneurons but not CA1 pyramidal cells, which is consistent with the expression of GluN1/2B/2D receptors in interneurons and GluN1/2A/2B receptors in pyramidal cells. Altogether, we uncover previously unknown functional and pharmacological properties of triheteromeric GluN1/2B/2D receptors that can facilitate advances in our understanding of their physiological roles in neural circuit function and therapeutic drug actions.

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GluN2B and GluN2D NMDARs dominate synaptic responses in the adult spinal cord

Cited by 66 publications

References 68 publications

Differential Efficacy of Ketamine in the AcuteversusChronic Stages of Complex Regional Pain Syndrome in Mice

Differential Efficacy of Ketamine in the AcuteversusChronic Stages of Complex Regional Pain Syndrome in Mice

Sex differences in a Murine Model of Complex Regional Pain Syndrome

Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors

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