Regulation of NMDA Receptor Subtypes in Pain Processing Neurons within Lamina I of the Spinal Cord
Bibliographic record
Abstract
Chronic pain is a condition affecting 18.9% of Canadians over the age of 18 (Schopflocher et al., 2011).Despite the prevalence of chronic pain, there are currently no effective and safe treatment options.In lamina I of the spinal cord dorsal horn, excitatory Nmethyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit are phosphorylated and potentiated by Src family kinase (SFK) through BDNF signalling in chronic pain models.However, the contribution of GluN2B to synaptic responses in the brain makes it a difficult target to specifically treat pain.The GluN2D subunit of NMDAR is highly expressed embryonically but uncommon at mature synapses in the brain, while playing a functional role in mature lamina I neurons.This study aimed to test whether GluN2D-containing NMDARs are necessary for BDNF-mediated potentiation of NMDARs, whether NMDARs containing the GluN2D subunit are functionally present at juvenile lamina I synapses and whether these receptors are directly potentiated by SFKs.Pharmacological inhibition of either GluN2D or GluN2B completely prevented potentiation by BDNF in adult spinal cord slices.Inhibition of GluN2A-and GluN2B-containing NMDARs resulted in significant remaining charge transfer through NMDARs, attributed to GluN2D-containing NMDARs.When GluN2B-or GluN2Dcontaining NMDARs were pharmacologically isolated, SFK activation failed to potentiate either isolated receptor subtype.We propose that lamina I of the spinal cord dorsal horn may contain triheteromeric GluN2B/D NMDARs which do not undergo potentiation in the presence of antagonists of GluN2B or GluN2D.Targeting the GluN2D subunit may provide a useful therapeutic strategy to ameliorate pain hypersensitivity as a result of BDNF-mediated potentiation.I would like to thank my supervisor, Dr. Michael Hildebrand, for all of his advice and support with this project.I would also like to thank Hadir Mahmoud for introducing me to electrophysiological recording and teaching me juvenile rat spinal cord isolation.Biocytin imaging could not have been completed without the help of Jeffrey Landrigan, who stained and imaged the tissue, while troubleshooting every step of the way.Finally, I would like to thank my sister, lab mate and mentor, Annemarie Dedek, who was a constant source of advice and inspiration throughout my work.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".