ArticleBrain : a journal of neurology2019
Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing.
Article in Brain : a journal of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 68 citations in OpenAlex.
- Glial cells in neuropathic pain.Physiological reviews · 2026Review
- Processing and sectioning of organ donor spinal cord tissue for electrophysiology on acute human spinal cord slices.Brain communications · 2026Article
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- Expression and localization of NMDA receptor GluN2 subunits in dorsal horn pain circuits across sex, species, and late postnatal development.bioRxiv : the preprint server for biology · 2025Article
- Spinal PTP1B Regulated NMDA Receptor-mediated Nociceptive Transmission and Peripheral Inflammation-induced Pain Sensitization.Molecular neurobiology · 2025Article
- Unveiling the Mechanisms of Pain in Endometriosis: Comprehensive Analysis of Inflammatory Sensitization and Therapeutic Potential.International journal of molecular sciences · 2025Review
- Evidence for spinal disinhibition as a pain-generating mechanism in fibromyalgia syndrome.Pain reports · 2025Article
- Article
- Pathology of pain and its implications for therapeutic interventions.Signal transduction and targeted therapy · 2024Review
- Brain-Derived Neurotrophic Factor, Nociception, and Pain.Biomolecules · 2024Review
- Constitutive KCC2 Cell- and Synapse-Specifically Regulates NMDA Receptor Activity in the Spinal Cord.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Characterizing Functional Contributions of Specific GluN2 Subunits to Individual Postsynaptic NMDAR Responses Using Biophysical Parameters.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Development of KCC2 therapeutics to treat neurological disorders.Frontiers in molecular neuroscience · 2024Article
- Green Light Exposure Elicits Anti-inflammation, Endogenous Opioid Release and Dampens Synaptic Potentiation to Relieve Post-surgical Pain.The journal of pain · 2023Article
- A cellular taxonomy of the adult human spinal cord.Neuron · 2023Article
- Levodopa-induced dyskinesia: interplay between the N-methyl-D-aspartic acid receptor and neuroinflammation.Frontiers in immunology · 2023Review
- Roles of Phosphorylation of N-Methyl-D-Aspartate Receptor in Chronic Pain.Cellular and molecular neurobiology · 2023Review
- Cannabinoid CB1 Receptor Expression and Localization in the Dorsal Horn of Male and Female Rat and Human Spinal Cord.Canadian journal of pain = Revue canadienne de la douleur · 2023Article
- Neuropathic pain; what we know and what we should do about it.Frontiers in pain research (Lausanne, Switzerland) · 2023Review
- KNeural regeneration research · 2022Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. In the rodent nerve injury model of neuropathic pain, BDNF-mediated loss of inhibition (disinhibition) gates the potentiation of excitatory GluN2B N-methyl-d-aspartate receptor (NMDAR) responses at lamina I dorsal horn synapses. However, the centrality of this mechanism across pain states and species, as well as the molecular linker involved, remain unknown. Here, we show that KCC2-dependent disinhibition is coupled to increased GluN2B-mediated synaptic NMDAR responses in a rodent model of inflammatory pain, with an associated downregulation of the tyrosine phosphatase STEP61. The decreased activity of STEP61 is both necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B NMDAR by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP61 as well as inflammation-mediated behavioural hypersensitivity. For the first time, we characterize GluN2B-mediated NMDAR responses at human lamina I synapses and show that a human ex vivo BDNF model of pathological pain processing downregulates KCC2 and STEP61 and upregulates phosphorylated GluN2B at dorsal horn synapses. Our results demonstrate that STEP61 is the molecular brake that is lost following KCC2-dependent disinhibition and that the decrease in STEP61 activity drives the potentiation of excitatory GluN2B NMDAR responses in rodent and human models of pathological pain. The ex vivo human BDNF model may thus form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.
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