ArticleBrain : a journal of neurology2022
Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain.
Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Sexually Dimorphic Neuroimmune Pathways in Chronic Pain: A Comprehensive Systematic Review of Cellular and Molecular Mechanisms.Biomolecules · 2026Pooled it
- BDNF-TrkB Signaling Engages a Src Family Kinase-Pannexin 1 Pathway During the Onset of Sustained Mechanical Hyperalgesia.International journal of molecular sciences · 2026Article
- Methylglyoxal alters C-fibre activity-dependent slowing and induces heat hyperalgesia in a sex-dependent manner, in rats.Pain reports · 2026Article
- 3-Nitrotyrosine activates excitatory interneurons by inhibiting GABA receptors in the rat spinal dorsal horn.Pain reports · 2026Article
- Sex-specific cardioprotective role of miR-30a-5p through estrogen-dependent mechanisms in a mouse model of heart failure.Cardiovascular diabetology · 2026Article
- Processing and sectioning of organ donor spinal cord tissue for electrophysiology on acute human spinal cord slices.Brain communications · 2026Article
- Development and validation of the electrosacrogram (ESG): a digital point-of-care tool for real-time neuro-sacral assessment after spinal cord injury.Journal of neuroengineering and rehabilitation · 2025Article
- Selective vulnerability of GABAergic neurons in chronic migraine.The journal of headache and pain · 2025Article
- A molecular map of the human spinal dorsal and ventral horn defines arrangement of neuronal types and glial sex differences.bioRxiv : the preprint server for biology · 2025Article
- Article
- 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
- Enteric glial S100B controls rhythmic colonic functions by regulating excitability and specificity in gut motor neurocircuits.The Journal of physiology · 2025Article
- Brain-Derived Neurotrophic Factor (BDNF) and Sex Differences in Metabolic Regulation.Journal of neurochemistry · 2025Review
- Role of Serum Brain-Derived Neurotrophic Factor as a Biomarker of Chronic Pain in Older Adults.European journal of pain (London, England) · 2025Observational
- Molecular Anatomy of Synaptic and Extrasynaptic Neurotransmission Between Nociceptive Primary Afferents and Spinal Dorsal Horn Neurons.International journal of molecular sciences · 2025Review
- Article
- Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue.Frontiers in neuroscience · 2025Article
- Review
- Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes.Channels (Austin, Tex.) · 2024Article
- An Open-Source Tool for Investigation of Differential RNA Expression Between Spinal Cord Cells of Male and Female Mice.Journal of neuroscience research · 2024Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund's adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
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