ArticleCell death & disease2019
P2Y12 regulates microglia activation and excitatory synaptic transmission in spinal lamina II neurons during neuropathic pain in rodents.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 1 of them a synthesis that pooled it.
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Who cites it
76 citing papers in PubMed, 1 synthesis or guideline pooled it, 122 citations in OpenAlex.
- The core of maintaining neuropathic pain: Crosstalk between glial cells and neurons (neural cell crosstalk at spinal cord).Brain and behavior · 2023Pooled it
- Calcium signaling in microglial immune functions: current understanding and implications for disease.Current opinion in immunology · 2026Review
- Glial cells in neuropathic pain.Physiological reviews · 2026Review
- EGR2 Facilitates LPS-Elicited Microglial Inflammation and Inflammatory Pain by Transcriptionally Activating MRTO4.Neurochemical research · 2026Article
- Heart failure-induced reprogramming of salt-evoked neurovascular coupling in the rat hypothalamus.The Journal of physiology · 2026Article
- Molecular Mechanisms of Electroacupuncture-Induced Spinal Microglial Reprogramming in Neuropathic Pain: A Systematic Search-Narrative Review.Brain sciences · 2026Review
- Clopidogrel, an ADP-P2Y12 Receptor Antagonist, Is Associated With Lower Opioid Consumption and a Reduced Incidence of Delirium in Cancer Patients Receiving Chemotherapy: A Nationwide Retrospective Cohort Study in Japan.Neuropsychopharmacology reports · 2026Article
- ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.Redox biology · 2026Review
- The relevance of cannabinoid receptor 2 in the central nervous system: an update over the last 3 years.Frontiers in behavioral neuroscience · 2026Review
- Peripheral Sympathetic Sprouting Drives Neuropathic Pain via Spinal Microglial P2Y12 Activation in a Rat Spinal Nerve Ligation Model.Journal of pain research · 2026Article
- Gastrodin alleviates neuronal damage in epileptic cell models by targeting P2RY12 to inhibit microglial hyperactivation.PloS one · 2026Article
- Midkine-Mediated Microglia Activation after Renal Injury Promotes Cognitive Impairment Following Ischemic Renal Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Microglia-derived neuroinflammatory pathways in neuropathic pain.The Korean journal of pain · 2026Review
- Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease.Annual review of pathology · 2026Review
- Microglia drive synaptic and functional connectivity deficits in the Ts65Dn mouse model of Down syndrome by affecting inhibition.Acta neuropathologica communications · 2025Article
- Increased levels of GFAP and purinergic P2X7 receptor in Alzheimer's disease brain are associated with Aβ, tau pathologies and synaptic loss.Alzheimer's research & therapy · 2025Article
- Early Life Injury Alters Spinal Astrocyte Development.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model.Brain, behavior, and immunity · 2025Article
- How microglia contribute to the induction and maintenance of neuropathic pain.Nature reviews. Neuroscience · 2025Review
- Exploring the Role of RhoA/ROCK Signaling in Pain: A Narrative Review.Aging and disease · 2025Review
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Peripheral nerve injury causes neuropathic pain and microglia activation. P2Y12 receptors on microglia are thought to be a key player in the surveillance of the local environment, but whether or how these receptors are engaged in the cross-talk between microglia and neurons of the dorsal horn remain ambiguous. Using a rodent model of nerve injury-induced pain, we investigated the roles of P2Y12 in microglia activation, excitatory synaptic transmission, and nociceptive allodynia. We found that spinal nerve ligation (SNL) significantly increased the level of P2Y12 receptors specifically in the microglia of the ipsilateral dorsal horn. Injections of P2Y12 antagonists (MRS2395 or clopidogrel) attenuated microglia activation and increased the paw withdrawal latency in response to thermal stimuli on the ipsilateral side without affecting the basal threshold on the contralateral side. These effects on pain behaviors were replicated in P2Y12 knockout mice. Patch-clamp recordings further revealed that partial sciatic nerve ligation (PSNL)-induced excessive miniature excitatory postsynaptic currents (mEPSCs) were significantly attenuated in P2Y12 knockout mice. Moreover, we found that SNL activates the GTP-RhoA/ROCK2 signaling pathway and elevates the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which was inhibited by the P2Y12 antagonist. The phosphorylation of p38 MAPK was inhibited by a ROCK inhibitor, but not vice versa, suggesting that p38 MAPK is downstream of ROCK activation. Our findings suggest that nerve injury engages the P2Y12 receptor-dependent GTP-RhoA/ROCK2 signaling pathway to upregulate excitatory synaptic transmission in the dorsal horn. This cross-talk ultimately participates in the manifestation of nociceptive allodynia, implicating P2Y12 receptor as a potential target for alleviating neuropathic pain.
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Registered trials
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