{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:30:33Z","timestamp":1787841033707,"version":"build-2784847793"},"reference-count":112,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Visceral hypersensitivity is a hallmark pathophysiological feature of irritable bowel syndrome, characterized by enhanced perception of visceral stimuli and a reduced pain threshold. Although previous studies have mainly attributed visceral hypersensitivity to peripheral inflammation, visceral afferent sensitization, and psychological stress, these mechanisms do not fully explain the persistent pain and discomfort observed in some patients without overt organic lesions or pronounced inflammation. Accumulating evidence indicates that the spinal cord is not merely a relay site for visceral sensory afferent input, but also a critical central locus for pain modulation and amplification. As resident immune cells of the central nervous system, spinal microglia can be activated by persistent visceral stimulation, inflammation, and stress, thereby contributing to the development and maintenance of visceral hypersensitivity through neuroimmune crosstalk. This review summarizes the role of spinal microglia in the development and progression of visceral hypersensitivity and the associated molecular mechanisms. For the first time in this research field, a two-dimensional reaction-diffusion numerical model was established using COMSOL Multiphysics to simulate the spatiotemporal diffusion and degradation patterns of key signaling molecules, including CSF1, ATP, and BDNF, within the microenvironment of the spinal dorsal horn. The model further incorporates coupled analyses of dynamic changes in microglial activation states and neuronal membrane responses, providing a theoretical basis for quantitatively elucidating microglia-mediated pain sensitization. Evidence indicates that signaling molecules such as ATP, CX3CL1, and CSF1 can drive the activation of microglia in the spinal dorsal horn and induce the release of mediators including TNF-\u03b1, IL-1\u03b2, and BDNF. These changes enhance excitatory synaptic transmission, weaken inhibitory neurotransmission, and promote spinal and central sensitization. Among these mechanisms, the BDNF-TrkB-KCC2\/NMDAR signaling axis represents a key molecular pathway underlying microglia-mediated pain amplification. Furthermore, peripheral factors, including intestinal inflammation, psychological stress, and gut microbiota dysbiosis, may further regulate spinal microglial reactivity through the gut-brain axis, thereby exacerbating visceral hypersensitivity. This review not only summarizes recent advances in understanding the involvement of spinal microglia in visceral hypersensitivity, but also provides a theoretical basis for mechanistic studies and targeted interventions in other neuroinflammation-related pathological processes and chronic pain disorders.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1934162","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:40:54Z","timestamp":1787838054000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroimmune regulation of visceral pain: roles of microglia, purinergic signaling, and neuroinflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Acupuncture and Massage, Changchun University of Chinese Medicine","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peizhe","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Acupuncture and Massage, Changchun University of Chinese Medicine","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Acupuncture and Massage, Changchun University of Chinese Medicine","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Acupuncture and Massage, Changchun University of Chinese Medicine","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Acupuncture and Massage, Changchun University of Chinese Medicine","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.22532","article-title":"Diagnosis and treatment of irritable bowel syndrome: a review","volume":"325","author":"Camilleri","year":"2021","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.03.035","article-title":"Rome IV-functional GI disorders: disorders of gut-brain interaction","volume":"150","author":"Drossman","year":"2016","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2025.2497399","article-title":"Mechanosensory Piezo2 regulated by gut microbiota participates in the development of visceral hypersensitivity and intestinal dysmotility","volume":"17","author":"Zheng","year":"2025","journal-title":"Gut Microbes"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s11894-011-0195-7","article-title":"Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome","volume":"13","author":"Barbara","year":"2011","journal-title":"Curr Gastroenterol Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2036.2003.01447.x","article-title":"Review article: visceral hypersensitivity","volume":"17","author":"Mertz","year":"2003","journal-title":"Aliment Pharmacol Ther"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70102-4","article-title":"Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms","volume":"13","author":"Jensen","year":"2014","journal-title":"Lancet Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-01972-w","article-title":"The neurobiology of irritable bowel syndrome","volume":"28","author":"Mayer","year":"2023","journal-title":"Mol Psychiatry"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-328515","article-title":"Irritable bowel syndrome: treatment based on pathophysiology and biomarkers","volume":"72","author":"Camilleri","year":"2023","journal-title":"Gut"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(20)30217-X","article-title":"Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: a systematic review and meta-analysis","volume":"5","author":"Oka","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1053\/j.gastro.2020.04.014","article-title":"Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study","volume":"160","author":"Sperber","year":"2021","journal-title":"Gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2026.02.003","article-title":"Bowel disorders","volume":"170","author":"Corsetti","year":"2026","journal-title":"Gastroenterology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-320633","article-title":"Understanding neuroimmune interactions in disorders of gut-brain interaction: from functional to immune-mediated disorders","volume":"72","author":"Vanuytsel","year":"2023","journal-title":"Gut"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00700-9","article-title":"Immune activation in irritable bowel syndrome: what is the evidence","volume":"22","author":"Aguilera-Lizarraga","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nri2566","article-title":"Reflex control of immunity","volume":"9","author":"Tracey","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003537","article-title":"Potentiation of visualized exosomal miR-1306-3p from primary sensory neurons contributes to chronic visceral pain via spinal P2X3 receptors","volume":"166","author":"Sun","year":"2025","journal-title":"Pain"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.70211","article-title":"Splanchnic and pelvic spinal afferent pathways relay sensory information from the mouse colorectum into distinct brainstem circuits","volume":"169","author":"Wang","year":"2025","journal-title":"J Neurochem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.997786","article-title":"Microglia morphophysiological diversity and its implications for the CNS","volume":"13","author":"Vidal-Itriago","year":"2022","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113683","article-title":"Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution","volume":"43","author":"Donovan","year":"2024","journal-title":"Cell Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1570159X23666250225091729","article-title":"Roles of microglia in synaptogenesis, synaptic pruning, and synaptic plasticity in physiological conditions and central nervous system disorders","volume":"24","author":"Xie","year":"2026","journal-title":"Curr Neuropharmacol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ado7829","article-title":"Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization","volume":"11","author":"Zhao","year":"2025","journal-title":"Sci Adv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2025.1700692","article-title":"Microglia-orchestrated neuroinflammation and synaptic remodeling: roles of pro-inflammatory cytokines and receptors in neurodegeneration","volume":"19","author":"Yang","year":"2025","journal-title":"Front Cell Neurosci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-021-03486-9","article-title":"Spinal microglia and astrocytes: two key players in chronic visceral pain pathogenesis","volume":"47","author":"Long","year":"2022","journal-title":"Neurochem Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2025.110373","article-title":"Spinal astrocyte-derived M-CSF mediates microglial reaction and drives visceral hypersensitivity following DSS-induced colitis","volume":"270","author":"Wu","year":"2025","journal-title":"Neuropharmacology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.12.012","article-title":"Gut-innervating TRPV1+ neurons drive chronic visceral pain via microglial P2Y12 receptor","volume":"13","author":"Defaye","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1177\/17448069231179118","article-title":"Spinal cathepsin S promotes visceral hypersensitivity via FKN\/CX3CR1\/p38 MAPK signaling pathways","volume":"19","author":"Sun","year":"2023","journal-title":"Mol Pain"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.11.009","article-title":"Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain","volume":"100","author":"Chen","year":"2018","journal-title":"Neuron"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1251","article-title":"Glia: a novel drug discovery target for clinical pain","volume":"2","author":"Watkins","year":"2003","journal-title":"Nat Rev Drug Discov"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2018.2","article-title":"Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential","volume":"19","author":"Inoue","year":"2018","journal-title":"Nat Rev Neurosci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051108","article-title":"Regulation of microglial functions by purinergic mechanisms in the healthy and diseased CNS","volume":"9","author":"Illes","year":"2020","journal-title":"Cells"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000000864","article-title":"Role of microglia and P2X4 receptors in chronic pain","volume":"6","author":"Kohno","year":"2021","journal-title":"Pain Rep"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110447","article-title":"The role of P2X4 receptors in chronic pain: a potential pharmacological target","volume":"129","author":"Zhang","year":"2020","journal-title":"BioMed Pharmacother"},{"key":"B33","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.brainresbull.2022.07.006","article-title":"P2X7 receptor in inflammation and pain","volume":"187","author":"Hu","year":"2022","journal-title":"Brain Res Bull"},{"key":"B34","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.bbi.2015.11.007","article-title":"Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain","volume":"55","author":"Gu","year":"2016","journal-title":"Brain Behav Immun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/glia.70109","article-title":"P2Y12 receptor function governs microglial surveillance and cell-cell interactions in the cerebral cortex","volume":"74","author":"P\u00f3sfai","year":"2026","journal-title":"Glia"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nn1805","article-title":"The P2Y12 receptor regulates microglial activation by extracellular nucleotides","volume":"9","author":"Haynes","year":"2006","journal-title":"Nat Neurosci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature04223","article-title":"BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain","volume":"438","author":"Coull","year":"2005","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/429815","article-title":"Microglia control neuronal network excitability via BDNF signalling","volume":"2013","author":"Ferrini","year":"2013","journal-title":"Neural Plast"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2026.1696689","article-title":"Advances in the multifunctional roles of CX3CL1 in the central nervous system","volume":"18","author":"Chen","year":"2026","journal-title":"Front Aging Neurosci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00121","article-title":"Fractalkine\/CX3CR1 signaling during neuropathic pain","volume":"8","author":"Clark","year":"2014","journal-title":"Front Cell Neurosci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0828-09.2009","article-title":"The liberation of fractalkine in the dorsal horn requires microglial cathepsin S","volume":"29","author":"Clark","year":"2009","journal-title":"J Neurosci"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2006.11.003","article-title":"Role of the CX3CR1\/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine","volume":"21","author":"Zhuang","year":"2007","journal-title":"Brain Behav Immun"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2061-14.2015","article-title":"Selective activation of microglia facilitates synaptic strength","volume":"35","author":"Clark","year":"2015","journal-title":"J Neurosci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/cells11132083","article-title":"The role of microglia in neuroinflammation of the spinal cord after peripheral nerve injury","volume":"11","author":"Pottorf","year":"2022","journal-title":"Cells"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3338-07.2008","article-title":"Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord","volume":"28","author":"Kawasaki","year":"2008","journal-title":"J Neurosci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2008.12.011","article-title":"MAP kinase and pain","volume":"60","author":"Ji","year":"2009","journal-title":"Brain Res Rev"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-109355","article-title":"The IKK-NF-kappaB pathway: a source for novel molecular drug targets in pain therapy","volume":"22","author":"Niederberger","year":"2008","journal-title":"FASEB J"},{"key":"B48","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1017\/S1740925X12000087","article-title":"Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain","volume":"7","author":"Trang","year":"2011","journal-title":"Neuron Glia Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2308-08.2008","article-title":"Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain","volume":"28","author":"Ulmann","year":"2008","journal-title":"J Neurosci"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200209011","article-title":"BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion","volume":"159","author":"Rivera","year":"2002","journal-title":"J Cell Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/cells9081772","article-title":"Deepening the mechanisms of visceral pain persistence: an evaluation of the gut-spinal cord relationship","volume":"9","author":"Lucarini","year":"2020","journal-title":"Cells"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706053114","article-title":"Granulocyte-colony-stimulating factor (G-CSF) signaling in spinal microglia drives visceral sensitization following colitis","volume":"114","author":"Basso","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20871","article-title":"Microglia and neuropathic pain","volume":"57","author":"Inoue","year":"2009","journal-title":"Glia"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.06.022","article-title":"Glia and pain: is chronic pain a gliopathy","volume":"154","author":"Ji","year":"2013","journal-title":"Pain"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00323.2020","article-title":"Spinal neuron-glia-immune interaction in cross-organ sensitization","volume":"319","author":"Qiao","year":"2020","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4334","article-title":"Emerging targets in neuroinflammation-driven chronic pain","volume":"13","author":"Ji","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"B57","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/j.1365-2982.2010.01491.x","article-title":"Role of spinal cord glia in the central processing of peripheral pain perception","volume":"22","author":"Bradesi","year":"2010","journal-title":"Neurogastroenterol Motil"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034406","article-title":"Microglia in physiology and disease","volume":"79","author":"Wolf","year":"2017","journal-title":"Annu Rev Physiol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.10.027","article-title":"Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo","volume":"23","author":"Li","year":"2012","journal-title":"Dev Cell"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2006.10.017","article-title":"Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury","volume":"21","author":"Beggs","year":"2007","journal-title":"Brain Behav Immun"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03009","article-title":"Cytokines in pain: harnessing endogenous anti-inflammatory signaling for improved pain management","volume":"10","author":"Vanderwall","year":"2019","journal-title":"Front Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.25887","article-title":"Microbiota regulates visceral pain in the mouse","volume":"6","author":"Luczynski","year":"2017","journal-title":"Elife"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-5-69","article-title":"Purinergic mechanosensory transduction and visceral pain","volume":"5","author":"Burnstock","year":"2009","journal-title":"Mol Pain"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13957","article-title":"P2X receptor channels in chronic pain pathways","volume":"175","author":"Bernier","year":"2018","journal-title":"Br J Pharmacol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nature01786","article-title":"P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury","volume":"424","author":"Tsuda","year":"2003","journal-title":"Nature"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3155","article-title":"P2X4R+ microglia drive neuropathic pain","volume":"15","author":"Beggs","year":"2012","journal-title":"Nat Neurosci"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-10-04017.2003","article-title":"p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain","volume":"23","author":"Jin","year":"2003","journal-title":"J Neurosci"},{"key":"B68","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/glia.22379","article-title":"Microglia and intractable chronic pain","volume":"61","author":"Tsuda","year":"2013","journal-title":"Glia"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/35068566","article-title":"Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity","volume":"410","author":"Samad","year":"2001","journal-title":"Nature"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03514.x","article-title":"Complete freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS","volume":"20","author":"Raghavendra","year":"2004","journal-title":"Eur J Neurosci"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-25-08692.2003","article-title":"Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases","volume":"23","author":"Viviani","year":"2003","journal-title":"J Neurosci"},{"key":"B72","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/nrn2533","article-title":"Pathological and protective roles of glia in chronic pain","volume":"10","author":"Milligan","year":"2009","journal-title":"Nat Rev Neurosci"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/nri3621","article-title":"Pathological pain and the neuroimmune interface","volume":"14","author":"Grace","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.jpain.2009.06.012","article-title":"Central sensitization: a generator of pain hypersensitivity by central neural plasticity","volume":"10","author":"Latremoliere","year":"2009","journal-title":"J Pain"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2011.83","article-title":"New insights into visceral hypersensitivity--clinical implications in IBS","volume":"8","author":"Zhou","year":"2011","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12490","article-title":"Stress and the microbiota-gut-brain axis in visceral pain: relevance to irritable bowel syndrome","volume":"22","author":"Moloney","year":"2016","journal-title":"CNS Neurosci Ther"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/9857201","article-title":"Spinal plasticity and behavior: BDNF-induced neuromodulation in uninjured and injured spinal cord","volume":"2016","author":"Garraway","year":"2016","journal-title":"Neural Plast"},{"key":"B78","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s12974-015-0371-z","article-title":"Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLC\u03b3, PKC, and PI3K\/Akt pathways during colitis","volume":"12","author":"Liu","year":"2015","journal-title":"J Neuroinflamm"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03656.x","article-title":"Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord","volume":"20","author":"Slack","year":"2004","journal-title":"Eur J Neurosci"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12516","article-title":"BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals","volume":"39","author":"Chen","year":"2014","journal-title":"Eur J Neurosci"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3819","article-title":"Cation-chloride cotransporters in neuronal development, plasticity and disease","volume":"15","author":"Kaila","year":"2014","journal-title":"Nat Rev Neurosci"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4397","article-title":"Microglia emerge as central players in brain disease","volume":"23","author":"Salter","year":"2017","journal-title":"Nat Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2947","article-title":"Neuronal circuitry for pain processing in the dorsal horn","volume":"11","author":"Todd","year":"2010","journal-title":"Nat Rev Neurosci"},{"key":"B84","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1152\/physrev.00043.2010","article-title":"Fast synaptic inhibition in spinal sensory processing and pain control","volume":"92","author":"Zeilhofer","year":"2012","journal-title":"Physiol Rev"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2007.07.002","article-title":"Liaisons dangereuses: P2X(7) and the inflammasome","volume":"28","author":"Di Virgilio","year":"2007","journal-title":"Trends Pharmacol Sci"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.7.3877","article-title":"The P2X7 receptor: a key player in IL-1 processing and release","volume":"176","author":"Ferrari","year":"2006","journal-title":"J Immunol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3295-09.2010","article-title":"P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide","volume":"30","author":"Clark","year":"2010","journal-title":"J Neurosci"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2010.06.021","article-title":"Microglia: proliferation and activation driven by the P2X7 receptor","volume":"42","author":"Monif","year":"2010","journal-title":"Int J Biochem Cell Biol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1585545","article-title":"P2X7 receptor as a key player in pathological pain: insights into neuropathic, inflammatory, and cancer pain","volume":"16","author":"Jiang","year":"2025","journal-title":"Front Pharmacol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.11.012","article-title":"ATP receptors gate microglia signaling in neuropathic pain","volume":"234","author":"Trang","year":"2012","journal-title":"Exp Neurol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S545420","article-title":"Microglia's phenotypic heterogeneity in pain pathogenesis and electroacupuncture analgesia: mechanisms and therapeutic potential","volume":"18","author":"Ji","year":"2025","journal-title":"J Pain Res"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2007.134221","article-title":"P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity","volume":"57","author":"Xu","year":"2008","journal-title":"Gut"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00129","article-title":"Fractalkine regulation of microglial physiology and consequences on the brain and behavior","volume":"8","author":"Paolicelli","year":"2014","journal-title":"Front Cell Neurosci"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/nature09615","article-title":"The myeloid cells of the central nervous system parenchyma","volume":"468","author":"Ransohoff","year":"2010","journal-title":"Nature"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.18.10896","article-title":"Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia","volume":"95","author":"Harrison","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B96","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.pharmthera.2010.01.002","article-title":"Chemokines, neuronal-glial interactions, and central processing of neuropathic pain","volume":"126","author":"Gao","year":"2010","journal-title":"Pharmacol Ther"},{"key":"B97","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/nn.4189","article-title":"Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain","volume":"19","author":"Guan","year":"2016","journal-title":"Nat Neurosci"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1007\/s40122-025-00718-6","article-title":"The role of biomarkers in acute pain: a narrative review","volume":"14","author":"Asimakopoulos","year":"2025","journal-title":"Pain Ther"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14496","article-title":"Involvement of microglial P2X7 receptor in pain modulation","volume":"30","author":"Zhang","year":"2024","journal-title":"CNS Neurosci Ther"},{"key":"B100","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.brainresbull.2019.11.006","article-title":"The role and pharmacological properties of the P2X7 receptor in neuropathic pain","volume":"155","author":"Zhang","year":"2020","journal-title":"Brain Res Bull"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-022-09868-0","article-title":"Spinal P2X4 receptors involved in visceral hypersensitivity of neonatal maternal separation rats","volume":"19","author":"Tang","year":"2023","journal-title":"Purinergic Signal"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610811104","article-title":"Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain","volume":"104","author":"Clark","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"B103","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.imlet.2021.02.001","article-title":"Dynamic role of macrophage CX3CR1 expression in inflammatory bowel disease","volume":"232","author":"Li","year":"2021","journal-title":"Immunol Lett"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114884","article-title":"CSF1R inhibitors are emerging immunotherapeutic drugs for cancer treatment","volume":"245","author":"Wen","year":"2023","journal-title":"Eur J Med Chem"},{"key":"B105","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1016\/j.pain.2010.09.030","article-title":"Central sensitization: implications for the diagnosis and treatment of pain","volume":"152","author":"Woolf","year":"2011","journal-title":"Pain"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-020518-114525","article-title":"Visceral pain","volume":"81","author":"Grundy","year":"2019","journal-title":"Annu Rev Physiol"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(87)90275-9","article-title":"Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following c fibre stimulation","volume":"26","author":"Dickenson","year":"1987","journal-title":"Neuropharmacology"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(91)90100-C","article-title":"The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states","volume":"44","author":"Woolf","year":"1991","journal-title":"Pain"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202516024","article-title":"Esketamine\/ketamine: dual-action mechanisms and clinical prospects beyond anesthesia in psychiatry, immunology, and oncology","volume":"13","author":"Wang","year":"2026","journal-title":"Adv Sci (Weinh)"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12094","article-title":"Ketamine for chronic pain: risks and benefits","volume":"77","author":"Niesters","year":"2014","journal-title":"Br J Clin Pharmacol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1097\/AAP.0000000000000808","article-title":"Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists","volume":"43","author":"Cohen","year":"2018","journal-title":"Reg Anesth Pain Med"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.31083\/JIN26766","article-title":"Beyond anesthesia: ketamine's expanding role in chronic pain and psychiatric disorders","volume":"24","author":"Zaki","year":"2025","journal-title":"J Integr Neurosci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1934162\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:40:56Z","timestamp":1787838056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1934162\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":112,"alternative-id":["10.3389\/fimmu.2026.1934162"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1934162","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"article-number":"1934162"}}