{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T02:36:30Z","timestamp":1776998190791,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012234","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T00:00:00Z","timestamp":1736812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008460","name":"National Center for Complementary and Integrative Health","doi-asserted-by":"publisher","award":["R01 AT010817"],"award-info":[{"award-number":["R01 AT010817"]}],"id":[{"id":"10.13039\/100008460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS118769"],"award-info":[{"award-number":["R01 NS118769"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS109170"],"award-info":[{"award-number":["R01 NS109170"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20 GM103449"],"award-info":[{"award-number":["P20 GM103449"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Chronic pain is a wide-spread condition that is debilitating and expensive to manage, costing the United States alone around $600 billion in 2010. In a common symptom of chronic pain called allodynia, non-painful stimuli produce painful responses with highly variable presentations across individuals. While the specific mechanisms remain unclear, allodynia is hypothesized to be caused by the dysregulation of excitatory-inhibitory (E-I) balance in pain-processing neural circuitry in the dorsal horn of the spinal cord. In this work, we analyze biophysically-motivated subcircuit structures that represent common motifs in neural circuits in laminae I-II of the dorsal horn. These circuits are hypothesized to be part of the neural pathways that mediate two different types of allodynia: static and dynamic. We use neural firing rate models to describe the activity of populations of excitatory and inhibitory interneurons within each subcircuit. By accounting for experimentally-observed responses under healthy conditions, we specify model parameters defining populations of subcircuits that yield typical behavior under normal conditions. Then, we implement a sensitivity analysis approach to identify the mechanisms most likely to cause allodynia-producing dysregulation of the subcircuit\u2019s E-I signaling. We find that disruption of E-I balance generally occurs either due to downregulation of inhibitory signaling so that excitatory neurons are \u201creleased\u201d from inhibitory control, or due to upregulation of excitatory neuron responses so that excitatory neurons \u201cescape\u201d their inhibitory control. Which of these mechanisms is most likely to occur, the subcircuit components involved in the mechanism, and the proportion of subcircuits exhibiting the mechanism can vary depending on the subcircuit structure. These results suggest specific hypotheses about diverse mechanisms that may be most likely responsible for allodynia, thus offering predictions for the high interindividual variability observed in allodynia and identifying targets for further experimental studies on the underlying mechanisms of this chronic pain symptom.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012234","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T13:40:53Z","timestamp":1736862053000},"page":"e1012234","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanisms for dysregulation of excitatory-inhibitory balance underlying allodynia in dorsal horn neural subcircuits"],"prefix":"10.1371","volume":"21","author":[{"given":"Alexander G.","family":"Ginsberg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott F.","family":"Lempka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2586-8001","authenticated-orcid":true,"given":"Victoria","family":"Booth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3402-4372","authenticated-orcid":true,"given":"Jennifer","family":"Crodelle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,1,14]]},"reference":[{"issue":"15","key":"pcbi.1012234.ref001","doi-asserted-by":"crossref","first-page":"379","DOI":"10.15585\/mmwr.mm7215a1","article-title":"Chronic Pain Among Adults\u2014United States, 2019\u20132021","volume":"72","author":"SM Rikard","year":"2023","journal-title":"Morbidity and Mortality Weekly Report"},{"issue":"4","key":"pcbi.1012234.ref002","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.neuron.2015.07.029","article-title":"Dorsal horn circuits for persistent mechanical pain","volume":"87","author":"C Peirs","year":"2015","journal-title":"Neuron"},{"issue":"4","key":"pcbi.1012234.ref003","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s00702-020-02159-1","article-title":"Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia","volume":"127","author":"C Peirs","year":"2020","journal-title":"Journal of neural transmission"},{"issue":"2","key":"pcbi.1012234.ref004","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3109\/15360288.2012.678473","article-title":"Relieving pain in America: A blueprint for transforming prevention, care, education, and research","volume":"26","author":"LS Simon","year":"2012","journal-title":"Journal of pain & palliative care pharmacotherapy"},{"key":"pcbi.1012234.ref005","volume-title":"Neuroscience: exploring the brain, enhanced edition: exploring the brain","author":"M Bear","year":"2020"},{"issue":"12","key":"pcbi.1012234.ref006","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nrn2947","article-title":"Neuronal circuitry for pain processing in the dorsal horn","volume":"11","author":"AJ Todd","year":"2010","journal-title":"Nature Reviews Neuroscience"},{"issue":"3","key":"pcbi.1012234.ref007","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1515\/nf-2017-A020","article-title":"An update on the spinal and peripheral pathways of pain signalling","volume":"23","author":"SG Lechner","year":"2017","journal-title":"e-Neuroforum"},{"key":"pcbi.1012234.ref008","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s12264-017-0136-z","article-title":"Spinal circuits transmitting mechanical pain and itch","volume":"34","author":"B Duan","year":"2018","journal-title":"Neuroscience bulletin"},{"key":"pcbi.1012234.ref009","doi-asserted-by":"crossref","first-page":"984042","DOI":"10.3389\/fpain.2022.984042","article-title":"Pain modulation in the spinal cord","volume":"3","author":"CJ Woolf","year":"2022","journal-title":"Frontiers in Pain Research"},{"issue":"3699","key":"pcbi.1012234.ref010","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1126\/science.150.3699.971","article-title":"Pain Mechanisms: A New Theory: A gate control system modulates sensory input from the skin before it evokes pain perception and response","volume":"150","author":"R Melzack","year":"1965","journal-title":"Science"},{"issue":"3","key":"pcbi.1012234.ref011","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.neuron.2014.01.018","article-title":"Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control","volume":"82","author":"J Braz","year":"2014","journal-title":"Neuron"},{"key":"pcbi.1012234.ref012","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s11916-010-0111-0","article-title":"Spinal cord mechanisms of chronic pain and clinical implications","volume":"14","author":"H Thomas Cheng","year":"2010","journal-title":"Current pain and headache reports"},{"issue":"10289","key":"pcbi.1012234.ref013","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1016\/S0140-6736(21)00393-7","article-title":"Chronic pain: an update on burden, best practices, and new advances","volume":"397","author":"SP Cohen","year":"2021","journal-title":"The Lancet"},{"key":"pcbi.1012234.ref014","volume-title":"StatPearls","author":"Y He","year":"2021"},{"issue":"2","key":"pcbi.1012234.ref015","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1152\/physrev.00025.2008","article-title":"Models and mechanisms of hyperalgesia and allodynia","volume":"89","author":"J Sandkuhler","year":"2009","journal-title":"Physiological reviews"},{"issue":"6","key":"pcbi.1012234.ref016","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/j.cell.2014.11.003","article-title":"Identification of spinal circuits transmitting and gating mechanical pain","volume":"159","author":"B Duan","year":"2014","journal-title":"Cell"},{"issue":"6","key":"pcbi.1012234.ref017","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1016\/j.celrep.2015.09.080","article-title":"Dorsal horn parvalbumin neurons are gate-keepers of touch-evoked pain after nerve injury","volume":"13","author":"H Petitjean","year":"2015","journal-title":"Cell reports"},{"issue":"6","key":"pcbi.1012234.ref018","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/nn.4549","article-title":"Identification of spinal circuits involved in touch-evoked dynamic mechanical pain","volume":"20","author":"L Cheng","year":"2017","journal-title":"Nature neuroscience"},{"issue":"6","key":"pcbi.1012234.ref019","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1016\/j.celrep.2019.07.048","article-title":"Recruitment of spinoparabrachial neurons by dorsal horn calretinin neurons","volume":"28","author":"H Petitjean","year":"2019","journal-title":"Cell reports"},{"issue":"5","key":"pcbi.1012234.ref020","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.neuron.2018.07.026","article-title":"Timing mechanisms underlying gate control by feedforward inhibition","volume":"99","author":"Y Zhang","year":"2018","journal-title":"Neuron"},{"issue":"16","key":"pcbi.1012234.ref021","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.1113\/jphysiol.2012.235655","article-title":"Morphological, neurochemical and electrophysiological features of parvalbumin-expressing cells: a likely source of axo-axonic inputs in the mouse spinal dorsal horn","volume":"590","author":"D Hughes","year":"2012","journal-title":"The Journal of physiology"},{"issue":"2","key":"pcbi.1012234.ref022","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/cne.901800213","article-title":"Golgi studies of the neurons in layer II of the dorsal horn of the medulla (trigeminal nucleus caudalis)","volume":"180","author":"S Gobel","year":"1978","journal-title":"Journal of Comparative Neurology"},{"key":"pcbi.1012234.ref023","unstructured":"Freeman WJ. Mass action in the nervous system. vol. 2004. Citeseer; 1975."},{"issue":"2","key":"pcbi.1012234.ref024","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/0748730406297512","article-title":"A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system","volume":"22","author":"A Phillips","year":"2007","journal-title":"Journal of Biological Rhythms"},{"issue":"4","key":"pcbi.1012234.ref025","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/BF00199471","article-title":"Electroencephalogram and visual evoked potential generation in a mathematical model of coupled cortical columns","volume":"73","author":"BH Jansen","year":"1995","journal-title":"Biological cybernetics"},{"issue":"1","key":"pcbi.1012234.ref026","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1113\/jphysiol.2002.017756","article-title":"Lamina-specific membrane and discharge properties of rat spinal dorsal horn neurones in vitro","volume":"541","author":"R Ruscheweyh","year":"2002","journal-title":"The Journal of physiology"},{"issue":"20","key":"pcbi.1012234.ref027","doi-asserted-by":"crossref","first-page":"4995","DOI":"10.1113\/JP276608","article-title":"Specialized mechanoreceptor systems in rodent glabrous skin","volume":"596","author":"J Walcher","year":"2018","journal-title":"The Journal of Physiology"},{"key":"pcbi.1012234.ref028","unstructured":"Ester M, Kriegel HP, Sander J, Xu X. A density-based algorithm for discovering clusters in large spatial databases with noise. In: Simoudis E, Han J, Fayyad U, editors. KDD\u201996: Proceedings of the Second International Conference on Knowledge Discovery and Data Mining. AAAI press; 1996. p. 226\u2013231."},{"key":"pcbi.1012234.ref029","unstructured":"Westlund KN. Neurophysiology of Pain: Peripheral, Spinal, Ascending, and Descending Pathways. In: Practical management of pain. Elsevier; 2022. p. 95\u2013109."},{"issue":"6951","key":"pcbi.1012234.ref030","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/nature01868","article-title":"Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain","volume":"424","author":"JA Coull","year":"2003","journal-title":"Nature"},{"issue":"6355","key":"pcbi.1012234.ref031","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/355075a0","article-title":"Peripheral nerve injury triggers central sprouting of myelinated afferents","volume":"355","author":"CJ Woolf","year":"1992","journal-title":"Nature"},{"issue":"15","key":"pcbi.1012234.ref032","doi-asserted-by":"crossref","first-page":"6724","DOI":"10.1523\/JNEUROSCI.22-15-06724.2002","article-title":"Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord","volume":"22","author":"KA Moore","year":"2002","journal-title":"Journal of Neuroscience"},{"issue":"31","key":"pcbi.1012234.ref033","doi-asserted-by":"crossref","first-page":"5608","DOI":"10.1523\/JNEUROSCI.0426-23.2023","article-title":"Modulation of SK Channels via Calcium Buffering Tunes Intrinsic Excitability of Parvalbumin Interneurons in Neuropathic Pain: A Computational and Experimental Investigation","volume":"43","author":"X Ma","year":"2023","journal-title":"Journal of Neuroscience"},{"issue":"15","key":"pcbi.1012234.ref034","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1523\/JNEUROSCI.1199-21.2022","article-title":"Multiscale computer model of the spinal dorsal horn reveals changes in network processing associated with chronic pain","volume":"42","author":"L Medlock","year":"2022","journal-title":"Journal of Neuroscience"},{"issue":"7","key":"pcbi.1012234.ref035","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1111\/ner.12178","article-title":"Mechanism of dorsal column stimulation to treat neuropathic but not nociceptive pain: analysis with a computational model","volume":"17","author":"JE Arle","year":"2014","journal-title":"Neuromodulation: Technology at the Neural Interface"},{"issue":"2","key":"pcbi.1012234.ref036","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.pain.2010.08.008","article-title":"Populations of inhibitory and excitatory interneurons in lamina II of the adult rat spinal dorsal horn revealed by a combined electrophysiological and anatomical approach","volume":"151","author":"T Yasaka","year":"2010","journal-title":"Pain"},{"issue":"4","key":"pcbi.1012234.ref037","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1113\/jphysiol.2013.264937","article-title":"Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn","volume":"592","author":"P Punnakkal","year":"2014","journal-title":"The Journal of physiology"},{"issue":"2","key":"pcbi.1012234.ref038","first-page":"021028","article-title":"Macroscopic description for networks of spiking neurons","volume":"5","author":"E Montbri\u00f3","year":"2015","journal-title":"Phys Rev X"},{"issue":"2","key":"pcbi.1012234.ref039","doi-asserted-by":"crossref","first-page":"024315","DOI":"10.1103\/PhysRevE.107.024315","article-title":"Exact finite-dimensional description for networks of globally coupled spiking neurons","volume":"107","author":"B Pietras","year":"2023","journal-title":"Physical Review E"},{"issue":"2","key":"pcbi.1012234.ref040","doi-asserted-by":"crossref","first-page":"024311","DOI":"10.1103\/PhysRevE.107.024311","article-title":"Population spiking and bursting in next-generation neural masses with spike-frequency adaptation","volume":"107","author":"A Ferrara","year":"2023","journal-title":"Physical Review E"},{"issue":"4","key":"pcbi.1012234.ref041","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s10827-022-00825-9","article-title":"Exact mean-field models for spiking neural networks with adaptation","volume":"50","author":"L Chen","year":"2022","journal-title":"Journal of Computational Neuroscience"},{"key":"pcbi.1012234.ref042","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1097\/j.pain.0000000000001055","article-title":"Peripheral afferents and spinal inhibitory system in dynamic and static mechanical allodynia","volume":"158","author":"JH La","year":"2017","journal-title":"Pain"},{"key":"pcbi.1012234.ref043","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1211\/jpp.60.6.0006","article-title":"Characterization of primary sensory neurons mediating static and dynamic allodynia in rat chronic constriction injury model","volume":"60","author":"W Yamamoto","year":"2008","journal-title":"J Pharm Pharmacol"},{"key":"pcbi.1012234.ref044","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0304-3959(99)00111-6","article-title":"Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones?","volume":"83","author":"MJ Field","year":"1999","journal-title":"Pain"},{"issue":"7","key":"pcbi.1012234.ref045","doi-asserted-by":"crossref","first-page":"e1007106","DOI":"10.1371\/journal.pcbi.1007106","article-title":"Modeling the daily rhythm of human pain processing in the dorsal horn","volume":"15","author":"J Crodelle","year":"2019","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"pcbi.1012234.ref046","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.neuron.2020.10.027","article-title":"Mechanical allodynia circuitry in the dorsal horn is defined by the nature of the injury","volume":"109","author":"C Peirs","year":"2021","journal-title":"Neuron"},{"key":"pcbi.1012234.ref047","doi-asserted-by":"crossref","first-page":"100509","DOI":"10.1016\/j.coisb.2024.100509","article-title":"Neural signaling in neuropathic pain: A computational modeling perspective","volume":"37","author":"X Ma","year":"2024","journal-title":"Current Opinion in Systems Biology"},{"key":"pcbi.1012234.ref048","unstructured":"Inc TM. Least Squares (Model Fitting) Algorithms; 2024. Available from: https:\/\/www.mathworks.com\/help\/optim\/ug\/least-squares-model-fitting-algorithms.html."},{"issue":"3","key":"pcbi.1012234.ref049","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1152\/jn.00254.2014","article-title":"Modeling effects of spinal cord stimulation on wide-dynamic range dorsal horn neurons: influence of stimulation frequency and GABAergic inhibition","volume":"112","author":"TC Zhang","year":"2014","journal-title":"Journal of neurophysiology"},{"issue":"1-2","key":"pcbi.1012234.ref050","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/0006-8993(86)90343-4","article-title":"Motor, sympathetic and sensory innervation of rat skeletal muscles","volume":"373","author":"J Peyronnard","year":"1986","journal-title":"Brain research"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1012234","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T13:54:27Z","timestamp":1737986067000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012234"}},"subtitle":[],"editor":[{"given":"Boris S.","family":"Gutkin","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,14]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012234","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.06.10.598179","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,14]]}}}