{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T08:34:00Z","timestamp":1782549240209,"version":"3.54.5"},"posted":{"date-parts":[[2025,5,30]]},"group-title":"Neuroscience","reference-count":114,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AA025967"],"award-info":[{"award-number":["R01 AA025967"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P50 AA022534"],"award-info":[{"award-number":["P50 AA022534"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AA029694"],"award-info":[{"award-number":["R01 AA029694"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Adverse in-utero conditions may exert a lifelong impact on neuroimmune function. Our prior work showed that prenatal alcohol exposure (PAE) increases pathological pain sensitivity (allodynia) following peripheral sciatic nerve injury. While the immune mechanism(s) of PAE-induced immune dysfunction are poorly understood, prior studies implicated the involvement of Toll-like receptor 4 (TLR4) and the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasomes. Interestingly, emerging data suggest a surprising overlap of spinal glial proinflammatory activation via the TLR4-NLRP3-interleukin (IL)-1\u03b2 axis due to opioid treatment in nerve-injured non-PAE rodents. Considering this preclinical evidence, we explored whether PAE poses a risk factor in creating proinflammatory immune bias consequent to opioid (morphine) exposure. We hypothesized that under nerve injury conditions, PAE may interact with morphine, promoting peripheral and CNS proinflammatory factors in a NLRP3-dependent manner. Using a minor nerve injury model in adult mice, we demonstrate that PAE prolongs the chronicity of ongoing allodynia in both sexes, with a more pronounced effect observed in male mice. Our study shows that PAE amplifies proinflammatory responses at the injury site and the spinal cord, driving morphine-prolonged allodynia through NLRP3 inflammasome activation. Furthermore, high mobility group box 1 (HMGB1), a well-established pain-promoting TLR4 agonist, is elevated in allodynic PAE mice. NLRP3 inhibitor, MCC950, effectively reverses morphine-induced allodynia and reduces Caspase-1 activity, IL-1\u03b2, and related proinflammatory factors. Although few sex-specific effects were observed, our data convincingly support that PAE and morphine interactions ultimately converge on NLRP3-driven mechanisms in both sexes. Together, this study suggests that PAE modulates later-life neuroimmune function and provides critical insights into immune regulators underlying PAE-induced biological vulnerability to pathological pain processing and adverse effects of opioids.<\/jats:p>","DOI":"10.1101\/2025.05.30.655639","type":"posted-content","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T20:25:33Z","timestamp":1748636733000},"source":"Crossref","is-referenced-by-count":2,"title":["Prenatal alcohol exposure promotes nerve injury-induced pathological pain following morphine treatment via NLRP3-mediated peripheral and central proinflammatory immune actions"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3020-0182","authenticated-orcid":false,"given":"Andrea A.","family":"Pasmay","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3401-9936","authenticated-orcid":false,"given":"Ariana N.","family":"Pritha","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette K.","family":"Fernandez-Oropeza","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5312-5626","authenticated-orcid":false,"given":"Melody S.","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane C.","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minerva","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1026-9604","authenticated-orcid":false,"given":"Carlos F.","family":"Valenzuela","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4446-8279","authenticated-orcid":false,"given":"Shahani","family":"Noor","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reginald Heber Fitz Hall-145, MSC08 4740. University of New Mexico HSC, Albuquerque, NM 87131. Tel: +1 (505) 272-4441, Fax: +1 (505) 272-8082"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041200112948000_2025.05.30.655639v2.1","doi-asserted-by":"crossref","unstructured":"S, P., D, D., K, S., J, R. & L, B. Alcohol\u2019s Impact on the Fetus. Nutrients 13, (2021).","DOI":"10.3390\/nu13103452"},{"key":"2026041200112948000_2025.05.30.655639v2.2","doi-asserted-by":"crossref","unstructured":"SN, M., GA, B. & LR, D. Fetal Alcohol Spectrum Disorders: A Review of the Neurobehavioral Deficits Associated With Prenatal Alcohol Exposure. Alcohol Clin Exp Res 43, (2019).","DOI":"10.1111\/acer.14040"},{"key":"2026041200112948000_2025.05.30.655639v2.3","doi-asserted-by":"crossref","unstructured":"AB, C., TF, C.-C. & MJ, S. Unisensory and Multisensory Responses in Fetal Alcohol Spectrum Disorders (FASD): Effects of Spatial Congruence. Neuroscience 430, (2020).","DOI":"10.1016\/j.neuroscience.2020.01.013"},{"key":"2026041200112948000_2025.05.30.655639v2.4","doi-asserted-by":"crossref","unstructured":"B, F. & L, X. Sensory Processing in Young Children with Fetal Alcohol Spectrum Disorder. Physical & Occupational Therapy In Pediatrics 39, (2019).","DOI":"10.1080\/01942638.2019.1573775"},{"key":"2026041200112948000_2025.05.30.655639v2.5","doi-asserted-by":"crossref","unstructured":"Saha, P. S. & Mayhan, W. G . Prenatal exposure to alcohol: mechanisms of cerebral vascular damage and lifelong consequences. Advances in Drug and Alcohol Research 2, 10818 (2022).","DOI":"10.3389\/adar.2022.10818"},{"key":"2026041200112948000_2025.05.30.655639v2.6","doi-asserted-by":"crossref","unstructured":"S, N. & ED, M. Lifelong Impacts of Moderate Prenatal Alcohol Exposure on Neuroimmune Function. Front Immunol 9, (2018).","DOI":"10.3389\/fimmu.2018.01107"},{"key":"2026041200112948000_2025.05.30.655639v2.7","doi-asserted-by":"crossref","unstructured":"LS, T. & JM, S. Effects of Moderate Prenatal Alcohol Exposure during Early Gestation in Rats on Inflammation across the Maternal-Fetal-Immune Interface and Later-Life Immune Function in the Offspring. J Neuroimmune Pharmacol 11, (2016).","DOI":"10.1007\/s11481-016-9691-8"},{"key":"2026041200112948000_2025.05.30.655639v2.8","doi-asserted-by":"crossref","unstructured":"Breuer, L. , Greenmyer, J. R. & Wilson, T . Clinical Diagnosis and Management of Fetal Alcohol Spectrum Disorder and Sensory Processing Disorder in Children. Children 11, (2024).","DOI":"10.3390\/children11010108"},{"key":"2026041200112948000_2025.05.30.655639v2.9","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/2480689"},{"key":"2026041200112948000_2025.05.30.655639v2.10","doi-asserted-by":"crossref","unstructured":"V, S., et al. Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice. Brain, Behavior, and Immunity 91, (2021).","DOI":"10.1016\/j.bbi.2020.11.018"},{"key":"2026041200112948000_2025.05.30.655639v2.11","doi-asserted-by":"crossref","unstructured":"B, R. & GW, L. Damage-associated molecular patterns in trauma. European Journal of Trauma and Emergency Surgery 46, (2020).","DOI":"10.1007\/s00068-019-01235-w"},{"key":"2026041200112948000_2025.05.30.655639v2.12","doi-asserted-by":"crossref","unstructured":"H, Y., et al. HMGB1 released from nociceptors mediates inflammation. Proceedings of the National Academy of Sciences 118, (2021).","DOI":"10.1073\/pnas.2102034118"},{"key":"2026041200112948000_2025.05.30.655639v2.13","doi-asserted-by":"crossref","unstructured":"Wan, W. et al. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation. Journal of Immunolofy Research (2016).","DOI":"10.1155\/2016\/6430423"},{"key":"2026041200112948000_2025.05.30.655639v2.14","doi-asserted-by":"crossref","unstructured":"Y, H., H, H. & G, N. Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends Biochem Sci 41, (2016).","DOI":"10.1016\/j.tibs.2016.09.002"},{"key":"2026041200112948000_2025.05.30.655639v2.15","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-7-9"},{"key":"2026041200112948000_2025.05.30.655639v2.16","doi-asserted-by":"crossref","unstructured":"Begum, E. et al. IL-18 Blockage Reduces Neuroinflammation and Promotes Functional Recovery in a Mouse Model of Spinal Cord Injury. Biomolecules 15, (2024).","DOI":"10.3390\/biom15010016"},{"key":"2026041200112948000_2025.05.30.655639v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107089"},{"key":"2026041200112948000_2025.05.30.655639v2.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ibneur.2022.12.007"},{"key":"2026041200112948000_2025.05.30.655639v2.19","doi-asserted-by":"crossref","unstructured":"Ohashi, Y. , Uchida, K. , Fukushima, K. , Inoue, G. & Takaso, M . Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain. Cureus 15, (2023).","DOI":"10.7759\/cureus.35331"},{"key":"2026041200112948000_2025.05.30.655639v2.20","doi-asserted-by":"crossref","unstructured":"Bhatt, M. , Sharma, M. & Das, B . The Role of Inflammatory Cascade and Reactive Astrogliosis in Glial Scar Formation Post-spinal Cord Injury. Cellular and Molecular Neurobiology 44, 78 (2024).","DOI":"10.1007\/s10571-024-01519-9"},{"key":"2026041200112948000_2025.05.30.655639v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/S1537-5897(03)00044-2"},{"key":"2026041200112948000_2025.05.30.655639v2.22","doi-asserted-by":"crossref","unstructured":"KO, F., HH, S., M, E. & TSK, P. The midbrain periaqueductal gray as an integrative and interoceptive neural structure for breathing. Neuroscience & Biobehavioral Reviews 98, (2019).","DOI":"10.1016\/j.neubiorev.2018.12.020"},{"key":"2026041200112948000_2025.05.30.655639v2.23","doi-asserted-by":"crossref","unstructured":"M, G., Z, J., Y, C., F, W. & Z, W. Inflammatory cytokines in midbrain periaqueductal gray contribute to diabetic induced pain hypersensitivity through phosphoinositide 3-kinase\/protein kinase B\/mammalian target of rapamycin signaling pathway. The Korean Journal of Pain 34, (2021).","DOI":"10.3344\/kjp.2021.34.2.176"},{"key":"2026041200112948000_2025.05.30.655639v2.24","doi-asserted-by":"crossref","unstructured":"V, N., R, S. & AL, H. Brainstem neuroimaging of nociception and pain circuitries. PAIN Reports 4, (2019).","DOI":"10.1097\/PR9.0000000000000745"},{"key":"2026041200112948000_2025.05.30.655639v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.04.012"},{"key":"2026041200112948000_2025.05.30.655639v2.26","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001306"},{"key":"2026041200112948000_2025.05.30.655639v2.27","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-023-01235-8"},{"key":"2026041200112948000_2025.05.30.655639v2.28","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02131-0"},{"key":"2026041200112948000_2025.05.30.655639v2.29","doi-asserted-by":"crossref","unstructured":"B, W., et al. Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord. Anesthesiology 140, (2024).","DOI":"10.1097\/ALN.0000000000004858"},{"key":"2026041200112948000_2025.05.30.655639v2.30","first-page":"1744","article-title":"Behavioural and Morphological Evidence for the Involvement of Glial Cell Activation in Delta Opioid Receptor Function: Implications for the Development of Opioid Tolerance","volume":"3","year":"2007","journal-title":"Molecular Pain"},{"key":"2026041200112948000_2025.05.30.655639v2.31","first-page":"746941","article-title":"Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward","volume":"7","year":"2007","journal-title":"The Scientific World Journal"},{"key":"2026041200112948000_2025.05.30.655639v2.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2005.10.001"},{"key":"2026041200112948000_2025.05.30.655639v2.33","doi-asserted-by":"crossref","unstructured":"P, Z., et al. Toll-Like Receptor 4 (TLR4)\/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility. Front Immunol 11, (2020).","DOI":"10.3389\/fimmu.2020.01455"},{"key":"2026041200112948000_2025.05.30.655639v2.34","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12313"},{"key":"2026041200112948000_2025.05.30.655639v2.35","doi-asserted-by":"crossref","unstructured":"A, E., et al. Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury. Brain Behav Immun 58, (2016).","DOI":"10.1016\/j.bbi.2016.08.004"},{"key":"2026041200112948000_2025.05.30.655639v2.36","doi-asserted-by":"crossref","unstructured":"PM, G., et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113, (2016).","DOI":"10.1073\/pnas.1602070113"},{"key":"2026041200112948000_2025.05.30.655639v2.37","doi-asserted-by":"crossref","unstructured":"MS, G.-F., et al. Oxycodone, fentanyl, and morphine amplify established neuropathic pain in male rats. Pain 160, (2019).","DOI":"10.1097\/j.pain.0000000000001652"},{"key":"2026041200112948000_2025.05.30.655639v2.38","first-page":"1744","article-title":"Acute Morphine Activates Satellite Glial Cells and Up-Regulates IL-1\u03b2 in Dorsal Root Ganglia in Mice via Matrix Metalloprotease-9","volume":"8","year":"2012","journal-title":"Molecular Pain"},{"key":"2026041200112948000_2025.05.30.655639v2.39","doi-asserted-by":"crossref","unstructured":"S, N., et al. The LFA-1 antagonist BIRT377 reverses neuropathic pain in prenatal alcohol-exposed female rats via actions on peripheral and central neuroimmune function in discrete pain-relevant tissue regions. Brain , Behavior, and Immunity 87, (2020).","DOI":"10.1016\/j.bbi.2020.01.002"},{"key":"2026041200112948000_2025.05.30.655639v2.40","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-1030-3"},{"key":"2026041200112948000_2025.05.30.655639v2.41","doi-asserted-by":"crossref","unstructured":"JJ, S., et al. Targeting the \u03b22-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure. Acta Neuropathol Commun 7, (2019).","DOI":"10.1186\/s40478-019-0701-y"},{"key":"2026041200112948000_2025.05.30.655639v2.42","doi-asserted-by":"crossref","unstructured":"S, N., et al. LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes. Neuroimmunol Neuroinflamm 6. Epub 20190722., (2019).","DOI":"10.20517\/2347-8659.2019.18"},{"key":"2026041200112948000_2025.05.30.655639v2.43","doi-asserted-by":"crossref","unstructured":"S, N., et al. Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels. Brain , Behavior, and Immunity 61, (2017).","DOI":"10.1016\/j.bbi.2016.12.016"},{"key":"2026041200112948000_2025.05.30.655639v2.44","doi-asserted-by":"crossref","unstructured":"S, N., et al. Prenatal alcohol exposure promotes NLRP3 inflammasome-dependent immune actions following morphine treatment and paradoxically prolongs nerve injury-induced pathological pain in female mice. Alcohol: Clinical and Experimental Research 47, (2023).","DOI":"10.1111\/acer.15214"},{"key":"2026041200112948000_2025.05.30.655639v2.45","doi-asserted-by":"crossref","unstructured":"A, T.-A., et al. MCC950 closes the active conformation of NLRP3 to an inactive state. Nature Chemical Biology 15, (2019).","DOI":"10.1038\/s41589-019-0278-6"},{"key":"2026041200112948000_2025.05.30.655639v2.46","doi-asserted-by":"crossref","unstructured":"H, L., et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. European Journal of Pharmacology 928, (2022).","DOI":"10.1016\/j.ejphar.2022.175091"},{"key":"2026041200112948000_2025.05.30.655639v2.47","doi-asserted-by":"crossref","unstructured":"J, J., G, Z., Y, W., P, R. & M, W. MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury. Front Mol Biosci 7, (2020).","DOI":"10.3389\/fmolb.2020.00037"},{"key":"2026041200112948000_2025.05.30.655639v2.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-26775-w"},{"key":"2026041200112948000_2025.05.30.655639v2.49","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.861312"},{"key":"2026041200112948000_2025.05.30.655639v2.50","doi-asserted-by":"crossref","unstructured":"Y, S., H, Y., D, W., H, Y. & D, H. NLRP3 inflammasome inhibitor MCC950 can reduce the damage of pancreatic and intestinal barrier function in mice with acute pancreatitis. Acta Cir\u00fargica Brasileira 37, (2022).","DOI":"10.1590\/acb370706"},{"key":"2026041200112948000_2025.05.30.655639v2.51","doi-asserted-by":"crossref","unstructured":"LM, B., et al. Moderate Prenatal Alcohol Exposure Reduces Plasticity and Alters NMDA Receptor Subunit Composition in the Dentate Gyrus. The Journal of Neuroscience 33, (2013).","DOI":"10.1523\/JNEUROSCI.1217-12.2013"},{"key":"2026041200112948000_2025.05.30.655639v2.52","doi-asserted-by":"crossref","unstructured":"LM, B., MA, A. & KK, C. A Limited Access Mouse Model of Prenatal Alcohol Exposure that Produces Long-Lasting Deficits in Hippocampal-Dependent Learning and Memory. Alcoholism: Clinical and Experimental Research 36, (2012).","DOI":"10.1111\/j.1530-0277.2011.01644.x"},{"key":"2026041200112948000_2025.05.30.655639v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02050-3"},{"key":"2026041200112948000_2025.05.30.655639v2.54","doi-asserted-by":"publisher","DOI":"10.5505\/tjtes.2013.86383"},{"key":"2026041200112948000_2025.05.30.655639v2.55","first-page":"8","article-title":"The influence of analgesic choice, administration, and duration on postoperative pain in rodents","volume":"39","year":"2000","journal-title":"Contemporary Topics in Laboratory Animal Science"},{"key":"2026041200112948000_2025.05.30.655639v2.56","doi-asserted-by":"crossref","unstructured":"T, M., et al. Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1\u03b2 and islet cellular death. Scientific Reports 10, (2020).","DOI":"10.1038\/s41598-020-74786-3"},{"key":"2026041200112948000_2025.05.30.655639v2.57","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3806"},{"key":"2026041200112948000_2025.05.30.655639v2.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104339"},{"key":"2026041200112948000_2025.05.30.655639v2.59","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02669-7"},{"key":"2026041200112948000_2025.05.30.655639v2.60","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Martel, I. , Negrini-Ferrari, S. E. & Pol, O . MCC950 Reduces the Anxiodepressive-like Behaviors and Memory Deficits Related to Paclitaxel-Induced Peripheral Neuropathy in Mice. Antioxidants (Basel ) 14, (2025).","DOI":"10.3390\/antiox14020143"},{"key":"2026041200112948000_2025.05.30.655639v2.61","doi-asserted-by":"crossref","unstructured":"W, H., et al. Microglial NLRP3 inflammasome activation mediates IL-1\u03b2 release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model. Journal of Neuroinflammation 16, (2019).","DOI":"10.1186\/s12974-019-1459-7"},{"key":"2026041200112948000_2025.05.30.655639v2.62","doi-asserted-by":"crossref","unstructured":"W, Z., et al. The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages. Scientific Reports 11, (2021).","DOI":"10.1038\/s41598-021-98437-3"},{"key":"2026041200112948000_2025.05.30.655639v2.63","doi-asserted-by":"crossref","unstructured":"A, B.-I. & MI, S. Use of fluorochrome-labeled inhibitors of caspases to detect neuronal apoptosis in the whole-mounted lamprey brain after spinal cord injury. Enzyme Res 2012, (2012).","DOI":"10.1155\/2012\/835731"},{"key":"2026041200112948000_2025.05.30.655639v2.64","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"2026041200112948000_2025.05.30.655639v2.65","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318238bba6"},{"key":"2026041200112948000_2025.05.30.655639v2.66","doi-asserted-by":"publisher","DOI":"10.1097\/FBP.0b013e328337be25"},{"key":"2026041200112948000_2025.05.30.655639v2.67","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-60759-3"},{"key":"2026041200112948000_2025.05.30.655639v2.68","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-180"},{"key":"2026041200112948000_2025.05.30.655639v2.69","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-1717-8"},{"key":"2026041200112948000_2025.05.30.655639v2.70","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-0918-2"},{"key":"2026041200112948000_2025.05.30.655639v2.71","doi-asserted-by":"crossref","first-page":"426","DOI":"10.3389\/fncel.2018.00426","article-title":"Inhibiting the NLRP3 Inflammasome With MCC950 Ameliorates Isoflurane-Induced Pyroptosis and Cognitive Impairment in Aged Mice","volume":"12","year":"2018","journal-title":"Front Cell Neurosci"},{"key":"2026041200112948000_2025.05.30.655639v2.72","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2009.08.004"},{"key":"2026041200112948000_2025.05.30.655639v2.73","doi-asserted-by":"crossref","unstructured":"CSJ, M., S, B. & WM, S. Sex differences in pain. Pain 157 (Supplement 1 ), (2016).","DOI":"10.1097\/j.pain.0000000000000389"},{"key":"2026041200112948000_2025.05.30.655639v2.74","doi-asserted-by":"crossref","unstructured":"Nicotra, L. , Tuke, J. , Grace, P. M. , Rolan, P. E. & Hutchinson, M. R . Sex differences in mechanical allodynia: how can it be preclinically quantified and analyzed? Frontiers in Behavioral Neuroscience 8, (2014).","DOI":"10.3389\/fnbeh.2014.00040"},{"key":"2026041200112948000_2025.05.30.655639v2.75","doi-asserted-by":"crossref","unstructured":"S, R., B, H. & SJ, M. Sex differences in neuroimmunity and pain. Journal of Neuroscience Research 95 ( 1\u20132 ), (2017).","DOI":"10.1002\/jnr.23831"},{"key":"2026041200112948000_2025.05.30.655639v2.76","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2023.101103"},{"key":"2026041200112948000_2025.05.30.655639v2.77","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2024.02.016"},{"key":"2026041200112948000_2025.05.30.655639v2.78","doi-asserted-by":"crossref","unstructured":"P, P., et al. Prenatal Alcohol Exposure Results in Sex-Specific Alterations in Circular RNA Expression in the Developing Mouse Brain. Front Neurosci 14, (2020).","DOI":"10.3389\/fnins.2020.581895"},{"key":"2026041200112948000_2025.05.30.655639v2.79","doi-asserted-by":"crossref","unstructured":"A, J., G, K., B, K., A, R. & B, K. Sex differences in hyperalgesia during morphine infusion: Effect of gonadectomy and estrogen treatment. Neuropharmacology 54, (2008).","DOI":"10.1016\/j.neuropharm.2008.04.004"},{"key":"2026041200112948000_2025.05.30.655639v2.80","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.879021"},{"key":"2026041200112948000_2025.05.30.655639v2.81","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-020-0087-2"},{"key":"2026041200112948000_2025.05.30.655639v2.82","doi-asserted-by":"crossref","unstructured":"Li, S. , et al. Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice. Cell Reports 41, (2022).","DOI":"10.1016\/j.celrep.2022.111532"},{"key":"2026041200112948000_2025.05.30.655639v2.83","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1434295"},{"key":"2026041200112948000_2025.05.30.655639v2.84","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24133"},{"key":"2026041200112948000_2025.05.30.655639v2.85","first-page":"54","article-title":"Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome","volume":"17","year":"2025","journal-title":"EMBO Molecular Medicine"},{"key":"2026041200112948000_2025.05.30.655639v2.86","unstructured":"Murphy, P. B. , Patel, P. & Barrett, M. J. Morphine. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025)."},{"key":"2026041200112948000_2025.05.30.655639v2.87","doi-asserted-by":"crossref","unstructured":"X, W., et al. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A 109, (2012).","DOI":"10.1073\/pnas.1200130109"},{"key":"2026041200112948000_2025.05.30.655639v2.88","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2023.05.082"},{"key":"2026041200112948000_2025.05.30.655639v2.89","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-019-00800-w"},{"key":"2026041200112948000_2025.05.30.655639v2.90","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2017.08.018"},{"key":"2026041200112948000_2025.05.30.655639v2.91","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000000640"},{"key":"2026041200112948000_2025.05.30.655639v2.92","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2826.2001.00714.x"},{"key":"2026041200112948000_2025.05.30.655639v2.93","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0444-6"},{"key":"2026041200112948000_2025.05.30.655639v2.94","doi-asserted-by":"publisher","DOI":"10.1016\/j.infbeh.2015.04.004"},{"key":"2026041200112948000_2025.05.30.655639v2.95","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2016.08.015"},{"key":"2026041200112948000_2025.05.30.655639v2.96","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1203557"},{"key":"2026041200112948000_2025.05.30.655639v2.97","doi-asserted-by":"crossref","unstructured":"Abdallah, C. G. & Geha, P. Chronic Pain and Chronic Stress: Two Sides of the Same Coin? Chronic Stress (Thousand Oaks) 1, (2017).","DOI":"10.1177\/2470547017704763"},{"key":"2026041200112948000_2025.05.30.655639v2.98","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2024.1445280"},{"key":"2026041200112948000_2025.05.30.655639v2.99","doi-asserted-by":"crossref","unstructured":"Wyns, A. et al. The Biology of Stress Intolerance in Patients with Chronic Pain-State of the Art and Future Directions. J Clin Med 12, (2023).","DOI":"10.3390\/jcm12062245"},{"key":"2026041200112948000_2025.05.30.655639v2.100","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20699"},{"key":"2026041200112948000_2025.05.30.655639v2.101","doi-asserted-by":"crossref","unstructured":"Duez, H. & Pourcet, B . Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway. Frontiers in Endocrinology 12, 630536 (2021).","DOI":"10.3389\/fendo.2021.630536"},{"key":"2026041200112948000_2025.05.30.655639v2.102","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2022.2040188"},{"key":"2026041200112948000_2025.05.30.655639v2.103","doi-asserted-by":"publisher","DOI":"10.1021\/bi901948j"},{"key":"2026041200112948000_2025.05.30.655639v2.104","doi-asserted-by":"crossref","unstructured":"Yan, J. , McCombe, P. A. , Pender, M. P. & Greer, J. M . Reduced I\u03baB-\u03b1 Protein Levels in Peripheral Blood Cells of Patients with Multiple Sclerosis-A Possible Cause of Constitutive NF-\u03baB Activation. J Clin Med 9, (2020).","DOI":"10.3390\/jcm9082534"},{"key":"2026041200112948000_2025.05.30.655639v2.105","doi-asserted-by":"publisher","DOI":"10.1002\/embr.201337983"},{"key":"2026041200112948000_2025.05.30.655639v2.106","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101834"},{"key":"2026041200112948000_2025.05.30.655639v2.107","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00622"},{"key":"2026041200112948000_2025.05.30.655639v2.108","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-020-00339-y"},{"key":"2026041200112948000_2025.05.30.655639v2.109","doi-asserted-by":"crossref","first-page":"ltad022","DOI":"10.1093\/immadv\/ltad022","article-title":"NLRP3 inflammasome activation in sensory neurons promotes chronic inflammatory and osteoarthritis pain","volume":"3","year":"2023","journal-title":"Immunother Adv"},{"key":"2026041200112948000_2025.05.30.655639v2.110","doi-asserted-by":"crossref","unstructured":"MM, G., et al. Interaction of Opioids with TLR4\u2014Mechanisms and Ramifications. Cancers 13, (2021).","DOI":"10.3390\/cancers13215274"},{"key":"2026041200112948000_2025.05.30.655639v2.111","doi-asserted-by":"crossref","unstructured":"KV, S., SL, P. & LC, F. Neuropathic pain-induced enhancement of spontaneous and pain-evoked neuronal activity in the periaqueductal gray that is attenuated by gabapentin. Pain 158, (2017).","DOI":"10.1097\/j.pain.0000000000000905"},{"key":"2026041200112948000_2025.05.30.655639v2.112","doi-asserted-by":"crossref","unstructured":"N, D., et al. HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia. Cell Reports 17, (2016).","DOI":"10.1016\/j.celrep.2016.09.076"},{"key":"2026041200112948000_2025.05.30.655639v2.113","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-11-92"},{"key":"2026041200112948000_2025.05.30.655639v2.114","doi-asserted-by":"crossref","unstructured":"JE, S., et al. The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1\u03b2 and IL-10 expression from immune cell culture. Neuroscience Letters 814, (2023).","DOI":"10.1016\/j.neulet.2023.137419"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.30.655639","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:11:48Z","timestamp":1775977908000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.30.655639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,30]]},"references-count":114,"URL":"https:\/\/doi.org\/10.1101\/2025.05.30.655639","relation":{},"subject":[],"published":{"date-parts":[[2025,5,30]]},"subtype":"preprint"}}