Neuropathic pain after spinal cord injury lacks any effective treatments, often leading to chronic pain. This study tested whether the daily administration of fully characterized polyphenolic extracts from grape stalks and coffee could prevent both reflexive and non-reflexive chronic neuropathic pain in spinal cord-injured mice by modulating the neuroimmune axis. Female CD1 mice underwent mild spinal cord contusion and received intraperitoneal extracts in weeks one, three, and six post-surgery. Reflexive pain responses were assessed weekly for up to 10 weeks, and non-reflexive pain was evaluated at the study's end. Neuroimmune crosstalk was investigated, focusing on glial activation and the expression of CCL2/CCR2 and CX3CL1/CX3CR1 in supraspinal pain-related areas, including the periaqueductal gray, rostral ventromedial medulla, anterior cingulate cortex, and amygdala. Repeated treatments prevented mechanical allodynia and thermal hyperalgesia, and also modulated non-reflexive pain. Moreover, they reduced supraspinal gliosis and regulated CCL2/CCR2 and CX3CL1/CX3CR1 signaling. Overall, the combination of polyphenols in these extracts may offer a promising pharmacological strategy to prevent chronic reflexive and non-reflexive pain responses by modifying central sensitization markers, not only at the contusion site but also in key supraspinal regions implicated in neuropathic pain. Overall, these data highlight the potential of polyphenolic extracts for spinal cord injury-induced chronic neuropathic pain.

Department of Chemical Engineering Agriculture and Food Technology Polytechnic School University of Girona 17003 Girona Catalonia Spain

Division of Neuroanatomy Department of Anatomy Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Research Group of Clinical Anatomy Embryology and Neuroscience Department of Medical Sciences University of Girona 17071 Girona Catalonia Spain

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Alizadeh A., Dyck S.M., Karimi-Abdolrezaee S. Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms. Front. Neurol. 2019;10:441408. doi: 10.3389/fneur.2019.00282. PubMed DOI PMC

Ahuja C.S., Wilson J.R., Nori S., Kotter M.R.N., Druschel C., Curt A., Fehlings M.G. Traumatic Spinal Cord Injury. Nat. Rev. Dis. Primers. 2017;3:17018. doi: 10.1038/nrdp.2017.18. PubMed DOI

Burke D., Fullen B.M., Stokes D., Lennon O. Neuropathic Pain Prevalence Following Spinal Cord Injury: A Systematic Review and Meta-Analysis. Eur. J. Pain. 2017;21:29–44. doi: 10.1002/ejp.905. PubMed DOI

Warner F.M., Cragg J.J., Jutzeler C.R., Finnerup N.B., Werhagen L., Weidner N., Maier D., Kalke Y.B., Curt A., Kramer J.L.K. Progression of Neuropathic Pain after Acute Spinal Cord Injury: A Meta-Analysis and Framework for Clinical Trials. J. Neurotrauma. 2018;36:1461–1468. doi: 10.1089/NEU.2018.5960. PubMed DOI

Hunt C., Moman R., Peterson A., Wilson R., Covington S., Mustafa R., Murad M.H., Hooten W.M. Prevalence of Chronic Pain after Spinal Cord Injury: A Systematic Review and Meta-Analysis. Reg. Anesth. Pain Med. 2021;46:328–336. doi: 10.1136/RAPM-2020-101960. PubMed DOI

Wilson J.R., Hashimoto R.E., Dettori J.R., Fehlings M.G. Spinal Cord Injury and Quality of Life: A Systematic Review of Outcome Measures. Evid. Based Spine Care J. 2011;2:37–44. doi: 10.1055/S-0030-1267085. PubMed DOI PMC

Rivers C.S., Fallah N., Noonan V.K., Whitehurst D.G., Schwartz C.E., Finkelstein J.A., Craven B.C., Ethans K., O’Connell C., Truchon B.C., et al. Health Conditions: Effect on Function, Health-Related Quality of Life, and Life Satisfaction After Traumatic Spinal Cord Injury. A Prospective Observational Registry Cohort Study. Arch. Phys. Med. Rehabil. 2018;99:443–451. doi: 10.1016/J.APMR.2017.06.012. PubMed DOI

Cavalli E., Mammana S., Nicoletti F., Bramanti P., Mazzon E. The Neuropathic Pain: An Overview of the Current Treatment and Future Therapeutic Approaches. Int. J. Immunopathol. Pharmacol. 2019;33:2058738419838383. doi: 10.1177/2058738419838383. PubMed DOI PMC

Echeverria-Villalobos M., Tortorici V., Brito B.E., Ryskamp D., Uribe A., Weaver T. The Role of Neuroinflammation in the Transition of Acute to Chronic Pain and the Opioid-Induced Hyperalgesia and Tolerance. Front. Pharmacol. 2023;14:1297931. doi: 10.3389/fphar.2023.1297931. PubMed DOI PMC

Ramos D., Cruz C.D. Involvement of Microglia in Chronic Neuropathic Pain Associated with Spinal Cord Injury—A Systematic Review. Rev. Neurosci. 2023;34:933–950. doi: 10.1515/revneuro-2023-0031. PubMed DOI

Shiao R., Lee-Kubli C.A. Neuropathic Pain After Spinal Cord Injury: Challenges and Research Perspectives. Neurotherapeutics. 2018;15:635–653. doi: 10.1007/s13311-018-0633-4. PubMed DOI PMC

Walters E.T. Neuroinflammatory Contributions to Pain after SCI: Roles for Central Glial Mechanisms and Nociceptor-Mediated Host Defense. Exp. Neurol. 2014;258:48–61. doi: 10.1016/j.expneurol.2014.02.001. PubMed DOI

Liu Y., Shi Y., Zhang M., Han F., Liao W., Duan X. Natural Polyphenols for Drug Delivery and Tissue Engineering Construction: A Review. Eur. J. Med. Chem. 2024;266:116141. doi: 10.1016/j.ejmech.2024.116141. PubMed DOI

Boadas-Vaello P., Vela J.M., Verdu E. New Pharmacological Approaches Using Polyphenols on the Physiopathology of Neuropathic Pain. Curr. Drug Targets. 2016;18:160–173. doi: 10.2174/1389450117666160527142423. PubMed DOI

Durham P.L., Antonopoulos S.R. Benefit of Dietary Supplementation of Nutraceuticals as an Integrative Approach for Management of Migraine: Evidence From Preclinical and Clinical Studies. Curr. Pain Headache Rep. 2024;28:373–381. doi: 10.1007/s11916-024-01230-w. PubMed DOI PMC

Soler-Martínez R., Deulofeu M., Bagó-Mas A., Dubový P., Verdú E., Fiol N., Boadas-Vaello P. Central Neuropathic Pain Development Modulation Using Coffee Extract Major Polyphenolic Compounds in Spinal-Cord-Injured Female Mice. Biology. 2022;11:1617. doi: 10.3390/biology11111617. PubMed DOI PMC

Bagó-Mas A., Korimová A., Deulofeu M., Verdú E., Fiol N., Svobodová V., Dubový P., Boadas-Vaello P. Polyphenolic Grape Stalk and Coffee Extracts Attenuate Spinal Cord Injury-Induced Neuropathic Pain Development in ICR-CD1 Female Mice. Sci. Rep. 2022;12:14980. doi: 10.1038/s41598-022-19109-4. PubMed DOI PMC

Álvarez-Pérez B., Homs J., Bosch-Mola M., Puig T., Reina F., Verdú E., Boadas-Vaello P. Epigallocatechin-3-Gallate Treatment Reduces Thermal Hyperalgesia after Spinal Cord Injury by down-Regulating RhoA Expression in Mice. Eur. J. Pain. 2016;20:341–352. doi: 10.1002/ejp.722. PubMed DOI

Becker S., Gandhi W., Schweinhardt P. Cerebral Interactions of Pain and Reward and Their Relevance for Chronic Pain. Neurosci. Lett. 2012;520:182–187. doi: 10.1016/j.neulet.2012.03.013. PubMed DOI

Miller A.H., Haroon E., Raison C.L., Felger J.C. Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits. Depress. Anxiety. 2013;30:297–306. doi: 10.1002/da.22084. PubMed DOI PMC

Castany S., Bagó-Mas A., Vela J.M., Verdú E., Bretová K., Svobodová V., Dubový P., Boadas-Vaello P. Transient Reflexive Pain Responses and Chronic Affective Nonreflexive Pain Responses Associated with Neuroinflammation Processes in Both Spinal and Supraspinal Structures in Spinal Cord-Injured Female Mice. Int. J. Mol. Sci. 2023;24:1761. doi: 10.3390/ijms24021761. PubMed DOI PMC

Toledano-Martos R., Bagó-Mas A., Deulofeu M., Homs J., Fiol N., Verdú E., Boadas-Vaello P. Natural Polyphenolic Coffee Extract Administration Relieves Chronic Nociplastic Pain in a Reserpine-Induced Fibromyalgia-like Female Mouse Model. Brain Behav. 2024;14:e3386. doi: 10.1002/BRB3.3386. PubMed DOI PMC

Wu J., Stoica B.A., Luo T., Sabirzhanov B., Zhao Z., Guanciale K., Nayar S.K., Foss C.A., Pomper M.G., Faden A.I. Isolated Spinal Cord Contusion in Rats Induces Chronic Brain Neuroinflammation, Neurodegeneration, and Cognitive Impairment. Cell Cycle. 2014;13:2446–2458. doi: 10.4161/cc.29420. PubMed DOI PMC

Wu J., Zhao Z., Kumar A., Lipinski M.M., Loane D.J., Stoica B.A., Faden A.I. Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury. J. Neurotrauma. 2016;33:1919–1935. doi: 10.1089/neu.2015.4348. PubMed DOI PMC

Wang L., Gunduz M.A., Semeano A.T., Yılmaz E.C., Alanazi F.A.H., Imir O.B., Yener U., Arbelaez C.A., Usuga E., Teng Y.D. Coexistence of Chronic Hyperalgesia and Multilevel Neuroinflammatory Responses after Experimental SCI: A Systematic Approach to Profiling Neuropathic Pain. J. Neuroinflamm. 2022;19:264. doi: 10.1186/s12974-022-02628-2. PubMed DOI PMC

Taoka Y., Okajima K. Spinal Cord Injury in the Rat. Prog. Neurobiol. 1998;56:341–358. doi: 10.1016/S0301-0082(98)00049-5. PubMed DOI

Young W. Chapter 17 Spinal Cord Contusion Models. Prog. Brain Res. 2002;137:231–255. doi: 10.1016/S0079-6123(02)37019-5. PubMed DOI

Arnold S.A., Hagg T. Anti-Inflammatory Treatments during the Chronic Phase of Spinal Cord Injury Improve Locomotor Function in Adult Mice. J. Neurotrauma. 2011;28:1995–2002. doi: 10.1089/neu.2011.1888. PubMed DOI PMC

Bisaz R., Boadas-Vaello P., Genoux D., Sandi C. Age-Related Cognitive Impairments in Mice with a Conditional Ablation of the Neural Cell Adhesion Molecule. Learn. Mem. 2013;20:183–193. doi: 10.1101/LM.030064.112. PubMed DOI

Heinricher M.M., Tavares I., Leith J.L., Lumb B.M. Descending Control of Nociception: Specificity, Recruitment and Plasticity. Brain Res. Rev. 2009;60:214–225. doi: 10.1016/J.BRAINRESREV.2008.12.009. PubMed DOI PMC

Willis W.D. Central Nervous System Mechanisms for Pain Modulation. Appl. Neurophysiol. 1985;48:153–165. doi: 10.1159/000101121. PubMed DOI

Ossipov M.H., Morimura K., Porreca F. Descending Pain Modulation and Chronification of Pain. Curr. Opin. Support. Palliat. Care. 2014;8:143–151. doi: 10.1097/SPC.0000000000000055. PubMed DOI PMC

McMullan S., Lumb B.M. Midbrain Control of Spinal Nociception Discriminates between Responses Evoked by Myelinated and Unmyelinated Heat Nociceptors in the Rat. Pain. 2006;124:59–68. doi: 10.1016/J.PAIN.2006.03.015. PubMed DOI

Eidson L.N., Murphy A.Z. Persistent Peripheral Inflammation Attenuates Morphine-Induced Periaqueductal Gray Glial Cell Activation and Analgesic Tolerance in the Male Rat. J. Pain. 2013;14:393–404. doi: 10.1016/J.JPAIN.2012.12.010. PubMed DOI PMC

Clark A.K., Yip P.K., Grist J., Gentry C., Staniland A.A., Marchand F., Dehvari M., Wotherspoon G., Winter J., Ullah J., et al. Inhibition of Spinal Microglial Cathepsin S for the Reversal of Neuropathic Pain. Proc. Natl. Acad. Sci. USA. 2007;104:10655. doi: 10.1073/pnas.0610811104. PubMed DOI PMC

Gao Y.J., Ren W.H., Zhang Y.Q., Zhao Z.Q. Contributions of the Anterior Cingulate Cortex and Amygdala to Pain- and Fear-Conditioned Place Avoidance in Rats. Pain. 2004;110:343–353. doi: 10.1016/j.pain.2004.04.030. PubMed DOI

Veinante P., Yalcin I., Barrot M. The Amygdala between Sensation and Affect: A Role in Pain. J. Mol. Psychiatry. 2013;1:9. doi: 10.1186/2049-9256-1-9. PubMed DOI PMC

Morton D.B., Griffiths P.H. Guidelines on the Recognition of Pain, Distress and Discomfort in Experimental Animals and an Hypothesis for Assessment. Vet. Rec. 1985;116:431–436. doi: 10.1136/vr.116.16.431. PubMed DOI

Finnerup N.B., Sindrup S.H., Jensen T.S. The Evidence for Pharmacological Treatment of Neuropathic Pain. Pain. 2010;150:573–581. doi: 10.1016/J.PAIN.2010.06.019. PubMed DOI

Attal N. Pharmacological Treatments of Neuropathic Pain: The Latest Recommendations. Rev. Neurol. 2019;175:46–50. doi: 10.1016/j.neurol.2018.08.005. PubMed DOI

Arango-Lasprilla J.C., Ketchum J.M., Starkweather A., Nicholls E., Wilk A.R. Factors Predicting Depression among Persons with Spinal Cord Injury 1 to 5 Years Post Injury. NeuroRehabilitation. 2011;29:9–21. doi: 10.3233/NRE-2011-0672. PubMed DOI PMC

Lazzaro I., Tran Y., Wijesuriya N., Craig A. Central Correlates of Impaired Information Processing in People with Spinal Cord Injury. J. Clin. Neurophysiol. 2013;30:59–65. doi: 10.1097/WNP.0b013e31827edb0c. PubMed DOI

Rao P.N., Mainkar O., Bansal N., Rakesh N., Haffey P., Urits I., Orhurhu V., Kaye A.D., Urman R.D., Gulati A., et al. Flavonoids in the Treatment of Neuropathic Pain. Curr. Pain Headache Rep. 2021;25:43. doi: 10.1007/s11916-021-00959-y. PubMed DOI

Pirvulescu I., Biskis A., Candido K.D., Knezevic N.N. Overcoming Clinical Challenges of Refractory Neuropathic Pain. Expert Rev. Neurother. 2022;22:595–622. doi: 10.1080/14737175.2022.2105206. PubMed DOI

Ruan J.Q., Nie L.Y., Qian L.N., Zhao K. Efficacy and Safety of Polyphenols for Osteoarthritis Treatment: A Meta-Analysis. Clin. Ther. 2021;43:e241–e253.e2. doi: 10.1016/J.CLINTHERA.2021.06.005. PubMed DOI

Coletro H.N., Diniz A.P., Guimarães N.S., Carraro J.C.C., Mendonça R.d.D., Meireles A.L. Polyphenols for Improvement of Inflammation and Symptoms in Rheumatic Diseases: Systematic Review. Sao Paulo Med. J. 2021;139:615–623. doi: 10.1590/1516-3180.2020.0766.r1.22042021. PubMed DOI PMC

Budh C.N., Lund I., Ertzgaard P., Holtz A., Hultling C., Levi R., Werhagen L., Lundeberg T. Pain in a Swedish Spinal Cord Injury Population. Clin. Rehabil. 2003;17:685–690. doi: 10.1191/0269215503cr664oa. PubMed DOI

Cardenas D.D., Bryce T.N., Shem K., Richards J.S., Elhefni H. Gender and Minority Differences in the Pain Experience of People with Spinal Cord Injury. Arch. Phys. Med. Rehabil. 2004;85:1774–1781. doi: 10.1016/j.apmr.2004.04.027. PubMed DOI

Kramer J.L.K., Minhas N.K., Jutzeler C.R., Erskine E.L.K.S., Liu L.J.W., Ramer M.S. Neuropathic Pain Following Traumatic Spinal Cord Injury: Models, Measurement, and Mechanisms. J. Neurosci. Res. 2017;95:1295–1306. doi: 10.1002/jnr.23881. PubMed DOI

Miller L.R., Cano A. Comorbid Chronic Pain and Depression: Who Is at Risk? J. Pain. 2009;10:619–627. doi: 10.1016/j.jpain.2008.12.007. PubMed DOI

Goesling J., Clauw D.J., Hassett A.L. Pain and Depression: An Integrative Review of Neurobiological and Psychological Factors. Curr. Psychiatry Rep. 2013;15:421. doi: 10.1007/s11920-013-0421-0. PubMed DOI

Mogil J.S., Wilson S.G., Bon K., Lee S.E., Chung K., Raber P., Pieper J.O., Hain H.S., Belknap J.K., Hubert L., et al. Heritability of Nociception I: Responses of 11 Inbred Mouse Strains on 12 Measures of Nociception. Pain. 1999;80:67–82. doi: 10.1016/s0304-3959(98)00197-3. PubMed DOI

Leo S., Straetemans R., D’Hooge R., Meert T. Differences in Nociceptive Behavioral Performance between C57BL/6J, 129S6/SvEv, B6 129 F1 and NMRI Mice. Behav. Brain Res. 2008;190:233–242. doi: 10.1016/j.bbr.2008.03.001. PubMed DOI

Bailey K.R., Crawley J.N. Chapter 5—Anxiety-Related Behaviors in Mice. In: Buccafusco J.J., editor. Methods of Behavior Analysis in Neuroscience. 2nd ed. CRC Press/Taylor & Francis; Boca Raton, FL, USA: 2009. pp. 77–101.

Castany S., Gris G., Vela J.M., Verdú E., Boadas-Vaello P. Critical Role of Sigma-1 Receptors in Central Neuropathic Pain-Related Behaviours after Mild Spinal Cord Injury in Mice. Sci. Rep. 2018;8:3873. doi: 10.1038/s41598-018-22217-9. PubMed DOI PMC

Castany S., Codony X., Zamanillo D., Merlos M., Verdú E., Boadas-Vaello P. Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development after Spinal Cord Injury in Mice. Front. Pharmacol. 2019;10:433451. doi: 10.3389/fphar.2019.00222. PubMed DOI PMC

Sandkühler J. Models and Mechanisms of Hyperalgesia and Allodynia. Physiol. Rev. 2009;89:707–758. doi: 10.1152/physrev.00025.2008. PubMed DOI

King T., Porreca F. Preclinical Assessment of Pain: Improving Models in Discovery Research. Curr. Top. Behav. Neurosci. 2014;20:101–120. doi: 10.1007/7854_2014_330. PubMed DOI

Williams R., Murray A. Prevalence of Depression After Spinal Cord Injury: A Meta-Analysis. Arch. Phys. Med. Rehabil. 2015;96:133–140. doi: 10.1016/j.apmr.2014.08.016. PubMed DOI

Le J., Dorstyn D. Anxiety Prevalence Following Spinal Cord Injury: A Meta-Analysis. Spinal Cord. 2016;54:570–578. doi: 10.1038/SC.2016.15. PubMed DOI

WHO . Depression and Other Common Mental Disorders: Global Health Estimates. WHO; Geneva, Switzerland: 2017.

do Espírito Santo C.C., da Silva Fiorin F., Ilha J., Duarte M.M.M.F., Duarte T., Santos A.R.S. Spinal Cord Injury by Clip-Compression Induces Anxiety and Depression-like Behaviours in Female Rats: The Role of the Inflammatory Response. Brain Behav. Immun. 2019;78:91–104. doi: 10.1016/j.bbi.2019.01.012. PubMed DOI

Krause J.S., Kemp B., Coker J. Depression after Spinal Cord Injury: Relation to Gender, Ethnicity, Aging, and Socioeconomic Indicators. Arch. Phys. Med. Rehabil. 2000;81:1099–1109. doi: 10.1053/apmr.2000.7167. PubMed DOI

Saurí J., Chamarro A., Gilabert A., Gifre M., Rodriguez N., Lopez-Blazquez R., Curcoll L., Benito-Penalva J., Soler D. Depression in Individuals with Traumatic and Nontraumatic Spinal Cord Injury Living in the Community. Arch. Phys. Med. Rehabil. 2017;98:1165–1173. doi: 10.1016/j.apmr.2016.11.011. PubMed DOI

Hayes K.C., Hull T.C.L., Delaney G.A., Potter P.J., Sequeira K.A.J., Campbell K., Popovich P.G. Elevated Serum Titers of Proinflammatory Cytokines and CNS Autoantibodies in Patients with Chronic Spinal Cord Injury. J. Neurotrauma. 2004;19:753–761. doi: 10.1089/08977150260139129. PubMed DOI

Davies A.L., Hayes K.C., Dekaban G.A. Clinical Correlates of Elevated Serum Concentrations of Cytokines and Autoantibodies in Patients with Spinal Cord Injury. Arch. Phys. Med. Rehabil. 2007;88:1384–1393. doi: 10.1016/j.apmr.2007.08.004. PubMed DOI

Schwab J.M., Zhang Y., Kopp M.A., Brommer B., Popovich P.G. The Paradox of Chronic Neuroinflammation, Systemic Immune Suppression and Autoimmunity after Traumatic Chronic Spinal Cord Injury. Exp. Neurol. 2014;258:121–129. doi: 10.1016/j.expneurol.2014.04.023. PubMed DOI PMC

Miller A.H., Raison C.L. The Role of Inflammation in Depression: From Evolutionary Imperative to Modern Treatment Target. Nat. Rev. Immunol. 2015;16:22–34. doi: 10.1038/nri.2015.5. PubMed DOI PMC

Allison D.J., Ditor D.S. Targeting Inflammation to Influence Mood Following Spinal Cord Injury: A Randomized Clinical Trial. J. Neuroinflamm. 2015;12:204. doi: 10.1186/s12974-015-0425-2. PubMed DOI PMC

Maldonado-Bouchard S., Peters K., Woller S.A., Madahian B., Faghihi U., Patel S., Bake S., Hook M.A. Inflammation Is Increased with Anxiety- and Depression-like Signs in a Rat Model of Spinal Cord Injury. Brain Behav. Immun. 2016;51:176–195. doi: 10.1016/J.BBI.2015.08.009. PubMed DOI PMC

Austin P.J., Fiore N.T. Supraspinal Neuroimmune Crosstalk in Chronic Pain States. Curr. Opin. Physiol. 2019;11:7–15. doi: 10.1016/J.COPHYS.2019.03.008. DOI

Mor D., Bembrick A.L., Austin P.J., Keay K.A. Evidence for Cellular Injury in the Midbrain of Rats Following Chronic Constriction Injury of the Sciatic Nerve. J. Chem. Neuroanat. 2011;41:158–169. doi: 10.1016/j.jchemneu.2011.01.004. PubMed DOI

Butler R.K., Nilsson-Todd L., Cleren C., Léna I., Garcia R., Finn D.P. Molecular and Electrophysiological Changes in the Prefrontal Cortex–Amygdala–Dorsal Periaqueductal Grey Pathway during Persistent Pain State and Fear-Conditioned Analgesia. Physiol. Behav. 2011;104:1075–1081. doi: 10.1016/j.physbeh.2011.05.028. PubMed DOI

Roberts J., Ossipov M.H., Porreca F. Glial Activation in the Rostroventromedial Medulla Promotes Descending Facilitation to Mediate Inflammatory Hypersensitivity. Eur. J. Neurosci. 2009;30:229–241. doi: 10.1111/j.1460-9568.2009.06813.x. PubMed DOI PMC

Wei F., Guo W., Zou S., Ren K., Dubner R. Supraspinal Glial–Neuronal Interactions Contribute to Descending Pain Facilitation. J. Neurosci. 2008;28:10482–10495. doi: 10.1523/JNEUROSCI.3593-08.2008. PubMed DOI PMC

Liu X., Bu H., Liu C., Gao F., Yang H., Tian X., Xu A., Chen Z., Cao F., Tian Y. Inhibition of Glial Activation in Rostral Ventromedial Medulla Attenuates Mechanical Allodynia in a Rat Model of Cancer-Induced Bone Pain. J. Huazhong Univ. Sci. Technol.—Med. Sci. 2012;32:291–298. doi: 10.1007/s11596-012-0051-5. PubMed DOI

White F.A., Jung H., Miller R.J. Chemokines and the Pathophysiology of Neuropathic Pain. Proc. Natl. Acad. Sci. USA. 2007;104:20151–20158. doi: 10.1073/pnas.0709250104. PubMed DOI PMC

Hulsebosch C.E., Hains B.C., Crown E.D., Carlton S.M. Mechanisms of Chronic Central Neuropathic Pain after Spinal Cord Injury. Brain Res. Rev. 2009;60:202–213. doi: 10.1016/j.brainresrev.2008.12.010. PubMed DOI PMC

Gao Y.J., Ji R.R. Chemokines, Neuronal–Glial Interactions, and Central Processing of Neuropathic Pain. Pharmacol. Ther. 2010;126:56–68. doi: 10.1016/j.pharmthera.2010.01.002. PubMed DOI PMC

Liou J.T., Lee C.M., Day Y.J. The Immune Aspect in Neuropathic Pain: Role of Chemokines. Acta Anaesthesiol. Taiwanica. 2013;51:127–132. doi: 10.1016/j.aat.2013.08.006. PubMed DOI

Knerlich-Lukoschus F., Noack M., Von Der Ropp-Brenner B., Lucius R., Mehdorn H.M., Held-Feindt J. Spinal Cord Injuries Induce Changes in CB1 Cannabinoid Receptor and C-C Chemokine Expression in Brain Areas Underlying Circuitry of Chronic Pain Conditions. J. Neurotrauma. 2011;28:619–634. doi: 10.1089/NEU.2010.1652. PubMed DOI

Guo W., Wang H., Zou S., Dubner R., Ren K. Chemokine Signaling Involving Chemokine (C-C Motif) Ligand 2 Plays Arole in Descending Pain Facilitation. Neurosci. Bull. 2012;28:193–207. doi: 10.1007/s12264-012-1218-6. PubMed DOI PMC

Chen X., Geller E.B., Rogers T.J., Adler M.W. The Chemokine CX3CL1/Fractalkine Interferes with the Antinociceptive Effect Induced by Opioid Agonists in the Periaqueductal Grey of Rats. Brain Res. 2007;1153:52–57. doi: 10.1016/J.BRAINRES.2007.03.066. PubMed DOI PMC

Bornhövd K., Quante M., Glauche V., Bromm B., Weiller C., Büchel C. Painful Stimuli Evoke Different Stimulus–Response Functions in the Amygdala, Prefrontal, Insula and Somatosensory Cortex: A Single-trial FMRI Study. Brain. 2002;125:1326–1336. doi: 10.1093/brain/awf137. PubMed DOI

Paulson P.E., Casey K.L., Morrow T.J. Long-Term Changes in Behavior and Regional Cerebral Blood Flow Associated with Painful Peripheral Mononeuropathy in the Rat. Pain. 2002;95:31–40. doi: 10.1016/S0304-3959(01)00370-0. PubMed DOI PMC

Neugebauer V., Li W., Bird G.C., Han J.S. The Amygdala and Persistent Pain. Neuroscientist. 2004;10:221–234. doi: 10.1177/1073858403261077. PubMed DOI

Neugebauer V. CHAPTER 15. Amygdala Pain Mechanisms. Handb. Exp. Pharmacol. 2015;227:261–284. PubMed PMC

Gonçalves L., Silva R., Pinto-Ribeiro F., Pêgo J.M., Bessa J.M., Pertovaara A., Sousa N., Almeida A. Neuropathic Pain Is Associated with Depressive Behaviour and Induces Neuroplasticity in the Amygdala of the Rat. Exp. Neurol. 2008;213:48–56. doi: 10.1016/J.EXPNEUROL.2008.04.043. PubMed DOI

Etkin A., Egner T., Kalisch R. Emotional Processing in Anterior Cingulate and Medial Prefrontal Cortex. Trends Cogn. Sci. 2011;15:85–93. doi: 10.1016/j.tics.2010.11.004. PubMed DOI PMC

Barthas F., Sellmeijer J., Hugel S., Waltisperger E., Barrot M., Yalcin I. The Anterior Cingulate Cortex Is a Critical Hub for Pain-Induced Depression. Biol. Psychiatry. 2015;77:236–245. doi: 10.1016/j.biopsych.2014.08.004. PubMed DOI

Berendse H.W., Groenewegen H.J. Restricted Cortical Termination Fields of the Midline and Intralaminar Thalamic Nuclei in the Rat. Neuroscience. 1991;42:73–102. doi: 10.1016/0306-4522(91)90151-D. PubMed DOI

Hsu M.M., Shyu B.C. Electrophysiological Study of the Connection between Medial Thalamus and Anterior Cingulate Cortex in the Rat. Neuroreport. 1997;8:2701–2707. doi: 10.1097/00001756-199708180-00013. PubMed DOI

Mcdonald A.J., Mascagni F., Guo L. Projections of the Medial and Lateral Prefrontal Cortices to the Amygdala: A Phaseolus Vulgaris Leucoagglutinin Study in the Rat. Neuroscience. 1996;71:55–75. doi: 10.1016/0306-4522(95)00417-3. PubMed DOI

Marcello L., Cavaliere C., Colangelo A.M., Bianco M.R., Cirillo G., Alberghina L., Papa M. Remodelling of Supraspinal Neuroglial Network in Neuropathic Pain Is Featured by a Reactive Gliosis of the Nociceptive Amygdala. Eur. J. Pain. 2013;17:799–810. doi: 10.1002/j.1532-2149.2012.00255.x. PubMed DOI

Sawada A., Niiyama Y., Ataka K., Nagaishi K., Yamakage M., Fujimiya M. Suppression of Bone Marrow-Derived Microglia in the Amygdale Improves Anxiety-like Behavior Induced by Chronic Partial Sciatic Nerve Ligation in Mice. Pain. 2014;155:1762–1772. doi: 10.1016/j.pain.2014.05.031. PubMed DOI

Cho I., Kim J.M., Kim E.J., Kim S.Y., Kam E.H., Cheong E., Suh M., Koo B.N. Orthopedic Surgery-Induced Cognitive Dysfunction Is Mediated by CX3CL1/R1 Signaling. J. Neuroinflamm. 2021;18:93. doi: 10.1186/s12974-021-02150-x. PubMed DOI PMC

Cao H., Gao Y.J., Ren W.H., Li T.T., Duan K.Z., Cui Y.H., Cao X.H., Zhao Z.Q., Ji R.R., Zhang Y.Q. Activation of Extracellular Signal-Regulated Kinase in the Anterior Cingulate Cortex Contributes to the Induction and Expression of Affective Pain. J. Neurosci. 2009;29:3307–3321. doi: 10.1523/JNEUROSCI.4300-08.2009. PubMed DOI PMC

Zhong X.L., Wei R., Zhou P., Luo Y.W., Wang X.Q., Duan J., Bi F.F., Zhang J.Y., Li C.Q., Dai R.P., et al. Activation of Anterior Cingulate Cortex Extracellular Signal-Regulated Kinase-1 and -2 (ERK1/2) Regulates Acetic Acid-Induced, Pain-Related Anxiety in Adult Female Mice. Acta Histochem. Cytochem. 2012;45:219–225. doi: 10.1267/ahc.12002. PubMed DOI PMC

Luo C., Zhang Y.L., Luo W., Zhou F.H., Li C.Q., Xu J.M., Dai R.P. Differential Effects of General Anesthetics on Anxiety-like Behavior in Formalin-Induced Pain: Involvement of ERK Activation in the Anterior Cingulate Cortex. Psychopharmacology. 2015;232:4433–4444. doi: 10.1007/s00213-015-4071-2. PubMed DOI

Semenova S., Contet C., Roberts A.J., Markou A. Mice Lacking the Β4 Subunit of the Nicotinic Acetylcholine Receptor Show Memory Deficits, Altered Anxiety- and Depression-like Behavior, and Diminished Nicotine-Induced Analgesia. Nicotine Tob. Res. 2012;14:1346–1355. doi: 10.1093/ntr/nts107. PubMed DOI PMC

Chen G., Zhang Y.Q., Qadri Y.J., Serhan C.N., Ji R.R. Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain. Neuron. 2018;100:1292–1311. doi: 10.1016/j.neuron.2018.11.009. PubMed DOI PMC

Ji R.R., Nackley A., Huh Y., Terrando N., Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology. 2018;129:343–366. doi: 10.1097/ALN.0000000000002130. PubMed DOI PMC

Montero-Atalaya M., Expósito S., Muñoz-Arnaiz R., Makarova J., Bartolom B., Martín E., Moreno-Arribas M.V., Herreras O. A Dietary Polyphenol Metabolite Alters CA1 Excitability Ex Vivo and Mildly Affects Cortico-Hippocampal Field Potential Generators in Anesthetized Animals. Cereb. Cortex. 2023;33:10411–10425. doi: 10.1093/cercor/bhad292. PubMed DOI PMC

Sandoval-Avila S., Diaz N.F., Gómez-Pinedo U., Canales-Aguirre A.A., Gutiérrez-Mercado Y.K., Padilla-Camberos E., Marquez-Aguirre A.L., Díaz-Martínez N.E. Neuroprotective Effects of Phytochemicals on Dopaminergic Neuron Cultures. Neurologia. 2019;34:114–124. doi: 10.1016/J.NRL.2016.04.018. PubMed DOI

Parepally J.M.R., Mandula H., Smith Q.R. Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin. Pharm. Res. 2006;23:873–881. PubMed

Bjarnason I. Gastrointestinal Safety of NSAIDs and Over-the-Counter Analgesics. Int. J. Clin. Pract. 2013;67:37–42. doi: 10.1111/IJCP.12048. PubMed DOI

Rice J.B., White A.G., Scarpati L.M., Wan G., Nelson W.W. Long-Term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin. Ther. 2017;39:2216–2229. doi: 10.1016/J.CLINTHERA.2017.09.011. PubMed DOI

Zimmermann M. Ethical Guidelines for Investigations of Experimental Pain in Conscious Animals. Pain. 1983;16:109–110. doi: 10.1016/0304-3959(83)90201-4. PubMed DOI

Basso D.M., Fisher L.C., Anderson A.J., Jakeman L.B., McTigue D.M., Popovich P.G. Basso Mouse Scale for Locomotion Detects Differences in Recovery after Spinal Cord Injury in Five Common Mouse Strains. J. Neurotrauma. 2006;23:635–659. doi: 10.1089/NEU.2006.23.635. PubMed DOI

Dixon W.J. Efficient Analysis of Experimental Observations. Annu. Rev. Pharmacol. Toxicol. 1980;20:441–462. doi: 10.1146/ANNUREV.PA.20.040180.002301. PubMed DOI

Hargreaves K., Dubner R., Brown F., Flores C., Joris J. A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia. Pain. 1988;32:77–88. doi: 10.1016/0304-3959(88)90026-7. PubMed DOI

Jakobsson J., Cordero M.I., Bisaz R., Groner A.C., Busskamp V., Bensadoun J.C., Cammas F., Losson R., Mansuy I.M., Sandi C., et al. KAP1-Mediated Epigenetic Repression in the Forebrain Modulates Behavioral Vulnerability to Stress. Neuron. 2008;60:818–831. doi: 10.1016/j.neuron.2008.09.036. PubMed DOI

Crawley J., Goodwin F.K. Preliminary Report of a Simple Animal Behavior Model for the Anxiolytic Effects of Benzodiazepines. Pharmacol. Biochem. Behav. 1980;13:167–170. doi: 10.1016/0091-3057(80)90067-2. PubMed DOI

Bourin M., Hascoët M. The Mouse Light/Dark Box Test. Eur. J. Pharmacol. 2003;463:55–65. doi: 10.1016/S0014-2999(03)01274-3. PubMed DOI

Porsolt R.D., Anton G., Blavet N., Jalfre M. Behavioural Despair in Rats: A New Model Sensitive to Antidepressant Treatments. Eur. J. Pharmacol. 1978;47:379–391. doi: 10.1016/0014-2999(78)90118-8. PubMed DOI

Crawley J.N. Behavioral Phenotyping of Rodents—PubMed. Comp. Med. 2003;53:140–146. PubMed

Paxinos G., Watson C. The Rat Brain in Stereotaxic Coordinates. 3rd ed. Academic Press; San Diego, CA, USA: 1997.

Keay K.A., Clement C.I., Depaulis A., Bandler R. Different Representations of Inescapable Noxious Stimuli in the Periaqueductal Gray and Upper Cervical Spinal Cord of Freely Moving Rats. Neurosci. Lett. 2001;313:17–20. doi: 10.1016/S0304-3940(01)02226-1. PubMed DOI

Paxinos G., Franklin K.B.J. Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates. 4th ed. Academic Press; Cambridge, MA, USA: 2013.