{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T06:25:27Z","timestamp":1772519127146,"version":"3.50.1"},"reference-count":148,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["Project 2022.05193.PTDC \u2013 https:\/\/doi:10.54499\/2022.05193"],"award-info":[{"award-number":["Project 2022.05193.PTDC \u2013 https:\/\/doi:10.54499\/2022.05193"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["Project PTDC\/MED-NEU\/28181\/2017"],"award-info":[{"award-number":["Project PTDC\/MED-NEU\/28181\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["Project PTDC\/MED-NEU\/28498\/2017"],"award-info":[{"award-number":["Project PTDC\/MED-NEU\/28498\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["Individual Employment Contract 2022.00128.CEECind - doi: http:\/\/10.54499\/2022.00128.CEECIND\/CP1735\/CT0019"],"award-info":[{"award-number":["Individual Employment Contract 2022.00128.CEECind - doi: http:\/\/10.54499\/2022.00128.CEECIND\/CP1735\/CT0019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["DL 57\/2016\/CP1355\/CT0015 - doi: http:\/\/10.54499\/DL57\/2016\/CP1355\/CT0015"],"award-info":[{"award-number":["DL 57\/2016\/CP1355\/CT0015 - doi: http:\/\/10.54499\/DL57\/2016\/CP1355\/CT0015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["PhD grant PRT\/BD\/154966\/2023 \u2013 doi: https:\/\/doi.org\/10.54499\/PRT\/BD\/154992\/2023"],"award-info":[{"award-number":["PhD grant PRT\/BD\/154966\/2023 \u2013 doi: https:\/\/doi.org\/10.54499\/PRT\/BD\/154992\/2023"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Chronic pain has been increasingly recognized not only as a sensory disorder but also as a condition that profoundly disrupts affective and motivational processes. Preclinical research indicates that persistent nociceptive input drives maladaptive changes in brain reward circuits, particularly within the mesocorticolimbic dopamine system. These alterations contribute to anhedonia, diminished motivation, and aberrant reward valuation, core symptoms frequently observed in patients with chronic pain. In this review, we synthesize evidence from rodent models demonstrating how chronic pain impairs the hedonic experience and motivational aspects of reward through disrupted dopaminergic signaling, neuroinflammatory pathways, and opioid system dysregulation. We also highlight the temporal dynamics in the emergence of hedonic deficits, the sex-dependent mechanisms, and the interplay between pain and drug-seeking behaviors. Finally, we discuss how these findings inform the search for and predict early biomarkers and therapeutic targets aimed at restoring hedonic tone. A deeper understanding of the neurobiological basis of reward dysfunction in chronic pain may provide critical insights for developing more effective, mechanism-based interventions.<\/jats:p>","DOI":"10.3390\/brainsci15121265","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:29:47Z","timestamp":1764084587000},"page":"1265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dysregulation of Hedonic Processing in Chronic Pain: Insights from Preclinical Data"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3872-1589","authenticated-orcid":false,"given":"Mariana","family":"Cerqueira-Nunes","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Faculdade de Medicina, Departamento de Biomedicina\u2014Unidade de Biologia Experimental, Universidade do Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Programa Doutoral em Neuroci\u00eancias, Faculdade de Medicina, Universidade do Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4279-4067","authenticated-orcid":false,"given":"Clara","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Faculdade de Medicina, Departamento de Biomedicina\u2014Unidade de Biologia Experimental, Universidade do Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8739-9995","authenticated-orcid":false,"given":"Vasco","family":"Galhardo","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Faculdade de Medicina, Departamento de Biomedicina\u2014Unidade de Biologia Experimental, Universidade do Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5191-3828","authenticated-orcid":false,"given":"Helder","family":"Cardoso-Cruz","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Faculdade de Medicina, Departamento de Biomedicina\u2014Unidade de Biologia Experimental, Universidade do Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0304-3959(99)00145-1","article-title":"From the gate to the neuromatrix","volume":"82","author":"Melzack","year":"1999","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.pain.2003.12.015","article-title":"Chronic pain patients are impaired on an emotional decision-making task","volume":"108","author":"Apkarian","year":"2004","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/WCO.0b013e32836336ad","article-title":"Predicting transition to chronic pain","volume":"26","author":"Apkarian","year":"2013","journal-title":"Curr. Opin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8123","DOI":"10.1007\/s12035-024-04073-z","article-title":"Chronic Pain-Related Cognitive Deficits: Preclinical Insights into Molecular, Cellular, and Circuit Mechanisms","volume":"61","author":"Han","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1093\/brain\/awt211","article-title":"Shape shifting pain: Chronification of back pain shifts brain representation from nociceptive to emotional circuits","volume":"136","author":"Hashmi","year":"2013","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nrn.2016.162","article-title":"Structural plasticity and reorganisation in chronic pain","volume":"18","author":"Kuner","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1097\/j.pain.0000000000003056","article-title":"Co-occurrence of chronic pain and anxiety\/depression symptoms in U.S. adults: Prevalence, functional impacts, and opportunities","volume":"165","author":"Brady","year":"2024","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.3390\/neurolint15040082","article-title":"Dynamics of Lateral Habenula-Ventral Tegmental Area Microcircuit on Pain-Related Cognitive Dysfunctions","volume":"15","author":"Pereira","year":"2023","journal-title":"Neurol. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1001\/archinte.163.20.2433","article-title":"Depression and pain comorbidity: A literature review","volume":"163","author":"Bair","year":"2003","journal-title":"Arch. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.pain.2004.06.016","article-title":"Suicidal ideation, plans, and attempts in chronic pain patients: Factors associated with increased risk","volume":"111","author":"Smith","year":"2004","journal-title":"Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1176\/appi.neuropsych.17120351","article-title":"Resting-State Functional Connectivity of the Habenula in Mood Disorder Patients With and Without Suicide-Related Behaviors","volume":"31","author":"Ambrosi","year":"2019","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1093\/ijnp\/pyx056","article-title":"Dopamine System Dysregulation in Major Depressive Disorders","volume":"20","author":"Belujon","year":"2017","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1021\/acsptsci.2c00005","article-title":"Comprehensive Preclinical Assessment of Sensory, Functional, Motivational-Affective, and Neurochemical Outcomes in Neuropathic Pain: The Case of the Sigma-1 Receptor","volume":"5","author":"Zamanillo","year":"2022","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20709","DOI":"10.1073\/pnas.1214605109","article-title":"Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry","volume":"109","author":"Navratilova","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/nn.3153","article-title":"Corticostriatal functional connectivity predicts transition to chronic back pain","volume":"15","author":"Baliki","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16383","DOI":"10.1523\/JNEUROSCI.1731-13.2013","article-title":"Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain","volume":"33","author":"Baliki","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1002\/ejp.1982","article-title":"Altered prefrontal-striatal theta-band oscillatory dynamics underlie working memory deficits in neuropathic pain rats","volume":"26","author":"Laranjeira","year":"2022","journal-title":"Eur. J. Pain"},{"key":"ref_18","first-page":"1532","article-title":"Reorganization of lateral habenula neuronal connectivity underlies pain-related impairment in spatial memory encoding","volume":"166","author":"Monteiro","year":"2024","journal-title":"Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138183","DOI":"10.1016\/j.neulet.2025.138183","article-title":"Inflammatory pain modifies reward preferences from larger delayed to smaller immediate rewards in male rats","volume":"852","author":"Monteiro","year":"2025","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149044","DOI":"10.1016\/j.brainres.2024.149044","article-title":"Orbitostriatal encoding of reward delayed gratification and impulsivity in chronic pain","volume":"1839","author":"Monteiro","year":"2024","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00213-008-1099-6","article-title":"Affective neuroscience of pleasure: Reward in humans and animals","volume":"199","author":"Berridge","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1037\/amp0000059","article-title":"Liking, wanting, and the incentive-sensitization theory of addiction","volume":"71","author":"Berridge","year":"2016","journal-title":"Am. Psychol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cerqueira-Nunes, M., Monteiro, C., Galhardo, V., and Cardoso-Cruz, H. (2024). Deciphering the role of the nucleus accumbens shell area on spatial memory deficits induced by neuropathic pain in rats. Appl. Biosci., 3.","DOI":"10.3390\/applbiosci3020019"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.euroneuro.2023.08.496","article-title":"Sucrose preference test: A systematic review of protocols for the assessment of anhedonia in rodents","volume":"77","author":"Primo","year":"2023","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8187","DOI":"10.1007\/s12035-025-04781-0","article-title":"Neuromodulation of Dopamine D2 Receptors Alters Orbitofrontal Neuronal Activity and Reduces Risk-Prone Behavior in Male Rats with Inflammatory Pain","volume":"62","author":"Dourado","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5861","DOI":"10.1523\/JNEUROSCI.0021-14.2014","article-title":"Activation of dopaminergic D2\/D3 receptors modulates dorsoventral connectivity in the hippocampus and reverses the impairment of working memory after nerve injury","volume":"34","author":"Dourado","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/nrn3360","article-title":"Sex differences in pain and pain inhibition: Multiple explanations of a controversial phenomenon","volume":"13","author":"Mogil","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Massaly, N., Moron, J.A., and Al-Hasani, R. (2016). A Trigger for Opioid Misuse: Chronic Pain and Stress Dysregulate the Mesolimbic Pathway and Kappa Opioid System. Front. Neurosci., 10.","DOI":"10.3389\/fnins.2016.00480"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.neuron.2015.08.019","article-title":"Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward","volume":"87","author":"McCall","year":"2015","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5124","DOI":"10.1038\/s41467-023-40860-3","article-title":"A glutamatergic DRN-VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice","volume":"14","author":"Wang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1177\/0333102419839957","article-title":"Ventral tegmental area deep brain stimulation for chronic cluster headache: Effects on cognition, mood, pain report behaviour and quality of life","volume":"39","author":"Cappon","year":"2019","journal-title":"Cephalalgia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1038\/s41593-021-00924-3","article-title":"Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior","volume":"24","author":"Markovic","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1523\/JNEUROSCI.4205-06.2007","article-title":"Opioid limbic circuit for reward: Interaction between hedonic hotspots of nucleus accumbens and ventral pallidum","volume":"27","author":"Smith","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1046\/j.1360-0443.2001.9611038.x","article-title":"Incentive-sensitization and addiction","volume":"96","author":"Robinson","year":"2001","journal-title":"Addiction"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nrn1747","article-title":"The human orbitofrontal cortex: Linking reward to hedonic experience","volume":"6","author":"Kringelbach","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10529","DOI":"10.1523\/JNEUROSCI.1678-17.2017","article-title":"Functional Heterogeneity within Rat Orbitofrontal Cortex in Reward Learning and Decision Making","volume":"37","author":"Izquierdo","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8159","DOI":"10.1523\/JNEUROSCI.0118-13.2013","article-title":"Effects of prefrontal cortical inactivation on neural activity in the ventral tegmental area","volume":"33","author":"Jo","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1016\/j.celrep.2017.04.073","article-title":"Cortico-Accumbens Regulation of Approach-Avoidance Behavior Is Modified by Experience and Chronic Pain","volume":"19","author":"Schwartz","year":"2017","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/npp.2016.235","article-title":"Chemogenetic Activation of Midbrain Dopamine Neurons Affects Attention, but not Impulsivity, in the Five-Choice Serial Reaction Time Task in Rats","volume":"42","author":"Boekhoudt","year":"2017","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/npp.2011.176","article-title":"Estradiol modulates effort-based decision making in female rats","volume":"37","author":"Uban","year":"2012","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.yhbeh.2015.06.010","article-title":"Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females","volume":"74","author":"Almey","year":"2015","journal-title":"Horm. Behav."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Bendis, P.C., Zimmerman, S., Onisiforou, A., Zanos, P., and Georgiou, P. (2024). The impact of estradiol on serotonin, glutamate, and dopamine systems. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1348551"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5373","DOI":"10.1210\/en.2012-1458","article-title":"Estrogen receptors are found in glia and at extranuclear neuronal sites in the dorsal striatum of female rats: Evidence for cholinergic but not dopaminergic colocalization","volume":"153","author":"Almey","year":"2012","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S1364-6613(00)01483-2","article-title":"Cognitive and emotional influences in anterior cingulate cortex","volume":"4","author":"Bush","year":"2000","journal-title":"Trends Cogn. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1002\/cne.23368","article-title":"Anterior insular cortex and emotional awareness","volume":"521","author":"Gu","year":"2013","journal-title":"J. Comp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nrn2555","article-title":"How do you feel--now? The anterior insula and human awareness","volume":"10","author":"Craig","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nature14188","article-title":"From circuits to behaviour in the amygdala","volume":"517","author":"Janak","year":"2015","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Yang, S., Boudier-Rev\u00e9ret, M., Choo, Y.J., and Chang, M.C. (2020). Association between chronic pain and alterations in the mesolimbic dopaminergic system. Brain Sci., 10.","DOI":"10.3390\/brainsci10100701"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1097\/j.pain.0000000000000611","article-title":"Increased fronto-hippocampal connectivity in the Prrxl1 knockout mouse model of congenital hypoalgesia","volume":"157","author":"Monteiro","year":"2016","journal-title":"Pain"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Marciano, G., Siniscalchi, A., Di Gennaro, G., Rania, V., Vocca, C., Palleria, C., Catarisano, L., Muraca, L., Citraro, R., and Evangelista, M. (2024). Assessing Gender Differences in Neuropathic Pain Management: Findings from a Real-Life Clinical Cross-Sectional Observational Study. J. Clin. Med., 13.","DOI":"10.3390\/jcm13195682"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.neuron.2015.02.018","article-title":"Pleasure systems in the brain","volume":"86","author":"Berridge","year":"2015","journal-title":"Neuron"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"E1314","DOI":"10.1152\/ajpendo.00137.2013","article-title":"Nucleus accumbens GLP-1 receptors influence meal size and palatability","volume":"304","author":"Dossat","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"R244","DOI":"10.1152\/ajpregu.00406.2010","article-title":"mu-Opioid receptor stimulation in the nucleus accumbens elevates fatty tastant intake by increasing palatability and suppressing satiety signals","volume":"301","author":"Katsuura","year":"2011","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1523\/JNEUROSCI.4458-13.2014","article-title":"Opioid hedonic hotspot in nucleus accumbens shell: Mu, delta, and kappa maps for enhancement of sweetness \u201cliking\u201d and \u201cwanting\u201d","volume":"34","author":"Castro","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1038\/sj.npp.1301376","article-title":"Endocannabinoid hedonic hotspot for sensory pleasure: Anandamide in nucleus accumbens shell enhances \u2018liking\u2019 of a sweet reward","volume":"32","author":"Mahler","year":"2007","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7308","DOI":"10.1523\/JNEUROSCI.22-16-07308.2002","article-title":"Positive and negative motivation in nucleus accumbens shell: Bivalent rostrocaudal gradients for GABA-elicited eating, taste \u201cliking\u201d\/\u201ddisliking\u201d reactions, place preference\/avoidance, and fear","volume":"22","author":"Reynolds","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.neuron.2016.12.005","article-title":"Pathway- and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity","volume":"93","author":"Tejeda","year":"2017","journal-title":"Neuron"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.neuron.2017.11.012","article-title":"Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens","volume":"96","author":"Mateo","year":"2017","journal-title":"Neuron"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.neuron.2015.09.038","article-title":"Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding","volume":"88","author":"Kremer","year":"2015","journal-title":"Neuron"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.nlm.2011.05.002","article-title":"The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning","volume":"96","author":"Boschen","year":"2011","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.biopsych.2016.09.007","article-title":"Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression","volume":"81","author":"Francis","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Pekarskaya, E.A., Galiza Soares, J.A., Hough, F.G., Langreck, C.B., Tucciarone, J.M., and Javitch, J.A. (2025). Habenular mu-opioid receptor knockout and chronic systemic receptor blockade promote negative affect and heighten nociceptive sensitivity. bioRxiv.","DOI":"10.1101\/2025.08.02.668171"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e191270","DOI":"10.1172\/JCI191270","article-title":"Distinct nucleus accumbens neural pathways underlie separate behavioral features of chronic pain and comorbid depression","volume":"135","author":"Liu","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1097\/j.pain.0000000000002192","article-title":"Chronic pain susceptibility is associated with anhedonic behavior and alterations in the accumbal ubiquitin-proteasome system","volume":"162","author":"Guimaraes","year":"2021","journal-title":"Pain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1097\/j.pain.0000000000003316","article-title":"Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations","volume":"165","author":"Serafini","year":"2024","journal-title":"Pain"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Creed, M.C., Ntamati, N.R., and Tan, K.R. (2014). VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems. Front. Behav. Neurosci., 8.","DOI":"10.3389\/fnbeh.2014.00008"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1016\/j.neuron.2012.02.016","article-title":"Activation of VTA GABA neurons disrupts reward consumption","volume":"73","author":"Phillips","year":"2012","journal-title":"Neuron"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"eadt0773","DOI":"10.1126\/science.adt0773","article-title":"Hedonic eating is controlled by dopamine neurons that oppose GLP-1R satiety","volume":"387","author":"Zhu","year":"2025","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1111\/j.1460-9568.2008.06130.x","article-title":"Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release","volume":"27","author":"Lecourtier","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1111\/j.1460-9568.2009.06924.x","article-title":"Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area","volume":"30","author":"Omelchenko","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/cne.21891","article-title":"The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta","volume":"513","author":"Jhou","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Alemi, M., Pereira, A.R., Cerqueira-Nunes, M., Monteiro, C., Galhardo, V., and Cardoso-Cruz, H. (2023). Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030820"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1007\/s00221-016-4558-z","article-title":"Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat","volume":"234","author":"Li","year":"2016","journal-title":"Exp. Brain Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1152\/jn.00012.2012","article-title":"Mapping pain activation and connectivity of the human habenula","volume":"107","author":"Shelton","year":"2012","journal-title":"J. Neurophysiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1523\/JNEUROSCI.1353-16.2016","article-title":"Habenula-Induced Inhibition of Midbrain Dopamine Neurons Is Diminished by Lesions of the Rostromedial Tegmental Nucleus","volume":"37","author":"Brown","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/cne.24572","article-title":"Relative contributions and mapping of ventral tegmental area dopamine and GABA neurons by projection target in the rat","volume":"527","author":"Breton","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"E7395","DOI":"10.1073\/pnas.1705643114","article-title":"Separate mesocortical and mesolimbic pathways encode effort and reward learning signals","volume":"114","author":"Hauser","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Shen, X., Ruan, X., and Zhao, H. (2012). Stimulation of midbrain dopaminergic structures modifies firing rates of rat lateral habenula neurons. PLoS ONE, 7.","DOI":"10.1371\/annotation\/4b2ddb3d-b45e-4a31-9872-4186b9e731a3"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5876","DOI":"10.1523\/JNEUROSCI.3604-09.2010","article-title":"Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area","volume":"30","author":"Shumake","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.neulet.2017.06.028","article-title":"Brain-derived neurotrophic factor in the infralimbic cortex alleviates inflammatory pain","volume":"655","author":"Yue","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.bbi.2023.01.014","article-title":"Depletion of microglial BDNF increases susceptibility to the behavioral and synaptic effects of chronic unpredictable stress","volume":"109","author":"Woodburn","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1126\/science.1253994","article-title":"Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens","volume":"345","author":"Schwartz","year":"2014","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.bbi.2014.04.003","article-title":"Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling","volume":"41","author":"Dellarole","year":"2014","journal-title":"Brain Behav. Immun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1097\/j.pain.0000000000000695","article-title":"Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain","volume":"157","author":"Okun","year":"2016","journal-title":"Pain"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1111\/bph.12810","article-title":"Anti-nociception mediated by a kappa opioid receptor agonist is blocked by a delta receptor agonist","volume":"172","author":"Taylor","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"109764","DOI":"10.1016\/j.neuropharm.2023.109764","article-title":"Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell","volume":"242","author":"Lorente","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Abdul, M., Yan, H.Q., Zhao, W.N., Lyu, X.B., Xu, Z., Yu, X.L., Gao, Y.H., and Cao, J.L. (2022). VTA-NAc glutaminergic projection involves in the regulation of pain and pain-related anxiety. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.1083671"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"8442","DOI":"10.1523\/JNEUROSCI.4036-14.2015","article-title":"Microglia disrupt mesolimbic reward circuitry in chronic pain","volume":"35","author":"Taylor","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1124\/pr.113.008144","article-title":"Neuroinflammation and comorbidity of pain and depression","volume":"66","author":"Walker","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/npp.2016.167","article-title":"Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation","volume":"42","author":"Miller","year":"2017","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1038\/npp.2013.115","article-title":"Chronic interferon-alpha decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates","volume":"38","author":"Felger","year":"2013","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/s41583-019-0218-1","article-title":"Astrocytes in chronic pain and itch","volume":"20","author":"Ji","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e869","DOI":"10.1097\/PR9.0000000000000869","article-title":"Angiotensin receptors and neuropathic pain","volume":"6","author":"Balogh","year":"2021","journal-title":"Pain Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bbi.2017.02.013","article-title":"Dopamine modulates astroglial and microglial activity via glial renin-angiotensin system in cultures","volume":"62","author":"Guerra","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.nbd.2014.12.007","article-title":"Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake","volume":"74","author":"Moratalla","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Fornari Laurindo, L., Aparecido Dias, J., Cressoni Araujo, A., Torres Pomini, K., Machado Galhardi, C., Rucco Penteado Detregiachi, C., Santos de Argollo Haber, L., Donizeti Roque, D., Dib Bechara, M., and Vialogo Marques de Castro, M. (2024). Immunological dimensions of neuroinflammation and microglial activation: Exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1305933"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.tins.2015.08.001","article-title":"Depression as a microglial disease","volume":"38","author":"Yirmiya","year":"2015","journal-title":"Trends Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9041","DOI":"10.1523\/JNEUROSCI.1023-16.2016","article-title":"Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid beta-Protein Oligomers","volume":"36","author":"Xu","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1186\/s12974-018-1301-7","article-title":"Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury","volume":"15","author":"Gong","year":"2018","journal-title":"J. Neuroinflam."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12974-025-03355-0","article-title":"Associations between inflammation and striatal dopamine D2-receptor availability in aging","volume":"22","author":"Crine","year":"2025","journal-title":"J. Neuroinflam."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12974-024-03207-3","article-title":"Single-cell sequencing reveals glial cell involvement in development of neuropathic pain via myelin sheath lesion formation in the spinal cord","volume":"21","author":"Li","year":"2024","journal-title":"J. Neuroinflam."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Hu, S., Tang, Z., Sun, S., Liu, L., Wang, Y., Xu, L., Yuan, J., Chen, Y., Sun, M., and Zhao, L. (2025). Single-Nucleus Transcriptomics Reveals Glial Metabolic-Immune Rewiring and Intercellular Signaling Disruption in Chronic Migraine. Biomolecules, 15.","DOI":"10.3390\/biom15070942"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cobeha.2018.10.002","article-title":"Pain And Opioid Systems, Implications In The Opioid Epidemic","volume":"26","author":"Massaly","year":"2019","journal-title":"Curr. Opin. Behav. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/nn.4053","article-title":"Different immune cells mediate mechanical pain hypersensitivity in male and female mice","volume":"18","author":"Sorge","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"33268","DOI":"10.1074\/jbc.M112.368142","article-title":"Estrogen facilitates spinal cord synaptic transmission via membrane-bound estrogen receptors: Implications for pain hypersensitivity","volume":"287","author":"Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.yfrne.2013.06.001","article-title":"Estrogenic influences in pain processing","volume":"34","author":"Amandusson","year":"2013","journal-title":"Front. Neuroendocr."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.pain.2007.09.028","article-title":"Modulation of pain by estrogens","volume":"132","author":"Craft","year":"2007","journal-title":"Pain"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Chen, Q., Zhang, W., Sadana, N., and Chen, X. (2021). Estrogen receptors in pain modulation: Cellular signaling. Biol. Sex. Differ., 12.","DOI":"10.1186\/s13293-021-00364-5"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.expneurol.2011.09.038","article-title":"Toll-like receptors in chronic pain","volume":"234","author":"Nicotra","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.bbi.2015.10.006","article-title":"Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord","volume":"55","author":"Taves","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nature11436","article-title":"Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive","volume":"490","author":"Lemos","year":"2012","journal-title":"Nature"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.1097\/j.pain.0000000000001925","article-title":"A pain-induced tonic hypodopaminergic state augments phasic dopamine release in the nucleus accumbens","volume":"161","author":"Gee","year":"2020","journal-title":"Pain"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0304-3959(02)00121-5","article-title":"Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity","volume":"99","author":"Hagelberg","year":"2002","journal-title":"Pain"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Towers, E.B., Williams, I.L., Qillawala, E.I., and Lynch, W.J. (2023). Role of nucleus accumbens dopamine 2 receptors in motivating cocaine use in male and female rats prior to and following the development of an addiction-like phenotype. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1237990"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00213-008-1188-6","article-title":"Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine","volume":"199","author":"Zhang","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Vandegrift, B.J., You, C., Satta, R., Brodie, M.S., and Lasek, A.W. (2017). Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187698"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Wang, Y., Yang, Z., Shi, X., Han, H., Li, A.N., Zhang, B., Yuan, W., Sun, Y.H., Li, X.M., and Lian, H. (2025). Investigating the effect of Arvcf reveals an essential role on regulating the mesolimbic dopamine signaling-mediated nicotine reward. Commun. Biol., 8.","DOI":"10.1038\/s42003-025-07837-y"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1037\/bne0000111","article-title":"Sex differences in a rat model of risky decision making","volume":"130","author":"Orsini","year":"2016","journal-title":"Behav. Neurosci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.psyneuen.2007.02.003","article-title":"Estrogen recruits the endocannabinoid system to modulate emotionality","volume":"32","author":"Hill","year":"2007","journal-title":"Psychoneuroendocrinology"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.bbr.2003.08.019","article-title":"Contribution of sex differences in the acute stress response to sex differences in water maze performance in the rat","volume":"151","author":"Beiko","year":"2004","journal-title":"Behav. Brain Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.yhbeh.2011.08.013","article-title":"Stress responses and the mesolimbic dopamine system: Social contexts and sex differences","volume":"60","author":"Trainor","year":"2011","journal-title":"Horm. Behav."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Sheng, J.A., Bales, N.J., Myers, S.A., Bautista, A.I., Roueinfar, M., Hale, T.M., and Handa, R.J. (2021). The Hypothalamic-Pituitary-Adrenal Axis: Development, Programming Actions of Hormones, and Maternal-Fetal Interactions. Front. Behav. Neurosci., 14.","DOI":"10.3389\/fnbeh.2020.601939"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41583-020-0310-6","article-title":"Qualitative sex differences in pain processing: Emerging evidence of a biased literature","volume":"21","author":"Mogil","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Higginbotham, J.A., Markovic, T., Massaly, N., and Moron, J.A. (2022). Endogenous opioid systems alterations in pain and opioid use disorder. Front. Syst. Neurosci., 16.","DOI":"10.3389\/fnsys.2022.1014768"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1007\/s12640-020-00166-4","article-title":"Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems","volume":"37","author":"Ziolkowska","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.neuron.2019.02.029","article-title":"Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System","volume":"102","author":"Massaly","year":"2019","journal-title":"Neuron"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"12217","DOI":"10.1523\/JNEUROSCI.1053-15.2015","article-title":"Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area mu Opioid Receptors","volume":"35","author":"Hipolito","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.drugalcdep.2018.02.014","article-title":"Prescription opioid misusing chronic pain patients exhibit dysregulated context-dependent associations: Investigating associative learning in addiction with the cue-primed reactivity task","volume":"187","author":"Garland","year":"2018","journal-title":"Drug Alcohol. Depend."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Cuitavi, J., Torres-Perez, J.V., Lorente, J.D., Campos-Jurado, Y., Andres-Herrera, P., Polache, A., Agustin-Pavon, C., and Hipolito, L. (2023). Crosstalk between Mu-Opioid receptors and neuroinflammation: Consequences for drug addiction and pain. Neurosci. Biobehav. Rev., 145.","DOI":"10.1016\/j.neubiorev.2022.105011"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1002\/glia.24374","article-title":"Focal mu-opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain","volume":"71","author":"Cuitavi","year":"2023","journal-title":"Glia"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1097\/j.pain.0000000000001282","article-title":"Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat","volume":"159","author":"Thompson","year":"2018","journal-title":"Pain"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/art.38191","article-title":"Disrupted brain circuitry for pain-related reward\/punishment in fibromyalgia","volume":"66","author":"Loggia","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1097\/j.pain.0000000000001232","article-title":"Altered prefrontal correlates of monetary anticipation and outcome in chronic pain","volume":"159","author":"Martucci","year":"2018","journal-title":"Pain"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.neuron.2010.03.002","article-title":"Predicting value of pain and analgesia: Nucleus accumbens response to noxious stimuli changes in the presence of chronic pain","volume":"66","author":"Baliki","year":"2010","journal-title":"Neuron"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nn.4199","article-title":"The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain","volume":"19","author":"Ren","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1177\/1073858403261077","article-title":"The amygdala and persistent pain","volume":"10","author":"Neugebauer","year":"2004","journal-title":"Neuroscientist"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.neubiorev.2013.12.006","article-title":"Psychological processing in chronic pain: A neural systems approach","volume":"39","author":"Simons","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.bbr.2008.09.038","article-title":"Ventral pallidum roles in reward and motivation","volume":"196","author":"Smith","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.cub.2019.01.048","article-title":"Rat Orbitofrontal Ensemble Activity Contains Multiplexed but Dissociable Representations of Value and Task Structure in an Odor Sequence Task","volume":"29","author":"Zhou","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"12304","DOI":"10.1523\/JNEUROSCI.0312-14.2014","article-title":"Anxiety- and depression-like behavior and impaired neurogenesis evoked by peripheral neuropathy persist following resolution of prolonged tactile hypersensitivity","volume":"34","author":"Dimitrov","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1093\/brain\/awl109","article-title":"Differential involvement of hypothalamic vasopressin neurons in multiple system atrophy","volume":"129","author":"Benarroch","year":"2006","journal-title":"Brain"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1097\/ALN.0b013e31822f16ae","article-title":"A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats","volume":"115","author":"Wang","year":"2011","journal-title":"Anesthesiology"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.physbeh.2014.03.030","article-title":"Acid-induced hyperalgesia and anxio-depressive comorbidity in rats","volume":"131","author":"Liu","year":"2014","journal-title":"Physiol. Behav."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0006-8993(78)90568-1","article-title":"The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats","volume":"143","author":"Grill","year":"1978","journal-title":"Brain Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0006-8993(78)90569-3","article-title":"The taste reactivity test. II. Mimetic Responses Gustatory Stimuli Chronic Thalamic Chronic Decerebrate rats","volume":"143","author":"Grill","year":"1978","journal-title":"Brain Res."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1097\/j.pain.0000000000000494","article-title":"Mesolimbic dopamine signaling in acute and chronic pain: Implications for motivation, analgesia, and addiction","volume":"157","author":"Taylor","year":"2016","journal-title":"Pain"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neulet.2009.07.050","article-title":"Sustained attention deficits in rats with chronic inflammatory pain","volume":"463","author":"Lima","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1523\/JNEUROSCI.5197-12.2013","article-title":"Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity","volume":"33","author":"Lima","year":"2013","journal-title":"J. Neurosci."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/12\/1265\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T05:33:48Z","timestamp":1764221628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/12\/1265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":148,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["brainsci15121265"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15121265","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}