Neuropharmacology最新文献

{"title":"Neural mechanisms, influencing factors and interventions in empathic pain","authors":"Furui Liu,&nbsp;Ziwan He,&nbsp;Yongjie Wang","doi":"10.1016/j.neuropharm.2025.110349","DOIUrl":"10.1016/j.neuropharm.2025.110349","url":null,"abstract":"<div><div>Empathic pain, defined as the emotional resonance with the suffering of others, is akin to the observer's own experience of pain and is vital for building and sustaining positive interpersonal relationships. Despite its importance, the neural mechanism of empathic pain remains poorly understood. In this review, we integrated and summarized the currently knowledge on the neural networks associated with empathic pain, focusing on key brain regions such as the insula, anterior cingulate cortex (ACC), ventral tegmental area (VTA), nucleus accumbens (NAc), and locus coeruleus (LC)/norepinephrine (NE)-sympatho-adrenomedullar (LC/NE-SAM) system. We also reviewed the factors that affect empathic pain, including gender, personal beliefs, the intimacy of relationships, and the nature of interpersonal relationships, and highlighted the central role of the insula and ACC in the neural circuitry of empathy, the importance of the IC-BLA and ACC-NAc/VTA connections in modulating empathic pain, and the involvement of the LC/NE-SAM system in mediating pain empathy. We further discussed how gender significantly influences empathic pain, with women showing more intense emotional reactions to social distress than men. It also summarized the roles of personal pain history and empathy levels in modulating empathic responses. Furthermore, the review emphasized the impact of social factors such as the nature of interpersonal relationships and experiences of social exclusion on empathic pain. By providing a detailed exploration of the neural mechanisms and influencing factors of empathic pain, this review aims to establish a robust foundation for developing targeted therapeutic strategies and improving pain management in clinical settings.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110349"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiplatelet therapy as a novel approach in Parkinson's disease: Repositioning Ticagrelor to alleviate rotenone-induced parkinsonism via modulation of ER stress, apoptosis, and autophagy","authors":"Muhammad Muneeb ,&nbsp;Dalaal M. Abdallah ,&nbsp;Hanan S. El-Abhar ,&nbsp;Walaa Wadie ,&nbsp;Kawkab A. Ahmed ,&nbsp;Yasmine S. Abul Fadl","doi":"10.1016/j.neuropharm.2025.110346","DOIUrl":"10.1016/j.neuropharm.2025.110346","url":null,"abstract":"<div><div>Cardiovascular diseases, such as myocardial infarction, ischemic stroke, and coronary heart ailments have been closely associated with Parkinson's disease (PD). Despite this established link, the potential neuroprotective impact of the potent antiplatelet agent ticagrelor (Tica) remains unexplored against PD. Thus, we hypothesized that Tica could be repurposed as a therapeutic agent against PD. Rotenone experimental model was adopted in Wistar male rats by administering rotenone subcutaneously on alternate days during a 21-day experimental period and treating a subset of rats with Tica orally for the last 11 consecutive days. The administration of Tica improved motor function (open field test, hanging wire test) and restored striatal histological features. Additionally, Tica opposed the rotenone effect and markedly obliterated the striatal α-synuclein content but enhanced the protein expression of tyrosine hydroxylase and dopamine content. On the molecular level, Tica inhibited striatal endoplasmic reticulum stress (ERS) as evidenced by the downregulation of the ER-resident transmembrane sensor inositol-requiring enzyme 1 alpha and its downstream molecular targets, TNF receptor-associated factor 2 and c-Jun N-terminal kinase, along with a reduction in caspase-3 activity. On the other hand, Tica augmented the autophagy machinery by upregulating the autophagosome markers Beclin-1 and light chain 3-II, while inhibiting the content of cathepsin D. Therefore, the current study is the first to accentuate the neuroprotective potential of Tica in a rat model of PD via modulating the crosstalk between ERS, apoptosis, and autophagy to represent a potential novel therapeutic candidate for managing PD, particularly in patients with or prone to cardiovascular diseases.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110346"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The neural basis of affective empathy: What is known from rodents","authors":"Siqi Peng ,&nbsp;Moyi Li ,&nbsp;Xiuqi Yang,&nbsp;Wei Xie","doi":"10.1016/j.neuropharm.2025.110347","DOIUrl":"10.1016/j.neuropharm.2025.110347","url":null,"abstract":"<div><div>Empathy is the cornerstone of social interactions between conspecies for human beings and other social animals. Human beings with empathy defects might either suffer unpleasant or failed social interactions as ASD patients, or even display antisocial behaviors. To find efficient cure for empathy defects, first of all, the neural mechanisms underpinning various empathy behaviors should be well studied and understood. And the research in the field of affective empathy thrives fast in recent years. It is necessary to review the important contributions in this field, especially for understanding the delicate neural mechanisms of diverse forms of affective empathy. Here, we have summarized the characteristics of various types of affective empathy. We also discuss the distinctions between empathy for pain and fear, as well as instinctive and experienced empathy. Our analysis further highlights the findings in the complex neural mechanisms and potential brain regions underlying different affective empathy behaviors. Above all, this work is expected to help enhance our comprehension of behavioral dynamics and neural basis of affective empathy along with its role in emotional regulation and social behavior.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110347"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of KIF15 contributes to oxaliplatin-induced cold hypersensitivity by limiting annexin A2 and enhancing TRPA1 localization in DRG neuronal membrane","authors":"Liu-Ying Wu ,&nbsp;Meng-Nan Zhai ,&nbsp;Xue-Qiang Bai ,&nbsp;Cheng He ,&nbsp;Yun-Ying Guo ,&nbsp;Yu-Qi Zhang ,&nbsp;Juan Wang ,&nbsp;Yong-Tao Gao ,&nbsp;Qi-Feng Tu ,&nbsp;Mei Liu ,&nbsp;Jun-Jie Chen ,&nbsp;Zhi-Jun Zhang","doi":"10.1016/j.neuropharm.2025.110343","DOIUrl":"10.1016/j.neuropharm.2025.110343","url":null,"abstract":"<div><div>Effective treatments for oxaliplatin-induced cold hypersensitivity remain a significant clinical challenge, primarily due to gaps in our understanding of the underlying pathophysiology. Our previous studies have indicated that kinesin-12 (KIF15) is expressed in neurons, suggesting its potential involvement in neurodevelopment and neuronal plasticity. However, its role in mediating chemotherapy-induced pain in primary sensory neurons has not yet been reported. In this study, we found that KIF15-knockout (Kif15-KO) mice showed an increase in cold sensitivity, with this heightened cold hypersensitivity being dependent on the accumulation of the TRP ankyrin 1 (TRPA1) channel on the cell membrane. We further demonstrated that in a model of oxaliplatin-induced peripheral neuropathy (OIPN), KIF15 expression was markedly reduced, coinciding with an increase in TRPA1 membrane localization and a physical interaction between KIF15 and Annexin A2 in peripheral sensory neurons. This suggests a mechanistic link where the loss of KIF15 disrupts the function of Annexin A2, enhancing the localization of TRPA1 on the cell membrane of dorsal root ganglion (DRG) neurons, thereby contributing to cold hypersensitivity. Our results offer a new understanding of the molecular mechanisms underlying chemotherapy-induced cold hypersensitivity, highlighting KIF15 as a key regulator and a potential therapeutic target for conditions like OIPN.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110343"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesencephalic astrocyte-derived neurotrophic factor (MANF): A novel therapeutic target for chemotherapy-induced peripheral neuropathy via regulation of integrated stress response and neuroinflammation","authors":"Juan Wang ,&nbsp;Shenghong Li ,&nbsp;Jishi Ye ,&nbsp;Yafei Yan ,&nbsp;Qi Liu ,&nbsp;Qiang Jia ,&nbsp;Yifan Jia ,&nbsp;Long Wang","doi":"10.1016/j.neuropharm.2025.110342","DOIUrl":"10.1016/j.neuropharm.2025.110342","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) represents a severe complication, impacting up to 90% of cancer patients administered with chemotherapeutic agents such as oxaliplatin. The purpose of our study was to examine the potential role and therapeutic efficacy of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF), given its recognized neuroprotective and immunomodulatory properties in diverse neurological disorders. Utilizing an oxaliplatin-induced CIPN mouse model, we investigated MANF expression in the dorsal root ganglia (DRG) and spinal cord, and evaluated the impacts of AAV-mediated MANF overexpression on CIPN. Our findings revealed substantial downregulation of MANF expression in both the DRG and spinal cord of CIPN inflicted mice, with MANF majorly localized in neurons as opposed to glial cells. Intrathecal administration of AAV-MANF preceding oxaliplatin treatment yielded several beneficial results. MANF overexpression diminished mechanical hypersensitivity and decreased Calcitonin Gene-Related Peptide (CGRP) expression in DRG and the spinal dorsal horn. These enhancements were concomitant with modulation of the integrated stress response (ISR) and neuroinflammation. Intervention with AAV-MANF effectively regulated ISR markers (BiP, CHOP, and p-eIF2α), mitigated activation of microglia and astrocytes in the DRG and spinal dorsal horn, and inhibited NFκB and ERK inflammatory signaling pathways. To conclude, our study underscores the potential of MANF as a viable therapeutic target for CIPN, manifesting its ability to modulate ISR and neuroinflammation. These insights recommend that continued exploration of MANF-centered approaches could facilitate the advancement of more efficacious interventions for this incapacitating chemotherapy complication.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110342"},"PeriodicalIF":4.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143151304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroimmune regulation of the prefrontal cortex tetrapartite synapse","authors":"Andrea Liss,&nbsp;Mahum T. Siddiqi,&nbsp;Paige Marsland,&nbsp;Florence P. Varodayan","doi":"10.1016/j.neuropharm.2025.110335","DOIUrl":"10.1016/j.neuropharm.2025.110335","url":null,"abstract":"<div><div>The prefrontal cortex (PFC) is an essential driver of cognitive, affective, and motivational behavior. There is clear evidence that the neuroimmune system directly influences PFC synapses, in addition to its role as the first line of defense against toxins and pathogens. In this review, we first describe the core structures that form the tetrapartite PFC synapse, focusing on the signaling microdomain created by astrocytic cradling of the synapse as well as the emerging role of the extracellular matrix in synaptic organization and plasticity. Neuroimmune signals (e.g. pro-inflammatory interleukin 1β) can impact the function of each core structure within the tetrapartite synapse, as well as promote intra-synaptic crosstalk, and we will provide an overview of recent advances in this field. Finally, evidence from <em>post mortem</em> human brain tissue and preclinical studies indicate that inflammation may be a key contributor to PFC dysfunction. Therefore, we conclude with a mechanistic discussion of neuroimmune-mediated maladaptive plasticity in neuropsychiatric disorders, with a focus on alcohol use disorder (AUD). Growing recognition of the neuroimmune system's role as a critical regulator of the <span>PFC</span> tetrapartite synapse provides strong support for targeting the neuroimmune system to develop new pharmacotherapeutics.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110335"},"PeriodicalIF":4.6,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel chimeric peptides of endomorphin-2 and the active fragments of ghrelin exhibit blood-brain barrier permeability and central antinociceptive effects with reduced opioid-related side effects","authors":"Yongling Liu ,&nbsp;Biao Xu ,&nbsp;Songxia Cheng ,&nbsp;Yan Wang ,&nbsp;Jiali Ding ,&nbsp;Xiaoyu Shen ,&nbsp;Bing Wu ,&nbsp;Liangquan Xu ,&nbsp;Jie Wei","doi":"10.1016/j.neuropharm.2025.110324","DOIUrl":"10.1016/j.neuropharm.2025.110324","url":null,"abstract":"<div><div>Pharmacological research has showed that multi-targeted drug therapies offer superior efficacy and reduced side effects compared to single-target drug therapies. In this study, we designed and characterized four novel chimeric peptides G (1–5)-EM2, EM2-G (1–5), G (1–9)-EM2 and EM2-G (1–9) which incorporate endomorphin-2 (EM-2) and the active fragments of ghrelin. Calcium mobilization assays revealed that these four chimeric peptides acted as weak mixed agonists for the μ-opioid receptor (MOR), κ-opioid receptor (KOR), and growth hormone secretagogue receptor 1α (GHS-R1α). The results of fluorescence imaging experiments indicated that G (1–5)-EM2 and G (1–9)-EM2 could penetrate the blood-brain barrier (BBB) following intravenous (i.v.) injection. All chimeric peptides induced almost equal antinociceptive effects compared with EM-2 or better antinociceptive effects than EM-2 after intracerebroventricular (i.c.v.) injection in the acute pain in mice. Among them, G (1–5)-EM2 could cross the BBB and enter the brain to induce antinociceptive effect through central opioid receptors after i. v. Injection. Our findings demonstrated that the chimeric peptides produced significant antinociception mainly via MOR, DOR and GHS-R1α without inducing antinociceptive tolerance, or with a lower tendency for antinociceptive tolerance after i. c.v. Injection in the acute pain in mice. Furthermore, the chimeric peptides mitigated or eliminated the digestive side effects associated with EM-2. The collective results highlight G (1–5)-EM2 as the most promising candidate among the chimeric peptides. The chimeric peptides represent a promising class of potential analgesics for clinical pain management. However, further optimization is necessary to maximize their therapeutic potential.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110324"},"PeriodicalIF":4.6,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice","authors":"Michael Noback ,&nbsp;Johnny A. Kenton ,&nbsp;Adam K. Klein ,&nbsp;Zoë A. Hughes ,&nbsp;Andrew C. Kruegel ,&nbsp;Yasmin Schmid ,&nbsp;Adam L. Halberstadt ,&nbsp;Jared W. Young","doi":"10.1016/j.neuropharm.2025.110334","DOIUrl":"10.1016/j.neuropharm.2025.110334","url":null,"abstract":"<div><div>Treating amotivated states remains difficult. Classical psychedelic drugs (5-HT_2A receptor agonists) such as LSD and psilocybin have shown therapeutic potential in treating such symptoms, but their development has been hindered by their undesirable hallucinogenic effects. There is increasing evidence that administration of psychedelics at dose levels too low to evoke a hallucinogenic effect (“microdoses”) may have therapeutic value in contexts of mood and cognition. 2,5-Dimethoxy-4-propylamphetamine (DOPR) is a psychedelic phenethylamine compound acting as a 5-HT_2A receptor agonist. We used a combination of behavioral assays to determine the motivational and hallucinogenic-like effects of DOPR and identify the dose ranges at which each of these effects were observed. In mice, the motivational effects of psychedelic compounds were assessed using the progressive ratio breakpoint task (PRBT, n = 80), a translational assay sensitive to changes in motivation. Psychedelic-like effects were gauged using the mouse head-twitch response (HTR, n = 72) assay, a preclinical readout of psychedelic potential. Significant improvements in PRBT performance were seen at doses as low as 0.0106 mg/kg in animals with low baseline PRBT scores while high-performing PRBT mice were unaffected. DOPR only induced significant HTR at doses ≥0.1 mg/kg. Together, these results indicate that the psychedelic DOPR may increase motivation in those with a low motivated state. Importantly, these effects may be attainable at low doses below the threshold required to induce psychedelic subjective effects. Hence, the ability of low doses of DOPR and other psychedelic drugs to alleviate amotivated states in rodents manipulated to induce disease-relevant states should be investigated.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110334"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-derived trimethylamine N-oxide involved in methamphetamine-induced depression-like behaviors of male mice","authors":"Xintao Wang ,&nbsp;Rongji Hui ,&nbsp;Qing Li ,&nbsp;Yun Lu ,&nbsp;Mengmeng Wang ,&nbsp;Yan Shi ,&nbsp;Bing Xie ,&nbsp;Bin Cong ,&nbsp;Chunling Ma ,&nbsp;Di Wen","doi":"10.1016/j.neuropharm.2025.110339","DOIUrl":"10.1016/j.neuropharm.2025.110339","url":null,"abstract":"<div><div>Methamphetamine (METH)-provoked psychiatric symptoms are a major health concern, with depression being a prevalent symptom among METH abusers. Recently, gut microbiota-derived metabolites have been involved in various psychosis pathogenesis, but their roles in METH-induced depression remain unclear. This study investigates the implication of gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) in METH-induced depressive-like behaviors (DLBs). We examined the circulating TMAO levels post-METH exposure besides exploring the impacts of TMAO on METH-triggered DLBs. Then, potential causes of TMAO alterations were explored, along with its effects on hippocampal neuronal damage and neuroinflammation. The findings showcased that METH-treated mice displayed DLBs accompanied by increased serum TMAO levels. Similarly, introducing TMAO to the drinking water elevated serum TMAO levels and induced DLBs. Although METH exposure did not notably alter the abundance of the gut microbiota, antibiotic (ABX) therapy suppressed the increased serum TMAO levels and the onset of DLBs. Additionally, choline and L-carnitine levels were elevated following METH exposure, which may be a potential mechanism for TMAO metabolic dysregulation. Elevated TMAO levels resulted in an elevation in Nissl-positive dead cells, the number of microglia, TNF-α, and IL-1β levels, along with TLR-4, NF-κB, and MyD88 expression in the hippocampal CA3 region. Inhibition of TMAO synthesis mitigated METH-provoked neuronal damage and neuroinflammation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110339"},"PeriodicalIF":4.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implication of system xc− in complete Freund's adjuvant-induced peripheral inflammation and associated nociceptive sensitization","authors":"Pauline Beckers ,&nbsp;Mathilde Charlier ,&nbsp;Lorie Azria-Richter ,&nbsp;Pauline Braconnier ,&nbsp;Nathalie Desmet ,&nbsp;Ann Massie ,&nbsp;Emmanuel Hermans","doi":"10.1016/j.neuropharm.2025.110340","DOIUrl":"10.1016/j.neuropharm.2025.110340","url":null,"abstract":"<div><h3>Background</h3><div>Persistent inflammation leading to neuronal sensitization in pain pathways, are key features of chronic inflammatory pain. Alike macrophages in the periphery, glial cells exacerbate hypersensitivity by releasing proalgesic mediators in the central nervous system. Expressed by peripheral and central immune cells, the cystine-glutamate antiporter system x_c⁻ plays a significant role in inflammatory responses, but its involvement in chronic inflammatory pain remains underexplored. We herein investigated the contribution of this exchanger in nociceptive hypersensitivity triggered by a peripheral inflammatory insult.</div></div><div><h3>Methods</h3><div>Complete Freund's adjuvant (CFA) was injected into the left hind paw of wild-type C57Bl/6 female mice, of xCT-deficient mice (specific subunit of system x_c⁻) and of mice receiving the system x_c⁻ inhibitor sulfasalazine. Paw edema was measured over three weeks and pain-associated behaviors were evaluated. Additionally, pro-inflammatory cytokine levels were assessed in blood samples.</div></div><div><h3>Results</h3><div>CFA injection led to a persistent increase in paw edema and hypersensitivity to mechanical and thermal stimuli, which were less pronounced in xCT-deficient mice. This reduced sensitivity was accompanied by lower systemic pro-inflammatory cytokine levels in xCT-deficient mice. Accordingly, pharmacological inhibition of system x_c⁻ with sulfasalazine, either before or after pain induction, efficiently reduced the algesic and inflammatory responses to CFA in wild-type mice.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a critical role for system x_c⁻ in the pathophysiology of inflammatory pain. xCT deficiency reduces pain behaviors and peripheral inflammation, positioning system x_c⁻ as a promising therapeutic target for alleviating chronic inflammatory pain.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110340"},"PeriodicalIF":4.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}