Neuropharmacology最新文献

{"title":"Sex differences in the BTBR idiopathic mouse model of autism spectrum disorders: Behavioural and redox-related hippocampal alterations","authors":"Maria Bove ,&nbsp;Vladyslav Sikora ,&nbsp;Martina Santoro ,&nbsp;Lisa Pia Agosti ,&nbsp;Maria Adelaide Palmieri ,&nbsp;Stefania Dimonte ,&nbsp;Paolo Tucci ,&nbsp;Stefania Schiavone ,&nbsp;Maria Grazia Morgese ,&nbsp;Luigia Trabace","doi":"10.1016/j.neuropharm.2024.110134","DOIUrl":"10.1016/j.neuropharm.2024.110134","url":null,"abstract":"<div><p>Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental diseases. Epidemiological data report that males have been diagnosed with autism more frequently than females. However, recent studies hypothesize that females’ low incidence might be underestimated due to standard clinical measures of ASD behavioural symptoms, mostly derived from males. Indeed, up to now, ASD mouse models focused mainly on males, considering the prevalence of the diagnosis in that sex. Regarding ASD aetiopathogenesis, it has been recently reported that oxidative stress might be implicated in its onset and development, suggesting an association with ASD typical repetitive behaviours that still need to be disentangled. Here, we investigated possible behavioural and molecular sex-related differences by using the BTBR mouse model of idiopathic ASD. To this aim, animals were exposed to behavioural tests related to different ASD core symptoms and comorbidities, <em>i.e.</em> stereotyped repertoire, social dysfunctions, hyperlocomotion and risk-taking behaviours. Moreover, we analyzed hippocampal levels of pro-oxidant and anti-oxidant enzymes, together with biomarkers of oxidative stress and lipid peroxidation.</p><p>Our results showed that BTBR females did not display the same patterns for repetitive behaviours as the male counterpart. From a biomolecular point of view, we found an increase in oxidative stress and pro-oxidant enzymes, accompanied by deficient enzymatic anti-oxidant response, only in BTBR males compared to C57BL/6 male mice, while no differences were retrieved in females.</p><p>Overall, our study suggests that in females there is an urgent need to depict the distinct ASD symptomatology, accompanied by the identification of sex-specific pharmacological targets.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110134"},"PeriodicalIF":4.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824003034/pdfft?md5=d86f5a258c6d9560cc8b1b529e40b201&pid=1-s2.0-S0028390824003034-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109943","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":"GPx1-ERK1/2-CREB pathway regulates the distinct vulnerability of hippocampal neurons to oxidative stress via modulating mitochondrial dynamics following status epilepticus","authors":"Ji-Eun Kim,&nbsp;Duk-Shin Lee,&nbsp;Su Hyeon Wang,&nbsp;Tae-Hyun Kim,&nbsp;Tae-Cheon Kang","doi":"10.1016/j.neuropharm.2024.110135","DOIUrl":"10.1016/j.neuropharm.2024.110135","url":null,"abstract":"<div><p>Glutathione peroxidase-1 (GPx1) and cAMP/Ca²⁺ responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110135"},"PeriodicalIF":4.6,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109940","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":"Dopaminergic system and neurons: Role in multiple neurological diseases","authors":"Heng Chen ,&nbsp;Jieshu Li ,&nbsp;Zhixing Huang ,&nbsp;Xiaoxiao Fan ,&nbsp;Xiaofei Wang ,&nbsp;Xing Chen ,&nbsp;Haitao Guo ,&nbsp;Hao Liu ,&nbsp;Shuqi Li ,&nbsp;Shaojun Yu ,&nbsp;Honghong Li ,&nbsp;Xinyu Huang ,&nbsp;Xuehua Ma ,&nbsp;Xinqi Deng ,&nbsp;Chunguo Wang ,&nbsp;Yonggang Liu","doi":"10.1016/j.neuropharm.2024.110133","DOIUrl":"10.1016/j.neuropharm.2024.110133","url":null,"abstract":"<div><p>The dopaminergic system is a complex and powerful neurotransmitter system in the brain. It plays an important regulatory role in motivation, reward, cognition, and motor control. In recent decades, research in the field of the dopaminergic system and neurons has increased exponentially and is gradually becoming a point of intervention in the study and understanding of a wide range of neurological diseases related to human health. Studies have shown that the dopaminergic system and neurons are involved in the development of many neurological diseases (including, but not limited to Parkinson's disease, schizophrenia, depression, attention deficit hyperactivity disorder, etc.) and that dopaminergic neurons either have too much stress or too weak function in the dopaminergic system can lead to disease. Therefore, targeting dopaminergic neurons is considered key to treating these diseases. This article provides a comprehensive review of the dopaminergic system and neurons in terms of brain region distribution, physiological function and subtypes of dopaminergic neurons, as well as the role of the dopaminergic system and neurons in a variety of diseases.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110133"},"PeriodicalIF":4.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142089304","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 PGC-1α/ERRα/ULK1 pathway contributes to Perioperative neurocognitive disorders by inducing mitochondrial dysfunction and activating NLRP3 inflammasome in aged mice","authors":"Wen Zhang ,&nbsp;Cui-cui Wu ,&nbsp;Meng-Meng Ge ,&nbsp;Xiao-Man Yuan ,&nbsp;Si-Yi Han ,&nbsp;Feng-Tian Zhao ,&nbsp;Xiao-Yu Zhang ,&nbsp;Feng Gao ,&nbsp;Yu-Ke Tian ,&nbsp;Guang-Xiong Zhang ,&nbsp;Xue-Bi Tian","doi":"10.1016/j.neuropharm.2024.110119","DOIUrl":"10.1016/j.neuropharm.2024.110119","url":null,"abstract":"<div><p>Perioperative neurocognitive disorders (PND) are intractable, indistinct, and considerably diminish the postoperative quality of life of patients. It has been proved that Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was involved in neurodegenerative diseases by regulating mitochondrial biogenesis. The underlying mechanisms of PGC-1α and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in PND are not well understood. In this study, we constructed a model of laparotomy in aged mice, and then examined the cognition changes with novel object recognition tests and fear condition tests. The protein levels of PGC-1α and NLRP3 in the hippocampus were detect after surgery. Our results showed that NLRP3 and downstream PI3K/AKT pathway expressions were augmented in the hippocampus after surgery, whereas, the expressions of PGC-1α/estrogen-related receptor α (ERRα)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway were diminished after surgery. In addition, we found that NLRP3 was mainly co-localized with neurons in the hippocampus, and synaptic-related proteins were reduced after surgery. At the same time, transmission electron microscopy (TEM) showed that mitochondria were impaired after surgery. Pharmacological treatment of MCC950, a selective NLRP3 inhibitor, effectively alleviated PND. Activation of PGC-1α with ZLN005 significantly ameliorated PND by enhancing the PGC-1α/ERRα/ULK1 signaling pathway, and further suppressing NLRP3 activation. As a result, we conclude that suppression of the PGC-1α/ERRα/ULK1 signaling pathway is the primary mechanism of PND which caused mitochondrial dysfunction, and activated NLRP3 inflammasome and downstream PI3K/AKT pathway, eventually improved cognitive dysfunction.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110119"},"PeriodicalIF":4.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093573","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":"Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice","authors":"Faranak Vahid-Ansari ,&nbsp;Adrian Newman-Tancredi ,&nbsp;Alberto Francisco Fuentes-Alvarenga ,&nbsp;Mireille Daigle ,&nbsp;Paul R. Albert","doi":"10.1016/j.neuropharm.2024.110132","DOIUrl":"10.1016/j.neuropharm.2024.110132","url":null,"abstract":"<div><p>Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4–8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After 1 h, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered 1 h prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110132"},"PeriodicalIF":4.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824003010/pdfft?md5=72086ec5144c0e0728aebe4520c29492&pid=1-s2.0-S0028390824003010-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109942","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":"Effects of four-week intranasal oxytocin administration on large-scale brain networks in older adults","authors":"Peiwei Liu ,&nbsp;Tian Lin ,&nbsp;Håkan Fischer ,&nbsp;David Feifel ,&nbsp;Natalie C. Ebner","doi":"10.1016/j.neuropharm.2024.110130","DOIUrl":"10.1016/j.neuropharm.2024.110130","url":null,"abstract":"<div><p>Oxytocin (OT) is a crucial modulator of social cognition and behavior. Previous work primarily examined effects of acute intranasal oxytocin administration (IN-OT) in younger males on isolated brain regions. Not well understood are <em>(i)</em> chronic IN-OT effects, <em>(ii)</em> in older adults, <em>(iii)</em> on large-scale brain networks, representative of OT's wider-ranging brain mechanisms. To address these research gaps, 60 generally healthy older adults (mean age = 70.12 years, range = 55–83) were randomly assigned to self-administer either IN-OT or placebo twice daily via nasal spray over four weeks. Chronic IN-OT reduced resting-state functional connectivity (rs-FC) of both the right insula and the left middle cingulate cortex with the salience network but enhanced rs-FC of the left medial prefrontal cortex with the default mode network as well as the left thalamus with the basal ganglia–thalamus network. No significant chronic IN-OT effects were observed for between-network rs-FC. However, chronic IN-OT increased selective rs-FC of the basal ganglia–thalamus network with the salience network and the default mode network, indicative of more specialized, efficient communication between these networks. Directly comparing chronic vs. acute IN-OT, reduced rs-FC of the right insula with the salience network and between the default mode network and the basal ganglia–thalamus network, and greater selective rs-FC of the salience network with the default mode network and the basal ganglia–thalamus network, were more pronounced after chronic than acute IN-OT. Our results delineate the modulatory role of IN-OT on large-scale brain networks among older adults.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110130"},"PeriodicalIF":4.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056130","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":"MiR-184-3p in the paraventricular nucleus participates in the neurobiology of depression via regulation of the hypothalamus-pituitary-adrenal axis","authors":"Da-Wei Xu ,&nbsp;Wei-Yu Li ,&nbsp;Tian-Shun Shi ,&nbsp;Cheng-Niu Wang ,&nbsp;Si-Yi Zhou ,&nbsp;Wei Liu ,&nbsp;Wei-Jia Chen ,&nbsp;Bao-Lun Zhu ,&nbsp;Hao Fei ,&nbsp;Dong-dong Cheng ,&nbsp;Zhi-Ming Cui ,&nbsp;Bo Jiang","doi":"10.1016/j.neuropharm.2024.110129","DOIUrl":"10.1016/j.neuropharm.2024.110129","url":null,"abstract":"<div><p>Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for the pathogenesis of depression, and increased activity of cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) plays a critical role. As a well-investigated microRNA (miRNA), miR-184 has two forms, miR-184-3p and miR-184-5p. Recently, miRNAs target genes predictive analysis and dual-luciferase reporter assays identified an inhibitory role of miR-184-3p on CRTC1 expression. Therefore, we speculated that miR-184-3p regulation was responsible for the effects of chronic stress on CRTC1 in the PVN. Various methods, including the chronic social defeat stress (CSDS) model of depression, behavioral tests, Western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer, were used. CSDS evidently downregulated the level of miR-184-3p, but not miR-184-5p, in the PVN. Genetic knockdown and pharmacological inhibition of miR-184-3p in the PVN induced various depressive-like symptoms (e.g., abnormal behaviors, HPA hyperactivity, enhanced CRTC1 function in PVN neurons, downregulation of hippocampal neurogenesis, and decreased brain-derived neurotrophic factor (BDNF) signaling) in naïve male C57BL/6J mice. In contrast, genetic overexpression and pharmacological activation of miR-184-3p in the PVN produced significant beneficial effects against CSDS. MiR-184-3p in the PVN was necessary for the antidepressant actions of two well-known SSRIs, fluoxetine and paroxetine. Collectively. miR-184-3p was also implicated in the neurobiology of depression and may be a viable target for novel antidepressants.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110129"},"PeriodicalIF":4.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046875","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":"Bioinformatics and validation reveal the potential target of curcumin in the treatment of diabetic peripheral neuropathy","authors":"Ziqiang Lin ,&nbsp;Suo Wang ,&nbsp;Yu Cao ,&nbsp;Jialing Lin ,&nbsp;Ailing Sun ,&nbsp;Wei Huang ,&nbsp;Jun Zhou ,&nbsp;Qingxiong Hong","doi":"10.1016/j.neuropharm.2024.110131","DOIUrl":"10.1016/j.neuropharm.2024.110131","url":null,"abstract":"<div><p>Diabetic peripheral neuropathy (DPN) is a common nerve-damaging complication of diabetes mellitus. Effective treatments are needed to alleviate and reverse diabetes-associated damage to the peripheral nerves. Curcumin is an effective neuroprotectant that plays a protective role in DPN promoted by Schwann cells (SCs) lesions. However, the potential molecular mechanism of curcumin remains unclear. Therefore, our aim is to study the detailed molecular mechanism of curcumin-mediated SCs repair in order to improve the efficacy of curcumin in the clinical treatment of DPN. First, candidate target genes of curcumin in rat SC line RSC96 cells stimulated by high glucose were identified by RNA sequencing and bioinformatic analyses. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out by Metascape, followed by 8 algorithms on Cytoscape to determine 4 hub genes, namly Hmox1, Pten, Vegfa and Myc. Next, gene set enrichment analysis (GSEA) and Pearson function showed that Hmox1 was significantly correlated with apoptosis. Subsequently, qRT-PCR, MTT assay, flow cytometry, caspase-3 activity detection and westernblot showed that curcumin treatment increased RSC96 cell viability, reduced cell apoptosis, increased Hmox1, Pten, Vegfa and Myc expression, and up-regulated Akt phosphorylation level under high glucose environment. Finally, molecular docking predicted the binding site of curcumin to Hmox1. These results suggest that curcumin can reduce the apoptosis of SCs induced by high glucose, and Hmox1 is a potential target for curcumin. Our findings provide new insights about the mechanism of action of curcumin on SC as a potential treatment in DPN.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110131"},"PeriodicalIF":4.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046874","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":"Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization","authors":"Marthe M. Vandeputte ,&nbsp;Sabrine Bilel ,&nbsp;Micaela Tirri ,&nbsp;Giorgia Corli ,&nbsp;Marta Bassi ,&nbsp;Nathan K. Layle ,&nbsp;Anna Fantinati ,&nbsp;Donna Walther ,&nbsp;Donna M. Iula ,&nbsp;Michael H. Baumann ,&nbsp;Christophe P. Stove ,&nbsp;Matteo Marti","doi":"10.1016/j.neuropharm.2024.110113","DOIUrl":"10.1016/j.neuropharm.2024.110113","url":null,"abstract":"<div><p>The emergence of new synthetic opioids (NSOs) has added complexity to recreational opioid markets worldwide. While NSOs with diverse chemical structures have emerged, brorphine currently remains the only NSO with a piperidine benzimidazolone scaffold. However, the emergence of new generations of NSOs, including brorphine analogues, can be anticipated. This study explored the pharmaco-toxicological, opioid-like effect profile of brorphine alongside its non-brominated analogue (orphine) and three other halogenated analogues (fluorphine, chlorphine, iodorphine). <em>In vitro</em>, radioligand binding assays in rat brain tissue indicated that all analogues bind to the μ-opioid receptor (MOR) with nM affinity. While analogues with smaller-sized substituents showed the highest MOR affinity, further <em>in vitro</em> characterization <em>via</em> two cell-based (HEK 293T) MOR activation (β-arrestin 2 and mini-G_αi recruitment) assays indicated that chlorphine, brorphine, and iodorphine were generally the most active MOR agonists. None of the compounds showed significant <em>in vitro</em> biased agonism compared to hydromorphone. <em>In vivo</em>, we investigated the effects of intraperitoneal (IP) administration of the benzimidazolones (0.01–15 mg/kg) on mechanical and thermal antinociception in male CD-1 mice. Chlorphine and brorphine overall induced the highest levels of antinociception. Furthermore, the effects on respiratory changes induced by a fixed dose (15 mg/kg IP) of the compounds were investigated using non-invasive plethysmography. Fluorphine-, chlorphine-, and brorphine-induced respiratory depressant effects were the most pronounced. For some compounds, pretreatment with naloxone (6 mg/kg IP) could not reverse respiratory depression. Taken together, brorphine-like piperidine benzimidazolones are opioid agonists that have the potential to cause substantial harm to users should they emerge as NSOs.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110113"},"PeriodicalIF":4.6,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000431","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":"Neuroinflammation evoked mechanisms for neuropathic itch in the spared nerve injury mouse model of neuropathic pain","authors":"Vittoria Borgonetti ,&nbsp;Martina Morozzi ,&nbsp;Nicoletta Galeotti","doi":"10.1016/j.neuropharm.2024.110120","DOIUrl":"10.1016/j.neuropharm.2024.110120","url":null,"abstract":"<div><p>A large portion of neuropathic pain suffering patients may also concurrently experience neuropathic itch, with a negative impact on the quality of life. The limited understanding of neuropathic itch and the low efficacy of current anti-itch therapies dictate the urgent need of a better comprehension of molecular mechanisms involved and development of relevant animal models. This study was aimed to characterize the itching phenotype in a model of trauma-induced peripheral neuropathy, the spared nerve injury (SNI), and the molecular events underlying the overlap with the nociceptive behavior. SNI mice developed hyperknesis and spontaneous itch 7–14 days after surgery that was prevented by gabapentin treatment. Itch was associated with pain hypersensitivity, loss of intraepidermal nerve fiber (IENF) density and increased epidermal thickness. In coincidence with the peak of scratching behavior, SNI mice showed a spinal overexpression of IBA1 and GFAP, microglia and astrocyte markers respectively. An increase of the itch neuropeptide B-type natriuretic peptide (BNP) in NeuN+ cells, of its downstream effector interleukin 17 (IL17) along with increased pERK1/2 levels occurred in the spinal cord dorsal horn and DRG. A raise in BNP and IL17 was also detected at skin level. Stimulation of HaCat cells with conditioned medium from BV2-stimulated SH-SY5Y cells produced a dramatic reduction of HaCat cell viability. This study showed that SNI mice might represent a model for neuropathic itch and pain. Collectively, our finding suggest that neuropathic itch might initiate at spinal level, then affecting skin epidermis events, through a glia-mediated neuroinflammation-evoked BNP/IL17 mechanism.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"259 ","pages":"Article 110120"},"PeriodicalIF":4.6,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824002892/pdfft?md5=36c72db0a875fadbdbddf24f8c75cd35&pid=1-s2.0-S0028390824002892-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002465","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}