Neuropharmacology最新文献_第4页

The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model 在海洛因和酒精共同使用模型中，迷幻药DOI通过靶向5-HT2A受体降低海洛因动机。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-26 DOI: 10.1016/j.neuropharm.2024.110163

{"title":"The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model","authors":"","doi":"10.1016/j.neuropharm.2024.110163","DOIUrl":"10.1016/j.neuropharm.2024.110163","url":null,"abstract":"<div><div>There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals’ break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350791","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}

引用次数: 0

Inhibition of KIF5b-mediated Nav1.8 transport by ropivacaine contributes to axonal regeneration following sciatic nerve injury in rats 罗哌卡因抑制 KIF5b 介导的 Nav1.8 转运有助于大鼠坐骨神经损伤后的轴突再生。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-25 DOI: 10.1016/j.neuropharm.2024.110169

{"title":"Inhibition of KIF5b-mediated Nav1.8 transport by ropivacaine contributes to axonal regeneration following sciatic nerve injury in rats","authors":"","doi":"10.1016/j.neuropharm.2024.110169","DOIUrl":"10.1016/j.neuropharm.2024.110169","url":null,"abstract":"<div><div>Peripheral nerve injury (PNI), typically caused by traumatic accidents or medical events, is currently one of the most common diseases that leads to limb disability. After PNI, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated at the lesion site. Our earlier study suggested that ropivacaine promotes axon regrowth by regulating Nav1.8-mediated macrophage signaling. Nevertheless, the mechanism of ropivacaine in regulation of Nav1.8 expression remains incompletely understood. Kinesin family 5b (KIF5b) was reported to mediate the Nav1.8 axonal transport from dorsal root ganglia (DRGs) to lesion site. Herein, we investigated whether ropivacaine promotes axon regeneration through inhibition of KIF5b-mediated Nav1.8 transport. Reduced levels of KIF5b and Nav1.8 in DRGs coincide with their increase at the lesion site. Nav1.8 mRNA was significantly increased at the lesion site but not in DRGs. Surprisingly, ropivacaine reversed the alterations of Nav1.8 and KIF5b protein expression without affecting Nav1.8 mRNA level. Due to KIF5b overexpression in DRGs, Nav1.8 protein level was significantly decreased in DRGs and increased at the lesion site. We also found KIF5b overexpression significantly impaired behavioral functions, reduced the recovery index of compound muscle action potential (CMAP) amplitude, inhibited axonal regrowth, slowed M1 macrophage infiltration and shift to M2 phenotype, and delayed myelin debris clearance. Notably, all aforementioned results caused by KIF5b overexpression were alleviated by ropivacaine. Furthermore, we demonstrated that inhibition of Nav1.8 transport by A-803467 produced mitigating effects on the impairment of regenerative capacity induced by KIF5b overexpression similar to ropivacaine. These results suggest that ropivacaine promotes axonal regeneration at least partially by inhibiting KIF5b-mediated Nav1.8 forward transport.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350788","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}

引用次数: 0

Increased levels of Escherichia-Shigella and Klebsiella in the gut contribute to the responsivity of placebo analgesia 肠道中的志贺氏菌和克雷伯氏菌水平升高，导致了安慰剂镇痛的反应性。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-25 DOI: 10.1016/j.neuropharm.2024.110168

{"title":"Increased levels of Escherichia-Shigella and Klebsiella in the gut contribute to the responsivity of placebo analgesia","authors":"","doi":"10.1016/j.neuropharm.2024.110168","DOIUrl":"10.1016/j.neuropharm.2024.110168","url":null,"abstract":"<div><div>Placebo analgesia is observed in both humans and animals. Given the complexity of placebo analgesia involving a variety of neurobiological, psychological, and psychosocial processes, further investigation into its underlying mechanisms is essential. Gut microbiota has been implicated in the responsivity of placebo analgesia, but its precise role remains unknown and warrants further investigations. Here, we conducted a conditioning training model with chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in mice, associating parecoxib with different cues. Hierarchical clustering analysis of placebo analgesia behaviors was employed to classify mice into responders and non-responders phenotypes. Approximately 40% of CFA mice undergoing conditioning training exhibited placebo analgesia. Notably, placebo analgesia responders displayed reduced anxiety-like behaviors. 16S rRNA results revealed a distinct composition of gut microbiota composition among the control, placebo analgesia non-responders and responders groups. Notably, levels of <em>Escherichia Shigella</em> and <em>Klebsiella</em> in the gut were increased considerably in the placebo analgesia responders as compared to both control and non-responders groups. In conclusion, placebo analgesia responders demonstrated marked analgesia, reduced anxiety-like behaviors, and increased levels of <em>Escherichia-Shigella</em> and <em>Klebsiella</em>, implying a potential linkage between gut microbiota and placebo analgesia.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350787","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}

引用次数: 0

Ketamine reverses chronic corticosterone-induced behavioral deficits and hippocampal synaptic dysfunction by regulating eIF4E/BDNF signaling 氯胺酮通过调节eIF4E/BDNF信号转导逆转慢性皮质酮诱导的行为缺陷和海马突触功能障碍

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-24 DOI: 10.1016/j.neuropharm.2024.110156

{"title":"Ketamine reverses chronic corticosterone-induced behavioral deficits and hippocampal synaptic dysfunction by regulating eIF4E/BDNF signaling","authors":"","doi":"10.1016/j.neuropharm.2024.110156","DOIUrl":"10.1016/j.neuropharm.2024.110156","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a debilitating illness with a high global burden. While Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-acting antidepressant effects, its mechanism remains incompletely understood. Recent research suggests that dysregulation of mRNA translation via the Eukaryotic initiation factor 4E (eIF4E) pathway might contribute to depression pathophysiology. This study investigates whether Ketamine modulates eIF4E signaling in the hippocampus during its antidepressant action. Herein, adult male mice were exposed to Corticosterone, a well-established model for anxiety and depression, followed by behavioral testing and biochemical analysis. Corticosterone induced depression-like symptoms and disrupted synaptic function, including reduced TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin signaling. Ketamine treatment reversed these deficits. Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. Importantly, these effects were reversed by 7,8-DHF, a BDNF/TrkB signaling agonist. Mice treated with Corticosterone, Ketamine, and eFT508 and subsequently exposed to 7,8-DHF displayed normalized depression-like behaviors and restored synaptic signaling, including increased eIF4E phosphorylation and MNK1 expression. Besides, 7,8-DHF treatment enhanced p-eIF2α levels compared to the eFT508-treated group. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350789","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}

引用次数: 0

Epigenetic mechanisms of bone cancer pain 骨癌疼痛的表观遗传机制

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-20 DOI: 10.1016/j.neuropharm.2024.110164

引用次数: 0

Flavors of GPCR signaling bias GPCR 信号偏差的味道。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-19 DOI: 10.1016/j.neuropharm.2024.110167

引用次数: 0

Anisomycin alleviates cognitive impairments and pathological features in 3xTg-AD mice Anisomycin 可减轻 3xTg-AD 小鼠的认知障碍和病理特征。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-18 DOI: 10.1016/j.neuropharm.2024.110159

{"title":"Anisomycin alleviates cognitive impairments and pathological features in 3xTg-AD mice","authors":"","doi":"10.1016/j.neuropharm.2024.110159","DOIUrl":"10.1016/j.neuropharm.2024.110159","url":null,"abstract":"<div><div>Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from <em>Streptomyces griseolus</em>, which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aβ and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292140","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}

引用次数: 0

Dissociation between the anti-allodynic effects of fingolimod (FTY720) and desensitization of S1P1 receptor-mediated G-protein activation in a mouse model of sciatic nerve injury 在坐骨神经损伤小鼠模型中，芬戈莫德（FTY720）的抗痛觉作用与 S1P1 受体介导的 G 蛋白激活脱敏之间的分离。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-18 DOI: 10.1016/j.neuropharm.2024.110165

{"title":"Dissociation between the anti-allodynic effects of fingolimod (FTY720) and desensitization of S1P1 receptor-mediated G-protein activation in a mouse model of sciatic nerve injury","authors":"","doi":"10.1016/j.neuropharm.2024.110165","DOIUrl":"10.1016/j.neuropharm.2024.110165","url":null,"abstract":"<div><div>Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292141","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}

引用次数: 0

Nano-pregabalin effectively mitigates Glut, CGRP and NE neurotransmitters abnormalities in the brain of gamma irradiated rats with reserpine-induced fibromyalgia model: Behavioral and neurochemical studies 纳米泼瑞巴林能有效缓解伽马射线照射下瑞舍平诱导的纤维肌痛模型大鼠脑内Glut、CGRP和NE神经递质的异常：行为和神经化学研究

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-17 DOI: 10.1016/j.neuropharm.2024.110162

{"title":"Nano-pregabalin effectively mitigates Glut, CGRP and NE neurotransmitters abnormalities in the brain of gamma irradiated rats with reserpine-induced fibromyalgia model: Behavioral and neurochemical studies","authors":"","doi":"10.1016/j.neuropharm.2024.110162","DOIUrl":"10.1016/j.neuropharm.2024.110162","url":null,"abstract":"<div><h3>Aims</h3><p>Fibromyalgia (FM) is an idiopathic syndrome with painful burdensome symptoms. Radiotherapy is one of the main therapeutic modalities for treating various malignancies and there is a probable association between FM exacerbation and exposure to ionizing radiation. Based on that nanomedicines progressively being explored for their promising applications in medicine, the aim of the current study is to assess the possible therapeutic benefits of nanoform of pregabalin (N-PG) in managing FM symptoms during being exposed to ionizing radiation.</p></div><div><h3>Main methods</h3><p>Rats were allocated into four groups. First group served as control, the other three groups received gamma radiation (2 Gy/day) after 1 h of reserpine administration (1 ml/kg per day, s.c.) to induce FM for three successive days. On the next day, third and fourth groups received (30 mg/kg, p.o.) of PG and N-PG, respectively once daily for ten consecutive days. Tail flick test was performed and von Frey filaments were used to assess mechanical allodynia/hyperalgesia, and then rats were sacrificed to obtain brains.</p></div><div><h3>Key findings</h3><p>N-PG effectively replenished reserpine effects and treated both allodynia and hyperalgesia, improved thermal allodynia, effectively recovered all neurotransmitters near to normal baseline, inhibited oxidative stress status via decreasing malondialdehyde (MDA), increasing glutathione (GSH) and superoxide dismutase (SOD), it had strong anti-inflammatory effect as verified by reducing both cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kB) in addition to inhibition of intrinsic apoptosis through caspase-3 (casp-3) decrease and B-cell lymphoma-2 (Bcl-2) increase. Histopathological and immunohistochemical results confirmed the biochemical findings.</p></div><div><h3>Significance</h3><p>N-PG could be a promising drug for treating FM especially when there is urgent need to expose patient to ionizing radiation.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274198","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}

引用次数: 0

Expression of sensitized β2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats 在 VTA 神经元中表达敏化的 β2 nAChR 亚基可增强雄性大鼠的尼古丁静脉注射自我给药能力

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-09-17 DOI: 10.1016/j.neuropharm.2024.110161

{"title":"Expression of sensitized β2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats","authors":"","doi":"10.1016/j.neuropharm.2024.110161","DOIUrl":"10.1016/j.neuropharm.2024.110161","url":null,"abstract":"<div><p>Ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) are important for nicotine reinforcement. To determine whether and to what extent these receptors are sufficient for nicotine reinforcement, we expressed β2Leu9′Ser (i.e. sensitized) nAChR subunits in the VTA of adult male rats and assessed the nicotine dose-response relationship in intravenous self-administration (SA). β2Leu9′Ser rats self-administered nicotine doses 50–100 fold lower than the lowest doses that control rats would respond for. Expression of WT β2 subunits confirmed that this enhanced sensitivity to nicotine was due to the Leu9′Ser mutation in β2. Higher unit doses were associated with strong escalation in β2Leu9′Ser rats over 17 fixed ratio sessions. Escalation was minimal or absent in control rats at the same unit doses. In progressive ratio SA, β2Leu9′Ser rats exhibited higher breakpoints than control rats when the nicotine unit dose was 1.5 μg/kg/inf or higher. In intermittent access SA, β2Leu9′Ser rats exhibited response patterns very similar to control rats. By adding nicotine dose-response data, progressive ratio assays, and intermittent access results that rule out stereotypy, these data significantly extend our previous finding that nicotine activation of the mesolimbic dopamine pathway is sufficient for nicotine reinforcement.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274200","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}

引用次数: 0