Neuropharmacology最新文献

Genetic inactivation of the CRF2 receptor eliminates morphine-induced sociability deficits in female mice

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-22 DOI: 10.1016/j.neuropharm.2025.110480

Angelo Contarino

Social behavior deficits, such as poor sociability and social isolation, are key clinical features of substance use disorders. The corticotropin-releasing factor (CRF) system may underlie the effects of substances of abuse but its implication in substance-induced social behavior deficits remains largely unknown. CRF signaling is mediated by two receptor types, termed CRF₁ and CRF₂. Using the genetic mouse model of CRF₂ receptor-deficiency and the three-chamber task for sociability, the present studies examined the specific role for the CRF₂ receptor in sociability deficits induced by morphine. Notably, to assess possible sex-linked differences, female and male CRF₂ receptor wild-type (CRF₂ WT) or knockout (CRF₂ KO) mice were used. Intraperitoneal administration of morphine (1 mg/kg) reliably eliminated the preference for an unfamiliar same-sex conspecific over an object in female CRF₂ WT, but not in CRF₂ KO, mice, revealing a key role for the CRF₂ receptor in opiate-induced sociability deficits. In contrast, morphine almost significantly and similarly reduced the preference for an unfamiliar same-sex conspecific over an object in male CRF₂ WT and CRF₂ KO mice, indicating no role for the CRF₂ receptor. Notably, treatment with morphine never affected distance travelled during the three-chamber test, indicating that CRF₂ receptor-dependent or -independent opiate effects were specific to social behavior. The present findings provide initial evidence of a critical sex-linked role for the CRF₂ receptor in social behavior deficits induced by opiate substances, suggesting new, sex-customized, therapeutic strategy for opioid use disorders.

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引用次数: 0

ACVR1 drives neuropathic pain by regulating NLRP3-Induced neuronal pyroptosis through the p38 and Smad1/5/8 pathways

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-16 DOI: 10.1016/j.neuropharm.2025.110469

Xiaoxu Zhang , Yuxin Miao , Zongxiao Li , Haoyue Xu , Zejun Niu

Background

Neuropathic pain is characterized by sustained pain hypersensitivity caused by nerve injury. The molecular mechanisms underlying this condition remain poorly understood. This study aims to elucidate the role of ACVR1 and its downstream pathways in mediating neuropathic pain through neuronal pyroptosis and neuroinflammation.

Methods

A spared nerve injury (SNI) model was established both in male and female mouse to induce neuropathic pain. Behavioral tests, Western blot, PCR, and immunofluorescence were used to assess the expression of ACVR1, p-Smad1/5/8, p-p38, and pyroptosis-related proteins (NLRP3, Caspase-1, and GSDMD-N). ACVR1, p38, and Smad1/5/8 were pharmacologically inhibited to evaluate their roles in neuropathic pain and pyroptosis.

Results

Behavioral analysis confirmed successful SNI model establishment, marked by reduced paw withdrawal thresholds (PWT). Protein and mRNA expression analysis revealed significant upregulation of ACVR1, p-Smad1/5/8, and p-p38 in the spinal cord, particularly in neurons. Furthermore, SNI enhanced pyroptosis-related protein expression, including NLRP3, Caspase-1, GSDMD-N, IL-1β and IL-18. Inhibition of ACVR1 alleviated mechanical allodynia, reduced neuronal pyroptosis, and decreased serum IL-1β and IL-18 levels. Similarly, p38 inhibition mitigated NLRP3-induced pyroptosis without altering ACVR1 expression. In contrast, Smad1/5/8 inhibition by DMH-1 effectively reduced pyroptosis and inflammation via NLRP3 but had no effect on p38 phosphorylation. Combined p38 and Smad1/5/8 pathway inhibition synergistically decreased pyroptosis-related protein expression, highlighting their interactive roles in ACVR1-mediated neuropathic pain.

Conclusion

These findings suggest that ACVR1 exacerbates neuropathic pain by activating neuronal pyroptosis and neuroinflammation via the p38 and Smad1/5/8 pathways. Targeting ACVR1 and its downstream signaling pathways may offer novel therapeutic strategies for neuropathic pain.

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引用次数: 0

The major component of Heteractis magnifica sea anemone venom, RpIII, exhibits strong subtype selectivity for insects over mammalian voltage-gated sodium channels

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-15 DOI: 10.1016/j.neuropharm.2025.110466

Oksana Sintsova , Steve Peigneur , Rimma Kalina , Nadezhda Otstavnykh , Mikhail Garbuz , Anna Klimovich , Nadezhda Priymenko , Margarita Shamatova , Aleksandra Pavlenko , Sergey Kozlov , Irina Gladkikh , Marina Isaeva , Jan Tytgat , Elena Leychenko

Voltage-gated sodium channels (Na_V) are molecular targets for the development of drugs for the treatment of diseases such as epilepsy, neuropathic pain, long QT syndrome, etc., as well as for insecticides. Therefore, the search for novel selective Na_V channel ligands is relevant. Using amplicon deep sequencing of tentacle cDNA libraries from sea anemones Heteractis magnifica, 36 transcripts related to RpIII neurotoxin, a Na_V channel modulators, were revealed. The recombinant RpIII was moderately toxic for mice (LD₅₀ 0.030 ± 0.004 mg/kg) but did not demonstrate any activity towards Na_V in human SH-SY5Y cells. The toxin inhibited inactivation of heterologously expressed mammalian, insect, and arachnid Na_V channels with higher specificity to insect channels. Cockroach (Blattella germanica) sodium channel BgNa_V1 (EC₅₀ of 2.4 ± 0.2 nM) and yellow fever mosquito (Aedes aegypti) channel AaNa_V1 (EC₅₀ of 1.5 ± 0.3 nM) were the most sensitive to RpIII, while mammals Na_V had EC₅₀ values above 100 nM except mNa_V1.6 (EC₅₀ of 43.8 ± 3.6 nM). The low nanomolar RpIII affinity to insect AaNa_V1 may be explained by the extensive intermolecular contacts found by docking study. According to the predicted data, the toxin lands on the ion channel between voltage-sensing domain IV and pore domain I, also known as toxin site 3, followed by stabilizing the channels in the open state what was measured at electrophysiological experiments.

{"title":"The major component of Heteractis magnifica sea anemone venom, RpIII, exhibits strong subtype selectivity for insects over mammalian voltage-gated sodium channels","authors":"Oksana Sintsova , Steve Peigneur , Rimma Kalina , Nadezhda Otstavnykh , Mikhail Garbuz , Anna Klimovich , Nadezhda Priymenko , Margarita Shamatova , Aleksandra Pavlenko , Sergey Kozlov , Irina Gladkikh , Marina Isaeva , Jan Tytgat , Elena Leychenko","doi":"10.1016/j.neuropharm.2025.110466","DOIUrl":"10.1016/j.neuropharm.2025.110466","url":null,"abstract":"<div><div>Voltage-gated sodium channels (Na<sub>V</sub>) are molecular targets for the development of drugs for the treatment of diseases such as epilepsy, neuropathic pain, long QT syndrome, etc., as well as for insecticides. Therefore, the search for novel selective Na<sub>V</sub> channel ligands is relevant. Using amplicon deep sequencing of tentacle cDNA libraries from sea anemones <em>Heteractis magnifica</em>, 36 transcripts related to RpIII neurotoxin, a Na<sub>V</sub> channel modulators, were revealed. The recombinant RpIII was moderately toxic for mice (LD<sub>50</sub> 0.030 ± 0.004 mg/kg) but did not demonstrate any activity towards Na<sub>V</sub> in human SH-SY5Y cells. The toxin inhibited inactivation of heterologously expressed mammalian, insect, and arachnid Na<sub>V</sub> channels with higher specificity to insect channels. Cockroach (<em>Blattella germanica</em>) sodium channel BgNa<sub>V</sub>1 (EC<sub>50</sub> of 2.4 ± 0.2 nM) and yellow fever mosquito (<em>Aedes aegypti</em>) channel AaNa<sub>V</sub>1 (EC<sub>50</sub> of 1.5 ± 0.3 nM) were the most sensitive to RpIII, while mammals Na<sub>V</sub> had EC<sub>50</sub> values above 100 nM except mNa<sub>V</sub>1.6 (EC<sub>50</sub> of 43.8 ± 3.6 nM). The low nanomolar RpIII affinity to insect AaNa<sub>V</sub>1 may be explained by the extensive intermolecular contacts found by docking study. According to the predicted data, the toxin lands on the ion channel between voltage-sensing domain IV and pore domain I, also known as toxin site 3, followed by stabilizing the channels in the open state what was measured at electrophysiological experiments.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110466"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838379","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

Luteolin attenuates trimethyltin chloride-induced hippocampal neurotoxicity through SIRT3/NRF2/HO-1 activation

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-15 DOI: 10.1016/j.neuropharm.2025.110461

Ning Ding , Pengyu Wang , Yu Fang , Yuanyuan Hu , Wei Wang , Jiping Wei , Jun Yu , Fei Cai

Trimethyltin chloride (TMT), a potent neurotoxicant, induces hippocampal damage associated with neuroinflammation and synaptic dysfunction, mimicking key features of neurodegenerative disorders. Luteolin (LUT), a natural flavonoid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic candidate. This study investigated the neuroprotective effects of LUT against TMT-induced hippocampal damage and explored the underlying mechanisms involving the SIRT3/NRF2/HO-1 signaling pathway.

In a murine model, LUT treatment (20 mg/kg, 14 days) significantly alleviated TMT-induced behavioral deficits, seizures, and ultrastructural hippocampal damage. Mechanistically, LUT restored synaptic protein expression (PSD95, SYN1, SYP) and suppressed neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-18) and glial activation (GFAP, IBA1). In vitro studies using SIRT3 inhibition confirmed the pathway's centrality to LUT's effects.

These results position LUT as a multi-target therapeutic candidate for hippocampal-related disorders, with dual efficacy in synaptic repair and anti-inflammatory modulation. Critically, this work bridges preclinical findings to clinical translation, suggesting LUT's applicability in neurotoxicant exposure scenarios or early neurodegenerative disease interventions. Further validation of bioavailability and safety profiles could accelerate its transition to clinical trials.

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引用次数: 0

Behavioral economics of polysubstance use: The role of orexin-1 receptors in nicotine-induced augmentation of synthetic opioid consumption

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-15 DOI: 10.1016/j.neuropharm.2025.110467

Sarah C. Honeycutt, Elizabeth A. Gilles-Thomas, David D. Lichte, Shannon L. McSain, Ashmita Mukherjee, Gregory C. Loney

Nicotine and opioid use disorders are highly comorbid in clinical populations. Ongoing nicotine administration facilitates opioid consumption in both rodents and humans. Moreover, preclinical studies support that former exposure to nicotine solely during adolescence augments opioid consumption in adulthood similarly to acute nicotine administration. This suggests that developmental nicotine exposure persistently alters the neural substrates underlying motivation in a manner that resembles the acute pharmacological actions of nicotine. The orexin system mediates motivation to consume opioids in large part through signaling at orexin-1 receptors (ORX1Rs). Both developmental nicotine exposure and acute nicotine administration profoundly alter functioning of the orexin system which may mediate the reinforcing enhancing properties of nicotine. Here, we used behavioral economic procedures to generate demand curves for consumption of the synthetic, short-acting, μ-opioid receptor agonist remifentanil (RMF) in adulthood following prior adolescent nicotine exposure (ANE) and again following reintroduction of acute nicotine administration (ANA). We found that ANE was sufficient to augment multiple indices of the motivational value of RMF in adulthood and these effects were further exacerbated by ANA given during RMF self-administration sessions. Additionally, we demonstrate that systemic antagonism of ORX1Rs with SB-334867 is more efficacious in limiting motivation for RMF in nicotine-exposed rats relative to controls and this differential efficacy was even greater in ANA conditions relative to former ANE. These findings support that nicotine-induced facilitation of orexin signaling may mechanistically contribute to augmented opioid consumption offering critical insight for treatment options for a population that is particularly vulnerable to developing opioid use disorder.

{"title":"Behavioral economics of polysubstance use: The role of orexin-1 receptors in nicotine-induced augmentation of synthetic opioid consumption","authors":"Sarah C. Honeycutt, Elizabeth A. Gilles-Thomas, David D. Lichte, Shannon L. McSain, Ashmita Mukherjee, Gregory C. Loney","doi":"10.1016/j.neuropharm.2025.110467","DOIUrl":"10.1016/j.neuropharm.2025.110467","url":null,"abstract":"<div><div>Nicotine and opioid use disorders are highly comorbid in clinical populations. Ongoing nicotine administration facilitates opioid consumption in both rodents and humans. Moreover, preclinical studies support that former exposure to nicotine solely during adolescence augments opioid consumption in adulthood similarly to acute nicotine administration. This suggests that developmental nicotine exposure persistently alters the neural substrates underlying motivation in a manner that resembles the acute pharmacological actions of nicotine. The orexin system mediates motivation to consume opioids in large part through signaling at orexin-1 receptors (ORX1Rs). Both developmental nicotine exposure and acute nicotine administration profoundly alter functioning of the orexin system which may mediate the reinforcing enhancing properties of nicotine. Here, we used behavioral economic procedures to generate demand curves for consumption of the synthetic, short-acting, μ-opioid receptor agonist remifentanil (RMF) in adulthood following prior adolescent nicotine exposure (ANE) and again following reintroduction of acute nicotine administration (ANA). We found that ANE was sufficient to augment multiple indices of the motivational value of RMF in adulthood and these effects were further exacerbated by ANA given during RMF self-administration sessions. Additionally, we demonstrate that systemic antagonism of ORX1Rs with SB-334867 is more efficacious in limiting motivation for RMF in nicotine-exposed rats relative to controls and this differential efficacy was even greater in ANA conditions relative to former ANE. These findings support that nicotine-induced facilitation of orexin signaling may mechanistically contribute to augmented opioid consumption offering critical insight for treatment options for a population that is particularly vulnerable to developing opioid use disorder.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110467"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869431","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

Activation of Epac2 improves Aβ-induced impairment of memory retrieval in an acute model of Alzheimer's disease

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-14 DOI: 10.1016/j.neuropharm.2025.110468

Tong Zhang , Yuequ Zhang , Pascal Chameau , Tingting Chen , Alejandro Marmolejo-Garza , Wanda Douwenga , Amalia M. Dolga , Helmut W. Kessels , Martina Schmidt , Ulrich L.M. Eisel

Impaired memory retrieval is one of the cognitive markers in the early stage of Alzheimer's Disease (AD). Previous studies report that exchange protein directly activated by cAMP 2 (Epac2) plays a specific and time-limited role in promoting memory retrieval. In this study, we investigated the effect of a novel Epac2 activator, S220, on neuronal and synaptic activities, and memory impairment in an acute AD mouse model. S220 treatment increased the firing rate of action potential and intracellular calcium in primary neuronal cultures. Moreover, S220 treatment increased synaptic currents in CA1 neurons. In the acute AD mouse model, intrahippocampal injection of amyloid-β (Aβ) oligomers impaired memory performance. Notably, administering S220 20 min before retention of contextual fear conditioning recovered the Aβ-induced memory impairment, suggesting an enhancing effect on memory retrieval. Collectively, our data demonstrate that the novel Epac2 activator S220 promotes synaptic communication and neuronal firing, and thereby improves Aβ-induced memory impairment via enhancing memory retrieval, indicating the role of Epac2 as a potential treatment target for AD.

{"title":"Activation of Epac2 improves Aβ-induced impairment of memory retrieval in an acute model of Alzheimer's disease","authors":"Tong Zhang , Yuequ Zhang , Pascal Chameau , Tingting Chen , Alejandro Marmolejo-Garza , Wanda Douwenga , Amalia M. Dolga , Helmut W. Kessels , Martina Schmidt , Ulrich L.M. Eisel","doi":"10.1016/j.neuropharm.2025.110468","DOIUrl":"10.1016/j.neuropharm.2025.110468","url":null,"abstract":"<div><div>Impaired memory retrieval is one of the cognitive markers in the early stage of Alzheimer's Disease (AD). Previous studies report that exchange protein directly activated by cAMP 2 (Epac2) plays a specific and time-limited role in promoting memory retrieval. In this study, we investigated the effect of a novel Epac2 activator, S220, on neuronal and synaptic activities, and memory impairment in an acute AD mouse model. S220 treatment increased the firing rate of action potential and intracellular calcium in primary neuronal cultures. Moreover, S220 treatment increased synaptic currents in CA1 neurons. In the acute AD mouse model, intrahippocampal injection of amyloid-β (Aβ) oligomers impaired memory performance. Notably, administering S220 20 min before retention of contextual fear conditioning recovered the Aβ-induced memory impairment, suggesting an enhancing effect on memory retrieval. Collectively, our data demonstrate that the novel Epac2 activator S220 promotes synaptic communication and neuronal firing, and thereby improves Aβ-induced memory impairment via enhancing memory retrieval, indicating the role of Epac2 as a potential treatment target for AD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110468"},"PeriodicalIF":4.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835056","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

Aged mice exhibit faster acquisition of intravenous opioid self-administration with variable effects on intake

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-12 DOI: 10.1016/j.neuropharm.2025.110464

Amanda L. Sharpe , Laci R. Liter , Darius Donohue , Kelsey A. Carter , Patricia Vangeneugden , Sofia M. Weaver , Michael B. Stout , Michael J. Beckstead

Although opioid abuse is more prevalent in young individuals, the rates of opioid use, overdose, and use disorders continue to climb among the elderly. Little is known about the biology underlying abuse potential in a healthy, aged population, in part due to technical and logistical difficulties testing intravenous self-administration in aged rodents. The goal of this study was to address a critical gap in the literature regarding age-dependent effects in opioid (remifentanil and fentanyl) self-administration. Male and female C57Bl/6J and C57Bl/6NJ mice were divided into young (mean: 19 weeks) and old (mean: 101 weeks) groups and were trained to self-administer intravenous fentanyl or remifentanil in daily operant sessions. Acquisition, intake, and cue-responding after forced abstinence were measured for both drugs, and a dose-response curve and dose-escalation were conducted for remifentanil and fentanyl, respectively. Surprisingly, old mice learned to self-administer both remifentanil and fentanyl faster and more accurately than young mice. Baseline intake of remifentanil was also greater in old mice compared to the young group; however, we did not see increased intake of fentanyl with age at either dose tested. Furthermore, old mice showed greater responding for cues previously associated with remifentanil after a forced abstinence, but this result was not observed with fentanyl. This first report of opioid self-administration in greater than 20-month-old mice suggests that old mice have an increased vulnerability for opioid use compared to younger counterparts, underscoring the importance of future work to uncover the biological mechanisms that are responsible.

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引用次数: 0

The role of testosterone in modulating positive and negative empathy in social interactions

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-12 DOI: 10.1016/j.neuropharm.2025.110465

Shiwei Zhuo , Yinhua Zhang , Chennan Lin , Wen Wu , Weiwei Peng

Empathy encompasses both negative (e.g., distress) and positive (e.g., shared joy) dimensions, yet the effects of testosterone on positive empathy and its modulation of intrinsic neural dynamics remain underexplored. This double-blind, placebo-controlled study examined how testosterone influences neural sensitivity to empathy within social inclusion and exclusion contexts, as well as its impact on resting-state EEG microstates—millisecond-scale transient patterns of brain activity. Healthy male participants received either testosterone or placebo before completing resting-state EEG recordings and an empathy task featuring social scenarios. While self-reported empathy ratings remained unchanged, testosterone amplified neurophysiological responses: it enhanced anterior N2 amplitude (250–310 ms), associated with negative empathy toward social exclusion, and increased posterior α-event-related desynchronization (8.28–10 Hz; 1226–1901 ms), linked to positive empathy during social inclusion. These findings suggest that testosterone enhances neural responsiveness to both threatening and affiliative social cues, reinforcing its role in adaptive social vigilance. Resting-state EEG microstate analysis further revealed that testosterone prolonged the temporal dominance of microstate E—a centro-parietal activity pattern associated with interoceptive awareness and emotional processing. Notably, these microstate E changes predicted increased emotional empathy across both positive and negative contexts. Together, our findings suggest that testosterone indirectly enhances empathy-related responsiveness by amplifying baseline interoceptive sensitivity to socially salient stimuli. These dual effects—enhanced intrinsic interoceptive processing and heightened neural reactivity to social cues—position testosterone as a key neuromodulator of context-adaptive social perception.

移情包括消极（如痛苦）和积极（如分享快乐）两个方面，但睾酮对积极移情的影响及其对内在神经动态的调节作用仍未得到充分探索。这项双盲安慰剂对照研究考察了睾酮如何影响神经系统在社会包容和排斥背景下对移情的敏感性，以及睾酮对静息态脑电图微态--毫秒级瞬时大脑活动模式--的影响。健康男性参与者在完成静息态脑电记录和以社会情景为特色的移情任务之前，会接受睾酮或安慰剂治疗。睾酮增强了前N2振幅（250-310毫秒），这与对社会排斥的负移情有关；睾酮增强了后α事件相关非同步化（8.28-10赫兹；1226-1901毫秒），这与社会包容过程中的正移情有关。这些研究结果表明，睾酮能增强神经对威胁性和附属性社会线索的反应能力，从而加强其在适应性社会警觉中的作用。静息态脑电图微态分析进一步显示，睾酮延长了微态E的时间优势--微态E是顶叶中央的一种活动模式，与内感知意识和情绪处理有关。值得注意的是，这些微态 E 的变化预示着情感共鸣在积极和消极情境中都会增加。总之，我们的研究结果表明，睾酮通过放大对社会显著刺激的基线内感知敏感性，间接增强了与移情相关的反应能力。这些双重效应--增强内在感受性处理和提高对社会线索的神经反应--将睾酮定位为情境适应性社会感知的关键神经调节器。

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引用次数: 0

Kinsenoside attenuates ER stress and inhibits inflammatory responses through IL-10/STAT/SOCS3 pathway in chronic pain relief

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-11 DOI: 10.1016/j.neuropharm.2025.110463

Wei Wang , Yingzhuo Ding , Chunxia Yu , Qingqing Chi , Xia Fu , Mengjiao Deng , Dongxia Duan , Jinbao Wei , Ronghua Ding , Yufei Xi , Qin Li , Le Ma

Neuro-inflammation contributes to neuropathic pain by sensitizing ionic channels. Kinsenoside, a traditional Chinese medicine, has recognized anti-inflammatory properties. However, it remains unclear whether kinsenoside can be used for pain therapy. Network pharmacology analysis revealed that 57 % of its targets are associated with pain, including inflammation and synaptic transmission. The analgesic effects of kinsenoside were confirmed in SNL and formalin rat models, with ED50 values of 47.99 μg and 36.80 μg, respectively. Transcriptome and WGCNA analyses indicated the involvement of cytokine release, anti-inflammatory activity, and synapse enrichment in the blue module. Furthermore, we confirmed that kinsenoside's efficacy was mainly mediated by IL-10 induction, phosphorylation of STAT3, and SOCS3 expression. Pretreatment with kinsenoside significantly inhibited the release of TNF-α, IL-1β, and IL-6. Kinsenoside also attenuated ER stress in both microglia and neural cells. Molecular docking analysis demonstrated significantly high binding energies of IL-10, STAT3, and SOCS3 with MHC. Additionally, whole-cell recordings revealed that bath application of kinsenoside reduced the frequency and amplitude of spinal glutamatergic transmission in a dose-dependent manner. In summary, pharmacological prediction and biological validation collectively indicate that kinsenoside significantly exerts significant analgesic effects by attenuating ER stress and inhibiting inflammatory responses via the IL-10/p-STAT3/SOCS3 axis, precisely regulating spinal glutamatergic transmission for pain relief.

神经炎症会使离子通道敏感，从而导致神经性疼痛。人参皂甙是一种传统中药，具有公认的抗炎特性。然而，人参皂苷是否可用于疼痛治疗仍不清楚。网络药理学分析表明，其 57% 的靶点与疼痛有关，包括炎症和突触传递。在SNL和福尔马林大鼠模型中，人参皂苷的镇痛效果得到了证实，ED50值分别为47.99微克和36.80微克。转录组和 WGCNA 分析表明，蓝色模块涉及细胞因子释放、抗炎活性和突触富集。此外，我们还证实人参皂苷的功效主要由 IL-10 诱导、STAT3 磷酸化和 SOCS3 表达介导。人参皂苷的预处理能显著抑制 TNF-α、IL-1β 和 IL-6 的释放。人参皂苷还能减轻小胶质细胞和神经细胞的ER应激。分子对接分析表明，IL-10、STAT3 和 SOCS3 与 MHC 的结合能明显较高。此外，全细胞记录显示，沐浴应用人参皂苷可以剂量依赖的方式降低脊髓谷氨酸能传导的频率和振幅。总之，药理预测和生物学验证共同表明，人参皂苷通过IL-10/p-STAT3/SOCS3轴减弱ER应激和抑制炎症反应，精确调节脊髓谷氨酸能传导以缓解疼痛，从而显著发挥镇痛作用。

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引用次数: 0

Demethylase FTO in the cerebrospinal fluid-contacting nucleus of mice contributes to neuropathic pain via mediating m6A demethylation of P2rx4 mRNA

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-04-11 DOI: 10.1016/j.neuropharm.2025.110462

Yu-Ting Zhang, Wei-Long Huang, Yi-Jun Zhang, Li-Cai Zhang

N6-methyladenosine (m6A) modification plays a crucial role in pain regulation by modulating pain-related gene expression. The cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) is closely associated with pain, and downregulation of P2X4 receptor (P2X4R) expression in this region alleviates hyperalgesia. However, the relationship between m6A modification and P2X4R in CSF-contacting nucleus remains unclear. This study aims to investigate the role and potential mechanisms of the m6A demethylase fat mass and obesity-associated protein (FTO) and P2X4R in neuropathic pain (NP) induced by spared nerve injury (SNI) in male mice. We observed decreased m6A levels and upregulated FTO expression in the CSF-contacting nucleus of SNI mice. FTO was primarily expressed in neurons of the CSF-contacting nucleus, with symmetrical distribution across its bilateral regions. In CSF-contacting nucleus, FTO overexpression reduced m6A methylation and promoted pain, while FTO inhibition increased m6A levels and alleviated pain hypersensitivity. The administration of the FTO inhibitor meclofenamic acid (MA) into CSF-contacting nucleus alleviated pain. FTO regulated the expression of P2rx4 mRNA and protein in CSF-contacting nucleus. Furthermore, P2rx4 mRNA is a downstream target of FTO-mediated m6A demethylation. In summary, the m6A demethylase FTO contributes to NP by upregulating the expression of P2rx4 mRNA and protein through mediating m6A demethylation of P2rx4 mRNA. Therefore, the m6A demethylase FTO in CSF-contacting nucleus may represent a novel therapeutic target for NP.

N6-甲基腺苷（m6A）修饰通过调节疼痛相关基因的表达，在疼痛调节中发挥着至关重要的作用。脑脊液接触核（CSF-contacting nucleus）与疼痛密切相关，下调该区域的P2X4受体（P2X4R）表达可缓解痛觉减退。然而，m6A修饰与CSF接触核中P2X4R之间的关系仍不清楚。本研究旨在探讨 m6A 去甲基化酶脂肪量与肥胖相关蛋白（FTO）和 P2X4R 在雄性小鼠裸神经损伤（SNI）诱导的神经性疼痛（NP）中的作用和潜在机制。我们观察到，SNI 小鼠脑脊液接触核中 m6A 水平下降，FTO 表达上调。FTO 主要在 CSF 接触核的神经元中表达，并在其双侧区域对称分布。在 CSF 接触核中，FTO 过度表达会降低 m6A 甲基化水平并促进疼痛，而抑制 FTO 则会增加 m6A 水平并减轻痛觉过敏。向CSF接触核内注射FTO抑制剂甲氯芬那酸（MA）可减轻疼痛。FTO 调节 CSF 接触核中 P2rx4 mRNA 和蛋白的表达。此外，P2rx4 mRNA 是 FTO 介导的 m6A 去甲基化的下游靶点。综上所述，m6A 去甲基化酶 FTO 通过介导 P2rx4 mRNA 的 m6A 去甲基化，上调 P2rx4 mRNA 和蛋白的表达，从而促进 NP 的形成。因此，CSF接触核中的m6A去甲基化酶FTO可能是NP的一个新的治疗靶点。

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引用次数: 0