Neuropharmacology最新文献_第4页

Brain-penetrant microtubule-stabilizer epothilone B delays isoflurane-induced unconsciousness in mice 脑渗透微管稳定剂艾替隆B延缓异氟醚诱导的小鼠意识缺失。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.neuropharm.2026.110834

Yixiang Huang , Zitong Qiu , Xinyue Yu, Sophia Lee, Xiran Zeng, Abbie Chang, Michael C. Wiest

Inhalational anesthetics are currently believed to cause unconsciousness by acting on multiple molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Inhalational anesthetics including isoflurane bind to cytoskeletal microtubules (MTs), potentially contributing to causing unconsciousness. This possibility is supported by our demonstration of isoflurane resistance in rats treated once with the brain-penetrant MT-stabilizing drug epothilone B (epoB), and by a recent study in mice using a similar drug given daily over two weeks, which found increased sensitivity to isoflurane. To further characterize the contribution of MTs as functionally relevant targets of volatile anesthetics in mice, we measured latencies to loss of righting reflex (LORR) under isoflurane in mice injected once subcutaneously with vehicle or epoB.

We found significantly increased LORR latencies (i.e., anesthetic resistance) in 8 mg/kg epoB-treated mice on the day following injection, with reduced effects on subsequent days. The 29-s within-subject increase in LORR latencies is not large compared to the variability among different animals, but it represents a statistically large within-subject effect as represented by a Cohen's d of 0.8. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results support that binding of the inhalational anesthetic isoflurane to MTs contributes to LORR in mice, as it does in rats. Our findings support the Orchestrated Objective Reduction (Orch OR) model that posits consciousness as a property of a quantum physical state of neural MTs. We also discuss possible sex differences in anesthetic mechanisms suggested by our data.

目前认为，吸入麻醉剂通过作用于多种分子靶点，包括神经离子通道、受体、线粒体、突触蛋白和细胞骨架蛋白，导致无意识。包括异氟醚在内的吸入麻醉剂与细胞骨架微管（MTs）结合，可能导致无意识。这种可能性得到了我们的证明，即大鼠对异氟烷产生了耐药性，这些大鼠曾接受过一次脑渗透性mt稳定药物epothilone B （epoB）的治疗，而最近的一项研究发现，每天服用类似药物的小鼠在两周内对异氟烷的敏感性增加。为了进一步表征MTs作为挥发性麻醉药在小鼠中的功能相关靶点的作用，我们测量了异氟醚对小鼠的转直反射（LORR）丧失的潜伏期，这些小鼠皮下注射一次载药或epoB。我们发现8 mg/kg epob处理的小鼠在注射后一天的LORR潜伏期（即麻醉抗性）显著增加，随后几天的影响减弱。与不同动物之间的可变性相比，29秒内LORR潜伏期的增加并不大，但它代表了统计学上较大的被试内效应，用Cohen's d = 0.8表示。这种影响不能用反复接触异氟醚的耐受性来解释。我们的研究结果支持吸入麻醉剂异氟醚与MTs的结合有助于小鼠的LORR，正如它在大鼠中的作用一样。我们的研究结果支持了“协调客观还原”（Orch OR）模型，该模型认为意识是神经mt量子物理状态的一种属性。我们还讨论了数据所提示的麻醉机制中可能存在的性别差异。

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引用次数: 0

Acetazolamide alleviates motion sickness by inhibiting inner ear carbonic anhydrase 2 and reducing endolymph volume 乙酰唑胺通过抑制内耳碳酸酐酶2和减少内淋巴体积减轻晕动病

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-07 DOI: 10.1016/j.neuropharm.2026.110829

Miao-Miao Chen , Chao-Yue Tian , Jian-Gang Ge , Xia Li , Bin Peng , Wei Ji , Lei Cui , Li-Hua Xu , Zheng-Lin Jiang

Motion sickness is common in aerospace, aviation and maritime operations, and travel by vehicles or ships. Existing preventive and therapeutic drugs for motion sickness induce central nervous system (CNS)-related side effects; therefore, there is an urgent need to find new anti-motion sickness targets and to develop novel drugs with reduced adverse effects. In this study, we found that rotational stimulation significantly upregulated carbonic anhydrase 2 (CA2) expression in the inner ears of guinea pigs and mice. Pretreatment with acetazolamide (AZ), an inhibitor of carbonic anhydrase, effectively mitigated motion sickness-related behavioral symptoms in both species and inhibited increase in the inner ear endolymph volume induced by rotational stimulation. Further investigations revealed that AZ mediated its anti-motion sickness effects primarily through mechanisms involving the reduction of intracellular H⁺ concentrations in vestibular epithelial cells, inhibition of Na⁺-K⁺-ATPase activity, and modulation of intracellular Na⁺ and K⁺ homeostasis, thereby attenuating endolymph accumulation in the inner ear. This study demonstrated for the first time an involvement of the inner ear CA2 in the induction of motion sickness and an anti-motion sickness effect of its inhibitor AZ, providing a new strategy for developing anti-motion sickness drugs acting on the inner ear.

晕动病在航天、航空和海上作业以及乘坐车辆或船只旅行中很常见。现有的预防和治疗晕车的药物会引起中枢神经系统（CNS）相关副作用；因此，迫切需要寻找新的抗晕动病靶点，开发副作用较小的新药。在这项研究中，我们发现旋转刺激显著上调豚鼠和小鼠内耳中的碳酸酐酶2 （CA2）表达。乙酰唑胺（acetazolamide， AZ）是一种碳酸酐酶抑制剂，可以有效缓解两种动物的晕动病相关行为症状，并抑制旋转刺激引起的内耳内淋巴体积增加。进一步的研究表明，阿兹兰抗晕动病的作用机制主要包括降低前庭上皮细胞内H+浓度，抑制Na+-K+- atp酶活性，调节细胞内Na+和K+稳态，从而减轻内耳淋巴积聚。本研究首次证实了内耳CA2参与晕动病的诱导及其抑制剂AZ的抗晕动病作用，为开发内耳抗晕动病药物提供了新的策略。

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引用次数: 0

NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord NLRP10消融通过抑制脊髓过度的NIX/ lc3依赖性有丝分裂来减轻神经性疼痛。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.neuropharm.2026.110831

Xiaoyu Zhang, Jiale Sun, Fengtian Zhao, Ting Liu, Shangchen Yu, Wen Zhang, Xuebi Tian

Objective

Neuropathic pain (NP) presents a significant clinical challenge due to its physical and psychological impact and the lack of effective treatments. While the pathogenesis of NP remains incompletely understood, emerging evidence suggests that Nod-like receptor pyrin domain-containing protein 10 (NLRP10) participates in neurological disorders via neuroinflammation and mitochondrial autophagy. This study investigates roles of NLRP10 in NP pathogenesis and elucidates its mechanism in triggering neuroinflammation-mediated NIX/LC3-dependent mitochondrial dysfunction.

Methods

A spared nerve injury (SNI) mouse model was established to investigate neuropathic pain (NP) mechanisms. Pain behaviors were assessed using the mechanical pain withdrawal threshold (MPWT). Adeno-associated virus (AAV) was administered to the spinal dorsal horn (SDH) to downregulate NLRP10 or overexpress NIX. Neuroinflammatory responses and alterations in mitophagy were subsequently evaluated using Western blotting, ELISA, immunofluorescence, and transmission electron microscopy.

Results

SNI mice exhibited upregulated NLRP10 inflammasome expression and enhanced activation of the downstream NLRP12/ASC/Caspase1 pathway in the SDH. This was accompanied by significant increases in NIX/LC3 protein concentrations and decreased mitochondrial-related protein levels after surgery. NLRP10 predominantly colocalized with neuronal marker NeuN in SDH. Transmission electron microscopy revealed characteristic mitochondrial damage. Knockdown of NLRP10 with mNLRP10 effectively suppressed inflammatory activation, attenuated excessive mitochondrial autophagy, and alleviated NP manifestations. Notably, NIX overexpression abolished the protective effects of NLRP10 reduction in SNI mice.

Conclusion

In summary, our findings demonstrate that NLRP10 downregulation inhibit NLRP12/ASC/Caspase1 pathway activation and prevents pathological mitochondrial autophagy, ultimately alleviating NP. These results identify NLRP10 as a promising therapeutic target for NP management.

目的：神经性疼痛（NP）由于其对身体和心理的影响以及缺乏有效的治疗方法，给临床带来了重大挑战。虽然NP的发病机制尚不完全清楚，但新出现的证据表明，nod样受体pyrin结构域蛋白10 （NLRP10）通过神经炎症和线粒体自噬参与神经系统疾病。本研究探讨了NLRP10在NP发病机制中的作用，并阐明了其引发神经炎症介导的NIX/ lc3依赖性线粒体功能障碍的机制。方法：建立神经损伤（SNI）小鼠模型，探讨神经性疼痛（NP）的机制。采用机械疼痛戒断阈值（MPWT）评估疼痛行为。将腺相关病毒（AAV）注入脊髓背角（SDH），下调NLRP10或过表达NIX。随后使用Western blotting、ELISA、免疫荧光和透射电镜评估神经炎症反应和线粒体自噬的改变。结果：SNI小鼠在SDH中NLRP10炎性小体表达上调，下游NLRP12/ASC/Caspase1通路激活增强。这伴随着手术后NIX/LC3蛋白浓度的显著增加和线粒体相关蛋白水平的降低。NLRP10在SDH中主要与神经元标记物NeuN共定位。透射电镜显示特征性线粒体损伤。用mNLRP10敲低NLRP10可有效抑制炎症激活，减轻线粒体过度自噬，减轻NP表现。值得注意的是，NIX过表达消除了SNI小鼠NLRP10减少的保护作用。结论：综上所述，我们的研究结果表明，NLRP10下调可抑制NLRP12/ASC/Caspase1通路的激活，阻止病理性线粒体自噬，最终缓解NP。这些结果确定NLRP10是NP治疗的有希望的治疗靶点。

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引用次数: 0

Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats 外周α -2拮抗剂vatinoxan改善右美托咪定诱导的血管周围脑脊液流动，而不影响雌性大鼠的脑电图活动。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-02 DOI: 10.1016/j.neuropharm.2026.110828

Hanna Antila , Sonja C. Jalonen , Niklas Daniel Åke Persson , Martta Peltoniemi , Terhi J. Lohela , Tuomas O. Lilius

Background

The glymphatic concept represents a brain-wide perivascular fluid network contributing to brain metabolite clearance. Dexmedetomidine, a sedative α₂-adrenergic receptor agonist, enhances perivascular cerebrospinal fluid (CSF) flow by reducing central noradrenergic tone and inducing sleep-like electroencephalogram (EEG) slow-wave activity. Concurrently, α₂-adrenergic agonists modulate peripheral physiological functions, possibly influencing the central glymphatic dynamics. Utilizing peripherally restricted α₂-adrenergic antagonist vatinoxan, we evaluated the role of physiological parameters on the glymphatic-enhancing properties of dexmedetomidine.

Methods

The effects of vatinoxan on the EEG spectral signature of dexmedetomidine and physiological parameters were investigated in female Sprague-Dawley rats. The whole-body distribution of intracisternally infused radiolabeled CSF tracer technetium-99m-labeled diethylenetriaminepentaacetic acid ([⁹⁹ᵐTc]Tc-DTPA) was quantified utilizing single-photon emission computed tomography (SPECT).

Results

While vatinoxan had no influence on the EEG spectral signature of dexmedetomidine sedation, it alleviated the peripheral effects, such as peripheral vasoconstriction, hyperglycemia, diuresis, and hyperosmolality. Vatinoxan created a unique CSF tracer distribution pattern by elevating the cortical tracer availability, quantified as area under the time–activity curve (AUC_0-91), by 36 % (AUC_0–91 ratio, 1.36; 95 % CI, 1.0–1.8), increasing the maximum tracer concentration (C_max) in the intracranial space by 39 % (C_max ratio, 1.39; 95 % CI, 1.06–1.81), and decreasing the tracer availability in the spinal canal by 25 % (AUC_0–91 ratio, 0.75; 95 % CI, 0.66–0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360 % (AUC_0–91 ratio, 4.6; 95 % CI, 2.7–7.8).

Conclusions

Antagonism of peripheral α₂-adrenergic receptors with vatinoxan during dexmedetomidine sedation enhances perivascular CSF influx, irrespective of slow-wave activity.

背景：类淋巴的概念代表了一个全脑范围的血管周围流体网络，有助于脑代谢物的清除。右美托咪定是一种镇静的α2-肾上腺素能受体激动剂，通过降低中枢去甲肾上腺素能张力和诱导睡眠样脑电图（EEG）慢波活动来增强血管周围脑脊液（CSF）的流动。同时，α2-肾上腺素能激动剂调节外周生理功能，可能影响中枢淋巴动力学。利用外周限制性α2-肾上腺素能拮抗剂瓦替诺坦，我们评估了生理参数对右美托咪定淋巴增强特性的作用。方法：观察瓦替诺散对雌性Sprague-Dawley大鼠右美托咪定脑电图特征及生理参数的影响。利用单光子发射计算机断层扫描（SPECT）定量观察脑内灌注放射性标记脑脊液示踪剂锝-99m标记二乙烯三胺五乙酸（[99 Tc]Tc- dtpa）的全身分布。结果：瓦替诺散对右美托咪定镇静的脑电图频谱特征无影响，但可减轻外周血管收缩、高血糖、利尿、高渗等外周效应。Vatinoxan通过将皮质示踪剂可用性（量化为时间-活性曲线下面积（AUC0-91））提高36% (AUC0-91比值，1.36;95% CI, 1.0-1.8)，将颅内间隙最大示踪剂浓度（Cmax）提高39% (Cmax比值，1.39;95% CI, 1.06-1.81)，并将椎管内示踪剂可用性降低25% (AUC0-91比值，0.75;95% CI, 0.66-0.85)，创造了独特的脑脊液示踪剂分布模式。同时，vatinoxan促进了360%的示踪剂从中枢神经系统的输出（AUC0-91比值，4.6;95% CI, 2.7-7.8）。结论：在右美托咪定镇静期间，伐他诺坦对外周α2-肾上腺素能受体的拮抗作用增强了血管周围脑脊液内流，而与慢波活性无关。

{"title":"Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats","authors":"Hanna Antila , Sonja C. Jalonen , Niklas Daniel Åke Persson , Martta Peltoniemi , Terhi J. Lohela , Tuomas O. Lilius","doi":"10.1016/j.neuropharm.2026.110828","DOIUrl":"10.1016/j.neuropharm.2026.110828","url":null,"abstract":"<div><h3>Background</h3><div>The glymphatic concept represents a brain-wide perivascular fluid network contributing to brain metabolite clearance. Dexmedetomidine, a sedative α<sub>2</sub>-adrenergic receptor agonist, enhances perivascular cerebrospinal fluid (CSF) flow by reducing central noradrenergic tone and inducing sleep-like electroencephalogram (EEG) slow-wave activity. Concurrently, α<sub>2</sub>-adrenergic agonists modulate peripheral physiological functions, possibly influencing the central glymphatic dynamics. Utilizing peripherally restricted α<sub>2</sub>-adrenergic antagonist vatinoxan, we evaluated the role of physiological parameters on the glymphatic-enhancing properties of dexmedetomidine.</div></div><div><h3>Methods</h3><div>The effects of vatinoxan on the EEG spectral signature of dexmedetomidine and physiological parameters were investigated in female Sprague-Dawley rats. The whole-body distribution of intracisternally infused radiolabeled CSF tracer technetium-99m-labeled diethylenetriaminepentaacetic acid ([<sup>99</sup>ᵐTc]Tc-DTPA) was quantified utilizing single-photon emission computed tomography (SPECT).</div></div><div><h3>Results</h3><div>While vatinoxan had no influence on the EEG spectral signature of dexmedetomidine sedation, it alleviated the peripheral effects, such as peripheral vasoconstriction, hyperglycemia, diuresis, and hyperosmolality. Vatinoxan created a unique CSF tracer distribution pattern by elevating the cortical tracer availability, quantified as area under the time–activity curve (AUC<sub>0-91</sub>), by 36 % (AUC<sub>0–91</sub> ratio, 1.36; 95 % CI, 1.0–1.8), increasing the maximum tracer concentration (C<sub>max</sub>) in the intracranial space by 39 % (C<sub>max</sub> ratio, 1.39; 95 % CI, 1.06–1.81), and decreasing the tracer availability in the spinal canal by 25 % (AUC<sub>0–91</sub> ratio, 0.75; 95 % CI, 0.66–0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360 % (AUC<sub>0–91</sub> ratio, 4.6; 95 % CI, 2.7–7.8).</div></div><div><h3>Conclusions</h3><div>Antagonism of peripheral α<sub>2</sub>-adrenergic receptors with vatinoxan during dexmedetomidine sedation enhances perivascular CSF influx, irrespective of slow-wave activity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110828"},"PeriodicalIF":4.6,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900861","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

Nose-to-brain delivery of dopamine to the striatum of rats using neurotransmitter-loaded solid lipid nanoparticles: an in vivo study by brain microdialysis 使用装载神经递质固体脂质纳米颗粒将多巴胺经鼻至脑输送到大鼠纹状体：一项脑微透析的体内研究

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-02 DOI: 10.1016/j.neuropharm.2026.110830

Laura Dazzi , Giuseppe Talani , Giuseppe Trapani , Luigi Capasso , Annalucia Carbone , Sante Di Gioia , Massimo Conese , Adriana Trapani , Enrico Sanna

The intranasal route is a noninvasive method of delivering therapeutic compounds to the Central Nervous System (CNS). However, challenges associated with this method include reduced drug absorption, limited administered volume, insufficient nasal permeability, and enzymatic nasal metabolism. Nanotechnology-based delivery systems are being developed to overcome these limitations and improve drug availability and therapeutic effectiveness. In this regard, we recently developed dopamine (DA)-loaded solid lipid nanoparticles (DA-SLNs) using self-emulsifying Gelucire® 50/13 to form PEGylated SLNs for intranasal administration. To enhance mucoadhesion, we coated these lipid nanoparticles with the mucoadhesive cationic polymer glycolchitosan (GCS). In the present study, we performed microdialysis and electrophysiological experiments in a male rat model to evaluate the ability of GCS-DA-SLNs, when administered intranasally, to modify striatal extracellular DA concentrations and induce changes in the functional properties of striatal neurons. The results showed that intranasal administration of GCS-DA-SLNs at DA doses of 2.5 and 4 mg/kg significantly increased the extracellular concentration of DA (+130 ± 38 %) and the extracellular concentration of DOPAC (only at the lower dose of 1 mg/kg, by 70 ± 3 %). Ex vivo electrophysiological recordings in striatal neurons revealed that intranasal administration of GCS-DA-SLNs, at a DA dose of 4 mg/kg, but not 2.5, mg/kg, enhanced HCN-mediated I_h current amplitude. A similar effect was also observed in vitro when striatal neurons were exposed to DA or the D1 receptor agonist SKF81297. Overall, our data underscore the significant potential of using GCS-DA-SLN nanocarriers to efficiently deliver DA and other therapeutic compounds via the nose-to-brain pathway.

鼻内途径是一种将治疗性化合物输送到中枢神经系统（CNS）的非侵入性方法。然而，与该方法相关的挑战包括药物吸收减少、给药量有限、鼻渗透性不足和酶促鼻代谢。人们正在开发基于纳米技术的递送系统，以克服这些限制，提高药物的可用性和治疗效果。在这方面，我们最近开发了多巴胺（DA）负载的固体脂质纳米颗粒（DA- sln），使用自乳化Gelucire®50/13形成聚乙二醇化的sln用于鼻内给药。为了增强粘着性，我们用粘着阳离子聚合物糖聚糖（GCS）包覆了这些脂质纳米颗粒。在本研究中，我们在雄性大鼠模型中进行了微透析和电生理实验，以评估经鼻给药gcs -DA- sln改变纹状体细胞外DA浓度和诱导纹状体神经元功能特性变化的能力。结果表明，经鼻给药剂量为2.5和4 mg/kg的gcs -DA- sln显著增加DA细胞外浓度（+130±38%）和DOPAC细胞外浓度（仅在较低剂量为1 mg/kg时，增加70±3%）。纹状体神经元的离体电生理记录显示，以4 mg/kg（而非2.5 mg/kg）的DA剂量鼻内给药GCS-DA-SLNs可增强hcn介导的Ih电流振幅。当纹状体神经元暴露于DA或D1受体激动剂SKF81297时，在体外也观察到类似的效果。总的来说，我们的数据强调了使用GCS-DA-SLN纳米载体通过鼻到脑途径有效递送DA和其他治疗性化合物的巨大潜力。

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引用次数: 0

Spinal Shati/nat8l regulates mechanical hyperalgesia through NAAG-mGluR3 signaling in neuropathic pain 脊髓沙/ nat81通过NAAG-mGluR3信号调控神经性疼痛的机械性痛觉过敏。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-31 DOI: 10.1016/j.neuropharm.2025.110819

Keisuke Miyamoto , Kousuke Tatsuta , Kazuyuki Sumi , Kyosuke Uno , Kazuki Tokoro , Shin-ichi Muramatsu , Naotaka Izuo , Kazuhiko Kume , Atsumi Nitta , Masahiro Ohsawa

Shati/nat8l catalyzes the synthesis of N-acetylaspartate (NAA), a precursor for N-acetylaspartylglutamate (NAAG), an endogenous agonist of group II metabotropic glutamate receptor 3 (mGluR3). Although spinal mGluR3 is known to modulate nociceptive signaling, the functional role of Shati/nat8l in pain transmission has remained unclear. In this study, we investigated the involvement of spinal Shati/nat8l in mechanical nociceptive processing and neuropathic pain.

We found that Shati/nat8l knockout (Shati−/−) mice exhibited a significantly decreased mechanical pain threshold compared to wild-type controls. This hypersensitivity was reversed by adeno-associated virus (AAV)-mediated expression of Shati/nat8l in the spinal dorsal horn. Intrathecal administration of NAAG—but not NAA—restored mechanical thresholds in Shati−/− mice, and this effect was blocked by the group II mGluR antagonist LY341495. In addition, treatment with LY341495 showed antinociceptive effect in normal mice at higher doses. In a peripheral nerve injury model, expression of Shati/nat8l mRNA in the ipsilateral dorsal horn was significantly decreased. Importantly, AAV-mediated restoration of Shati/nat8l expression in the dorsal horn alleviated neuropathic mechanical hyperalgesia and normalized Shati/nat8l mRNA levels.

These findings suggest that downregulation of spinal Shati/nat8l contributes to mechanical hypersensitivity by impairing the NAAG-mGluR3 signaling pathway. Targeting the Shati/nat8l–NAAG–mGluR3 axis may offer a novel therapeutic strategy for the treatment of neuropathic pain.

Shati/nat8l可催化n -乙酰天冬氨酸（NAA）的合成，NAA是n -乙酰天冬氨酸谷氨酸（NAAG）的前体，NAAG是II组代谢型谷氨酸受体3 （mGluR3）的内源性激动剂。虽然已知脊髓mGluR3可以调节伤害性信号，但Shati/ nat81在疼痛传递中的功能作用仍不清楚。在这项研究中，我们研究了脊髓沙/ nat81在机械性伤害知觉加工和神经性疼痛中的参与。我们发现，与野生型对照相比，Shati/nat8l基因敲除（Shati-/-）小鼠的机械痛阈值显著降低。这种超敏反应被腺相关病毒（AAV）介导的脊髓背角Shati/ nat81的表达逆转。鞘内给药naag（而非naag）恢复了Shati-/-小鼠的机械阈值，这种作用被II组mGluR拮抗剂LY341495阻断。此外，LY341495在高剂量下对正常小鼠具有抗伤害感受性作用。在周围神经损伤模型中，同侧背角Shati/ nat81mrna的表达明显降低。重要的是，aav介导的背角Shati/nat8l表达的恢复减轻了神经性机械性痛觉过敏，并使Shati/nat8l mRNA水平正常化。这些发现表明，脊柱Shati/nat8l的下调通过损害NAAG-mGluR3信号通路参与机械超敏反应。靶向Shati/nat8l-NAAG-mGluR3轴可能为神经性疼痛的治疗提供一种新的治疗策略。

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引用次数: 0

TRPC6 mediates neuronal hyperexcitability in the lateral habenula to drive trigeminal neuralgia-associated anxiety TRPC6介导外侧缰神经高兴奋性驱动三叉神经痛相关焦虑

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.neuropharm.2025.110818

Fengxian Hu , Zhenling Liu , Xiaoman Min , Kaixin Zhang , Hengye Zhao , Wei Liu , Yi Tao , Qingyue Jia , Yaqing Gao , Xianrui Meng , Yu Wang , Hongyun Wu , Wenqiang Cui

Persistent facial and oral discomfort, particularly trigeminal neuralgia (TN), is frequently accompanied by anxiety, which has been closely linked to increased excitability of neurons in the lateral habenula (LHb). However, the mechanisms underlying this hyperexcitability remain unclear. Here, we show that partial transection of the infraorbital nerve (pT-ION) significantly upregulated the expression of transient receptor potential canonical 6 (TRPC6), β isoform of calcium/calmodulin-dependent protein kinase II (βCaMKII), phosphorylated extracellular regulated kinase (p-ERK), and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in the LHb. Pharmacological blockade of either TRPC6 or βCaMKII effectively reversed pT-ION-induced mechanical hypersensitivity and anxiety-like behaviors. TRPC6 overexpression in the LHb reproduced the behavioral and electrophysiological phenotypes observed in pT-ION mice, including increased LHb neuronal excitability. In contrast, bilateral knockdown of TRPC6 attenuated both pain- and anxiety-like behaviors and normalized neuronal activity in the LHb. Our study identified TRPC6 as a key mediator of LHb neuronal hyperexcitability, contributing to trigeminal neuralgia-associated pain and anxiety via the βCaMKII/ERK/CREB pathway, and suggests its potential as a target for treatment.

持续的面部和口腔不适，特别是三叉神经痛（TN），经常伴有焦虑，这与外侧缰（LHb）神经元兴奋性增加密切相关。然而，这种超兴奋性的机制尚不清楚。在这里，我们发现眶下神经的部分横断（pT-ION）显著上调了LHb中瞬时受体电位规范6 （TRPC6）、钙/钙调素依赖性蛋白激酶II （β camkii）的β亚型、磷酸化的细胞外调节激酶（p-ERK）和磷酸化的环腺苷单磷酸反应元件结合蛋白（p-CREB）的表达。药物阻断TRPC6或βCaMKII均可有效逆转pt - ion诱导的机械超敏反应和焦虑样行为。TRPC6在LHb中的过表达再现了在pT-ION小鼠中观察到的行为和电生理表型，包括LHb神经元兴奋性增加。相比之下，双侧TRPC6的敲低减轻了LHb的疼痛和焦虑样行为以及正常化的神经元活动。我们的研究发现TRPC6是LHb神经元高兴奋性的关键介质，通过βCaMKII/ERK/CREB通路促进三叉神经痛相关的疼痛和焦虑，并提示其作为治疗靶点的潜力。

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引用次数: 0

Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and A2a receptor-expressing medium spiny neurons in nucleus accumbens core and shell 羟考酮渴求的潜伏期与表达D1和A2a受体的伏隔核和壳中棘神经元中CP-AMPAR的上调有关。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-26 DOI: 10.1016/j.neuropharm.2025.110816

Kimberley A. Mount , Hayley M. Kuhn, Eun-Kyung Hwang, Madelyn M. Beutler, Marina E. Wolf

A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naïve animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions after forced abstinence from extended-access oxycodone or saline self-administration, using male and female wild-type and transgenic rats. Before incubation (abstinence days 1–2), CP-AMPAR upregulation was not detected in either D1 or A2a (D2) receptor-expressing MSN. After incubation had stably plateaued (abstinence days 17–33), CP-AMPARs were elevated in both MSN subtypes in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell prevents expression of oxycodone incubation. However, CP-AMPAR upregulation on both MSN subtypes contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.

治疗阿片类药物使用障碍的一个主要问题是长期戒断后的持续渴望。这已经在啮齿类动物身上用渴望的潜伏期模型进行了模拟，在这种模型中，线索诱导的药物寻求在自我戒断药物的第一周增加，然后在较长一段时间内保持高水平。包括羟考酮在内的几种阿片类药物的潜伏期已被报道，但对潜在的突触可塑性知之甚少。相反，可卡因和甲基苯丙胺渴望的培养依赖于伏隔核（NAc）中谷氨酸突触通过钙渗透AMPARs （CP-AMPARs）的结合而增强。在drug-naïve动物中，CP-AMPARs比钙不渗透性AMPARs具有更高的电导率，并具有其他独特的特性。本研究以雄性和雌性野生型和转基因大鼠为研究对象，研究了在强制戒断可酮或生理盐水后，NAc核和壳区中棘神经元（MSN）中AMPAR的传递。在孵育前（禁食1-2天），在表达D1或A2a （D2）受体的MSN中均未检测到CP-AMPAR上调。在孵育达到稳定的平台期（禁食17-33天）后，两个亚区两种MSN亚型的cp - ampar均升高。这些结果解释了先前的研究表明，将选择性CP-AMPAR拮抗剂注入NAc核或壳中可阻止氧可酮孵育的表达。然而，CP-AMPAR对两种MSN亚型的上调与可卡因和甲基苯丙胺培养后D1 MSN的选择性上调形成对比。我们的研究结果表明，尽管在MSN亚型特异性上存在差异，但CP-AMPAR上调在精神兴奋剂和羟考酮培养中具有共同作用。

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引用次数: 0

Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach 细胞模型探索抗精神病诱导代谢综合征的生物学基础：迈向个体特异性途径

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-24 DOI: 10.1016/j.neuropharm.2025.110814

Maria Fiore , Silvia Saltarelli , Laura De Mastro , Enrico D'Ambrosio , Antonia Ianniello , Alessandro Bertolino , Giulio Pergola , Maria Favia , Antonio Rampino

Background

Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). In vitro cell models of peripheral tissues provide a valid platform to investigate the biochemical and molecular alterations induced by SGAs at the peripheral level in conjunction with their effects on the central nervous system. This scoping review summarizes two decades of studies utilizing established cell lines and primary rodent cells to examine the direct dysmetabolic effects of antipsychotics (APs) on lipid and glucose metabolism, inflammatory pathways, and mitochondrial function.

Methods

We identified published scientific literature in the PubMed database using the following search strategy: (“antipsychotic” OR “olanzapine” OR “clozapine” OR “risperidone” OR “quetiapine” OR “haloperidol”) AND (“metabolic syndrome” OR “insulin action” OR “insulin resistance” OR “up-regulation” OR “down-regulation” OR “dyslipidemia”) AND (cell models).

Results

Out of 121 articles identified, 21 met the eligibility criteria and were included in the review, with their methods and findings organized according to the AP-affected biological processes implicated in MetS.

Conclusions

Independent studies on cell models confirm the AP-pathogenic role on gene and protein expression regulation involved in lipid and glucose metabolism, inflammatory processes, and impairments at the mitochondrial level.

In the final section of the manuscript, we highlight the potential of individual-specific stem-cell–based models, like induced pluripotent stem cells, to investigate gene-by-medication interactions relevant to AP-induced MetS. However, these stem-cell approaches fall outside the scope of the present review and were not included in our literature search.

背景：患有严重精神疾病的个体发生代谢综合征（MetS）的风险增加，部分原因是第二代抗精神病药物（SGAs）的代谢不良副作用。体外外周组织细胞模型为研究SGAs在外周水平诱导的生化和分子改变及其对中枢神经系统的影响提供了一个有效的平台。本综述总结了二十年来利用已建立的细胞系和原代啮齿动物细胞来研究抗精神病药物（APs）对脂质和葡萄糖代谢、炎症途径和线粒体功能的直接代谢不良影响的研究。方法我们使用以下搜索策略在PubMed数据库中识别已发表的科学文献：（抗精神病药）或“奥氮平”或“氯氮平”或“利培酮”或“喹硫平”或“氟哌啶醇”)和（代谢综合征”或“胰岛素作用”或“胰岛素抵抗”或“上调”或“下调”或“血脂异常”）和（细胞模型）。结果在121篇文章中，21篇符合入选标准，纳入了本综述，他们的方法和发现是根据与MetS相关的ap影响的生物学过程组织的。对细胞模型的独立研究证实了ap在脂质和糖代谢、炎症过程和线粒体水平损伤的基因和蛋白质表达调控中的致病作用。在论文的最后部分，我们强调了基于个体特异性干细胞模型的潜力，如诱导多能干细胞，研究与ap诱导的MetS相关的基因-药物相互作用。然而，这些干细胞方法不在本综述的范围之内，也没有包括在我们的文献检索中。

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引用次数: 0

Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility 短RFamide， CFamide和FCamide肽作为ASIC 3的新阳性调节剂，具有相似的增强作用，但可逆性不同。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110813

Maurizio Toft , Maëva Meynier , Hélène Lubrano Di Scampamorte , Cédric Vallée , Miguel Salinas , Peijun Zhang , Jessica Tacco , Anne-Sophie Gay , Emmanuel Bourinet , Eric Lingueglia , Emmanuel Deval

Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FR

\overline{CC}

RFamide) and a CFamide peptide (FR

\overline{CRC}

Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FR

\overline{CC}

RFamide peptide was much slower than those of FR

\overline{CRC}

Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR

\overline{CC}

RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs’ modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.

酸敏感离子通道（asic）是DEG/ENaC家族的成员，包括唯一已知的肽门控离子通道。虽然asic是由质子门控的，但它们也对肽敏感，并由软体动物FMRFamide和其他以RFamide基序结尾的哺乳动物神经肽调节。我们发现了一组合成的短修饰六肽，它们不仅以RFamide基序结尾，而且以CFamide和FCamide结尾，它们是ASIC3酸诱导活性的有效正向调节剂。我们重点研究了其中的两个，RFamide肽（FR RFamide）和CFamide肽（FR Famide），证明它们对ASIC3具有相似的特异性和作用。这两种多肽的增强作用是由于对脱敏作用的强烈减缓，导致酸性pH（≤pH6.6）诱导的电流量增加，表观亲和范围为1 ~ 5 μM。令人惊讶的是，FR RFamide肽的洗脱动力学比FR Famide和其他已知的RFamide肽慢得多，这表明它们的作用机制可能存在差异。计算模型和结构-功能分析揭示了这两种肽与ASIC3的非质子结合位点的相互作用，正如之前报道的其他RFamide肽一样，但我们的数据还表明FR RFamide可能直接或间接涉及质子结合域的其他作用。这些发现扩大了我们对肽对asic的调节的理解，鉴定了新的ASIC3短调节因子，包括具有新的CFamide和FCamide结尾基序的肽，并使用它们的冲刷动力学作为新参数显示了这些肽之间的差异。

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引用次数: 0