Appropriate processing of aversive information is essential for survival. We previously demonstrated that serotonin neurons in the median raphe nucleus (MRN) play a key role in such processing; however, MRN responses to predictive cues of aversive events remain unclear. Here, we found that the MRN serotonin neurons were activated by aversive air-puff stimuli but not by auditory cues predicting the air puff. Moreover, delayed activation of the ventral hippocampus-projecting MRN serotonin neurons, together with subsequent 5-HT2A receptor signaling, was required for aversion. These findings shed light on the roles of the hippocampus-projecting MRN serotonin neurons and elucidate their molecular mechanisms.
{"title":"Delayed response of the median raphe serotonin neurons projecting to the ventral hippocampus to aversive stimuli","authors":"Hinako Morishita , Harune Hori , Hiroyuki Kawai , Hisashi Shirakawa , Hitoshi Hashimoto , Kazuki Nagayasu","doi":"10.1016/j.jphs.2025.12.003","DOIUrl":"10.1016/j.jphs.2025.12.003","url":null,"abstract":"<div><div>Appropriate processing of aversive information is essential for survival. We previously demonstrated that serotonin neurons in the median raphe nucleus (MRN) play a key role in such processing; however, MRN responses to predictive cues of aversive events remain unclear. Here, we found that the MRN serotonin neurons were activated by aversive air-puff stimuli but not by auditory cues predicting the air puff. Moreover, delayed activation of the ventral hippocampus-projecting MRN serotonin neurons, together with subsequent 5-HT<sub>2A</sub> receptor signaling, was required for aversion. These findings shed light on the roles of the hippocampus-projecting MRN serotonin neurons and elucidate their molecular mechanisms.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 91-96"},"PeriodicalIF":2.9,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pericytes are perivascular cells that contribute to maintaining vascular integrity and central nervous system homeostasis. β2-microglobulin (B2M) is a component of the major histocompatibility complex class I molecule; it has recently been implicated in age-related and injury-associated inflammation. Here, we investigated the phenotypic and transcriptomic effects of B2M on mouse brain pericytes in vitro. B2M treatment increased Bromodeoxyuridine (BrdU) incorporation into the cultured pericytes as well as the number of Ki67-positive pericytes. Morphologically, B2M promoted pericyte extension. Toll-like receptor 4 (TLR4), one of the key molecules that regulates B2M function, was involved in the B2M-dependent pericyte proliferation. These findings were consistent with RNA-seq results showing differential expression of genes related to cell proliferation. These results suggest that B2M directly acts on pericytes and regulates part of their functional responses through TLR4 signaling.
{"title":"β2 microglobulin promotes pericyte proliferation through toll-like receptor 4","authors":"Yoshino Yonezu , Akiko Uyeda , Hidemi Misawa , Rieko Muramatsu","doi":"10.1016/j.jphs.2025.12.001","DOIUrl":"10.1016/j.jphs.2025.12.001","url":null,"abstract":"<div><div>Pericytes are perivascular cells that contribute to maintaining vascular integrity and central nervous system homeostasis. β<sub>2</sub>-microglobulin (B2M) is a component of the major histocompatibility complex class I molecule; it has recently been implicated in age-related and injury-associated inflammation. Here, we investigated the phenotypic and transcriptomic effects of B2M on mouse brain pericytes <em>in vitro</em>. B2M treatment increased Bromodeoxyuridine (BrdU) incorporation into the cultured pericytes as well as the number of Ki67-positive pericytes. Morphologically, B2M promoted pericyte extension. Toll-like receptor 4 (TLR4), one of the key molecules that regulates B2M function, was involved in the B2M-dependent pericyte proliferation. These findings were consistent with RNA-seq results showing differential expression of genes related to cell proliferation. These results suggest that B2M directly acts on pericytes and regulates part of their functional responses through TLR4 signaling.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 81-89"},"PeriodicalIF":2.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.jphs.2025.11.007
Olesia F. Moroz , Viktoriia I. Kravchenko , Alexander V. Zholos
Essential oils have long been recognized for their therapeutic potential, with growing interest in their molecular mechanisms of action in neurological health. Among emerging targets, polymodal Ca2+-permeable Transient Receptor Potential (TRP) cation channels have gained particular attention for their roles in neuronal signaling, synaptic plasticity, and modulation of cognitive, neurodegenerative, and psychological disorders. This review explores the ability of essential oil constituents to modulate TRP channels. The major channels to be discussed here include TRPV1, TRPM8, and TRPA1 and some other TRPVs and TRPMs. Some TRPC members have also been reviewed, albeit more briefly. Key bioactive compounds – including menthol, linalool, and eugenol – are highlighted for their ability to interact with TRP channels, while influencing neurophysiological pathways related to learning, memory, neuroinflammation, and emotional regulation. Preclinical evidence suggests these interactions may offer neuroprotective, anxiolytic, and antidepressant effects. However, challenges such as bioavailability, standardization, and safety remain barriers to clinical translation. This review underscores the therapeutic promise of essential oil constituents as modulators of TRP channels and outlines future directions for their integration into neurotherapeutic strategies.
{"title":"Constituents of essential oils as modulators of TRP channels: Focus on cognitive functions, neurodegenerative, and psychological diseases","authors":"Olesia F. Moroz , Viktoriia I. Kravchenko , Alexander V. Zholos","doi":"10.1016/j.jphs.2025.11.007","DOIUrl":"10.1016/j.jphs.2025.11.007","url":null,"abstract":"<div><div>Essential oils have long been recognized for their therapeutic potential, with growing interest in their molecular mechanisms of action in neurological health. Among emerging targets, polymodal Ca<sup>2+</sup>-permeable Transient Receptor Potential (TRP) cation channels have gained particular attention for their roles in neuronal signaling, synaptic plasticity, and modulation of cognitive, neurodegenerative, and psychological disorders. This review explores the ability of essential oil constituents to modulate TRP channels. The major channels to be discussed here include TRPV1, TRPM8, and TRPA1 and some other TRPVs and TRPMs. Some TRPC members have also been reviewed, albeit more briefly. Key bioactive compounds – including menthol, linalool, and eugenol – are highlighted for their ability to interact with TRP channels, while influencing neurophysiological pathways related to learning, memory, neuroinflammation, and emotional regulation. Preclinical evidence suggests these interactions may offer neuroprotective, anxiolytic, and antidepressant effects. However, challenges such as bioavailability, standardization, and safety remain barriers to clinical translation. This review underscores the therapeutic promise of essential oil constituents as modulators of TRP channels and outlines future directions for their integration into neurotherapeutic strategies.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 69-80"},"PeriodicalIF":2.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1016/j.jphs.2025.11.006
Yasushi Yabuki , Norifumi Shioda
Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid–liquid phase separation (LLPS) followed by a sol–gel transition in vitro, the key factors governing their phase transition remain to be elucidated in vivo. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol–gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.
神经退行性疾病，如阿尔茨海默病和帕金森病，在超老龄化社会中呈上升趋势。然而，朊病毒样蛋白（如α-突触核蛋白和Tau）聚集和繁殖的机制仍不清楚，这些蛋白与神经变性的发病机制有关。虽然已知朊病毒样蛋白在体外经历液-液相分离（LLPS），然后是溶胶-凝胶转变，但控制其相变的关键因素仍有待于在体内阐明。大多数朊病毒样蛋白被归类为RNA结合蛋白，最近的研究表明RNA在介导LLPS和随后的这些蛋白的溶胶-凝胶转化中起着关键作用。本文综述了RNA g -四重复合物（rG4s）作为神经退行性疾病病理关键分子的研究进展，并介绍了RNA诱导朊蛋白样蛋白相变的最新进展。
{"title":"RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery","authors":"Yasushi Yabuki , Norifumi Shioda","doi":"10.1016/j.jphs.2025.11.006","DOIUrl":"10.1016/j.jphs.2025.11.006","url":null,"abstract":"<div><div>Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid–liquid phase separation (LLPS) followed by a sol–gel transition <em>in vitro</em>, the key factors governing their phase transition remain to be elucidated <em>in vivo</em>. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol–gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 64-68"},"PeriodicalIF":2.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1016/j.jphs.2025.11.005
Yifan Shi , Pingping Xu , Jun-ichi Morishige , Yunze Yang , Tomohiro Iba , Naoto Nagata , Takashi Hosono , Ryo Miyazaki , Naoki Sakane , Masanori Ono , Tomoko Fujiwara , Hiroshi Fujiwara , Hitoshi Ando
Objective
This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle.
Methods
Female C57BL/6J mice were administered imeglimin either as a single oral dose at Zeitgeber time (ZT) 0 or 12 (acute study) or via a 0.2 % admixture in chow for 4 weeks (chronic study). Clock gene mRNA expression in skeletal muscle and liver was analyzed by quantitative real-time PCR.
Results
Acute imeglimin administration at ZT 12 increased the peak mRNA expression of clock genes (Nr1d1 and Dbp in skeletal muscle; Per2 in liver), whereas dosing at ZT 0 decreased Nr1d1 and Dbp in both tissues. In the chronic study, imeglimin decreased the peak expression of Nr1d1 and Dbp in skeletal muscle, while liver rhythms remained unchanged. Nampt and Sirt1 expression was unaffected in either tissue.
Conclusion
In this study, we demonstrated that imeglimin alters peripheral clock gene expression in healthy mice under both acute bolus administration and chronic mixed-feeding conditions. Further studies are warranted to clarify underlying mechanisms and their physiological relevance.
{"title":"Acute and chronic effects of imeglimin on peripheral circadian clocks in mice","authors":"Yifan Shi , Pingping Xu , Jun-ichi Morishige , Yunze Yang , Tomohiro Iba , Naoto Nagata , Takashi Hosono , Ryo Miyazaki , Naoki Sakane , Masanori Ono , Tomoko Fujiwara , Hiroshi Fujiwara , Hitoshi Ando","doi":"10.1016/j.jphs.2025.11.005","DOIUrl":"10.1016/j.jphs.2025.11.005","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle.</div></div><div><h3>Methods</h3><div>Female C57BL/6J mice were administered imeglimin either as a single oral dose at Zeitgeber time (ZT) 0 or 12 (acute study) or via a 0.2 % admixture in chow for 4 weeks (chronic study). Clock gene mRNA expression in skeletal muscle and liver was analyzed by quantitative real-time PCR.</div></div><div><h3>Results</h3><div>Acute imeglimin administration at ZT 12 increased the peak mRNA expression of clock genes (<em>Nr1d1</em> and <em>Dbp</em> in skeletal muscle; <em>Per2</em> in liver), whereas dosing at ZT 0 decreased <em>Nr1d1</em> and <em>Dbp</em> in both tissues. In the chronic study, imeglimin decreased the peak expression of <em>Nr1d1</em> and <em>Dbp</em> in skeletal muscle, while liver rhythms remained unchanged. <em>Nampt</em> and <em>Sirt1</em> expression was unaffected in either tissue.</div></div><div><h3>Conclusion</h3><div>In this study, we demonstrated that imeglimin alters peripheral clock gene expression in healthy mice under both acute bolus administration and chronic mixed-feeding conditions. Further studies are warranted to clarify underlying mechanisms and their physiological relevance.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 51-58"},"PeriodicalIF":2.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Quantitative assessment of gait abnormality is essential for osteoarthritis (OA) model. We aimed to establish a low-cost, non-invasive and markerless gait analysis pipeline using machine learning. Rat OA model was induced by intraarticular injection of monosodium iodoacetate, and walking behavior was recorded. Joint coordinates were analyzed using DeepLabCut, and hierarchical clustering based on our summarized features separated OA and healthy animals with high accuracy. Principal coordinates analysis demonstrated significant group separation while preserving intra-group variability. We developed a reproducible and non-biased method for gait analysis in OA rats, which can be applicable for pain and movement disorder models.
{"title":"Development of a quantitative gait analysis in an osteoarthritis rat model using machine learning","authors":"Shinya Takenouchi , Takashi Minato , Masahiro Fukuda , Koji Kobayashi , Takahisa Murata","doi":"10.1016/j.jphs.2025.11.004","DOIUrl":"10.1016/j.jphs.2025.11.004","url":null,"abstract":"<div><div>Quantitative assessment of gait abnormality is essential for osteoarthritis (OA) model. We aimed to establish a low-cost, non-invasive and markerless gait analysis pipeline using machine learning. Rat OA model was induced by intraarticular injection of monosodium iodoacetate, and walking behavior was recorded. Joint coordinates were analyzed using DeepLabCut, and hierarchical clustering based on our summarized features separated OA and healthy animals with high accuracy. Principal coordinates analysis demonstrated significant group separation while preserving intra-group variability. We developed a reproducible and non-biased method for gait analysis in OA rats, which can be applicable for pain and movement disorder models.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 59-63"},"PeriodicalIF":2.9,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We pharmacologically analyzed clonidine-induced tension changes in endothelium-denuded guinea pig thoracic aorta (GP-TA). Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba2+, it elicited a pronounced contraction that was almost completely abolished by verapamil. In contrast, phenylephrine alone evoked a robust contraction, which was also further enhanced in the presence of Ba2+; this Ba2+-potentiated component was nearly abolished by verapamil. The Ba2+-enhanced clonidine-evoked contraction was insensitive to the α2-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α1-AR antagonists prazosin and tamsulosin, yielding pA2 values of 8.26 and 9.92, respectively. Clonidine competitively inhibited phenylephrine-induced contraction, with a pA2 value of 5.67 in the presence of verapamil. Moreover, clonidine suppressed the sustained component of the phenylephrine response; this inhibition was attenuated by Ba2+ but remained unchanged in the presence of verapamil. These findings indicate that, in GP-TA, clonidine acts as a biased and partial agonist primarily at α1L-ARs, promoting Ca2+ influx through L-type voltage-dependent Ca2+ channels (VDCCs). These L-type VDCC-mediated responses are negatively regulated by Ba2+-sensitive K+ channels. In addition, clonidine itself appears to directly or indirectly activate Ba2+-sensitive K+ channels, thereby suppressing the α1L-AR–L-type VDCC functional coupling.
我们从药理学上分析了可乐定诱导的内皮剥落豚鼠胸主动脉（GP-TA）的张力变化。可乐定对基底张力变化不大；然而，在四乙基铵（TEA）或Ba2+存在时，它引起明显的收缩，而维拉帕米几乎完全消除了这种收缩。相比之下，单用苯肾上腺素引起了强烈的收缩，在Ba2+的存在下收缩也进一步增强；这种Ba2+增强成分几乎被维拉帕米消除。Ba2+增强的clonidine诱发的收缩对α2-肾上腺素受体（AR）拮抗剂idazoxan不敏感，但被α1-AR拮抗剂prazosin和tamsulosin竞争性抑制，pA2值分别为8.26和9.92。可乐定竞争性地抑制苯肾上腺素诱导的收缩，维拉帕米存在时pA2值为5.67。此外，可乐定抑制了苯肾上腺素反应的持续成分；这种抑制作用被Ba2+减弱，但在维拉帕米存在时保持不变。这些发现表明，在GP-TA中，可乐定主要在α1L-ARs中作为一种偏倚和部分激动剂，通过l型电压依赖性Ca2+通道（VDCCs）促进Ca2+内流。这些l型vdcc介导的反应受到Ba2+敏感的K+通道的负调控。此外，可乐定本身似乎直接或间接激活Ba2+敏感的K+通道，从而抑制α 1l - ar - l型VDCC功能偶联。
{"title":"Clonidine-induced tension changes in guinea pig thoracic aorta: roles of α1L-adrenoceptors, L-type voltage-dependent Ca2+ channels, and K+ channels","authors":"Keisuke Obara, Ryusei Ono, Daiki Kato, Minori Gohara, Qianghaodi Hong, Yusuke Matsuyama, Ayano Yashiro, Kento Yoshioka, Yoshio Tanaka","doi":"10.1016/j.jphs.2025.11.002","DOIUrl":"10.1016/j.jphs.2025.11.002","url":null,"abstract":"<div><div>We pharmacologically analyzed clonidine-induced tension changes in endothelium-denuded guinea pig thoracic aorta (GP-TA). Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba<sup>2+</sup>, it elicited a pronounced contraction that was almost completely abolished by verapamil. In contrast, phenylephrine alone evoked a robust contraction, which was also further enhanced in the presence of Ba<sup>2+</sup>; this Ba<sup>2+</sup>-potentiated component was nearly abolished by verapamil. The Ba<sup>2+</sup>-enhanced clonidine-evoked contraction was insensitive to the α<sub>2</sub>-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α<sub>1</sub>-AR antagonists prazosin and tamsulosin, yielding p<em>A</em><sub>2</sub> values of 8.26 and 9.92, respectively. Clonidine competitively inhibited phenylephrine-induced contraction, with a p<em>A</em><sub>2</sub> value of 5.67 in the presence of verapamil. Moreover, clonidine suppressed the sustained component of the phenylephrine response; this inhibition was attenuated by Ba<sup>2+</sup> but remained unchanged in the presence of verapamil. These findings indicate that, in GP-TA, clonidine acts as a biased and partial agonist primarily at α<sub>1L</sub>-ARs, promoting Ca<sup>2+</sup> influx through L-type voltage-dependent Ca<sup>2+</sup> channels (VDCCs). These L-type VDCC-mediated responses are negatively regulated by Ba<sup>2+</sup>-sensitive K<sup>+</sup> channels. In addition, clonidine itself appears to directly or indirectly activate Ba<sup>2+</sup>-sensitive K<sup>+</sup> channels, thereby suppressing the α<sub>1L</sub>-AR–L-type VDCC functional coupling.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 41-50"},"PeriodicalIF":2.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The orexinergic system is dysregulated in patients with Alzheimer's disease (AD). In the present study, we evaluated the effects of chronic administration of dual orexin receptor antagonists, suvorexant (Suv) and lemborexant (Lem), on long-term potentiation (LTP) in the hippocampal CA1 region of wild-type (WT) and APPNL−G-F knock-in (APP-KI) mice. LTP was enhanced in APP-KI mice compared with WT mice. Chronic administration of Suv and Lem further potentiated LTP in WT mice. In contrast, in APP-KI mice, Suv moderately and Lem markedly reduced LTP. These findings suggest that orexin receptor antagonists bidirectionally modulate LTP in WT and AD model mice.
{"title":"Bidirectional effects of orexin receptor antagonists on long-term potentiation in the hippocampus of wild type and Alzheimer's disease model mice","authors":"Yoshiaki Ohi , Kazuhiro Hada , Yuki Murata , Daisuke Kodama , Yoshifumi Wakiya","doi":"10.1016/j.jphs.2025.11.003","DOIUrl":"10.1016/j.jphs.2025.11.003","url":null,"abstract":"<div><div>The orexinergic system is dysregulated in patients with Alzheimer's disease (AD). In the present study, we evaluated the effects of chronic administration of dual orexin receptor antagonists, suvorexant (Suv) and lemborexant (Lem), on long-term potentiation (LTP) in the hippocampal CA1 region of wild-type (WT) and APP<sup>NL−G-F</sup> knock-in (APP-KI) mice. LTP was enhanced in APP-KI mice compared with WT mice. Chronic administration of Suv and Lem further potentiated LTP in WT mice. In contrast, in APP-KI mice, Suv moderately and Lem markedly reduced LTP. These findings suggest that orexin receptor antagonists bidirectionally modulate LTP in WT and AD model mice.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 37-40"},"PeriodicalIF":2.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Social behaviors rely on the integration of multiple sensory cues. Among these, ultrasonic vocalizations (USVs) serve as primary auditory cues in rodents. Although the function of USVs has been extensively studied in pup–female and male–female interactions, their role in male–male interactions remain to be elucidated. We tested whether adult male mice recognize male-emitted USVs as social cues using a two-choice playback paradigm. We demonstrated that male mice preferred male-emitted USVs and that oxytocin signaling is essential for perceiving male-emitted USVs. This study provides new insights into the neural mechanisms of male–male social behavior.
{"title":"Male mice recognize male-emitted ultrasonic vocalizations in a two-choice test via oxytocin signaling","authors":"Tomoya Takemoto , Shotaro Kawano , Rei Endo , Kohei Kitagawa , Yukio Ago , Takefumi Kikusui , Hitoshi Hashimoto , Takanobu Nakazawa","doi":"10.1016/j.jphs.2025.11.001","DOIUrl":"10.1016/j.jphs.2025.11.001","url":null,"abstract":"<div><div>Social behaviors rely on the integration of multiple sensory cues. Among these, ultrasonic vocalizations (USVs) serve as primary auditory cues in rodents. Although the function of USVs has been extensively studied in pup–female and male–female interactions, their role in male–male interactions remain to be elucidated. We tested whether adult male mice recognize male-emitted USVs as social cues using a two-choice playback paradigm. We demonstrated that male mice preferred male-emitted USVs and that oxytocin signaling is essential for perceiving male-emitted USVs. This study provides new insights into the neural mechanisms of male–male social behavior.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 23-28"},"PeriodicalIF":2.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jphs.2025.10.005
Yi-Ni Bao , Zi-Meng Zhang , Han Jiang , Rui Wang , Shen Zhang , Dan-Li Zhou , Wen-Ling Dai , Ji-Hua Liu
Aims
Blocking peripheral nerve growth factor (NGF) obviously alleviated neuropathic pain, however, the effect and mechanism of spinal NGF in neuropathic pain are remain controversial. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.
Methods
Chronic constriction injury (CCI) of the sciatic nerve was used to instill neuropathic pain. Pain behaviors were assessed using Von Frey filaments and Hargreaves test. For in vitro studies, primary neurons and astrocytes were cultured. RT-PCR, immunofluorescence and Western blot were used to assess the cell signaling pathway.
Results
Blocking spinal NGF effectively reduced CCI-induced neuropathic pain and suppressed astrocyte activation both in vivo and in vitro. The trends of changes in spinal NGF and the astrocyte marker matched the trends of changes in pain thresholds in CCI. Moreover, NGF-induced hypersensitivity could be abolished by astrocyte inhibitor. NGF was found mainly expressed in spinal neurons, and that the NGF receptor tropomyosin receptor kinase A (TrkA) but not p75, was widely expressed in spinal astrocytes. Dopamine D1/D2 receptor complex could promote NGF expression in spinal neurons, which bind to TrkA to promote astrocytes activation via ASK1-JNK/NF-κB signaling.
Conclusions
These findings imply that D1/D2 receptor complex promotes NGF secretion in spinal neurons, which bind to TrkA to promote astrocyte activation and neuropathic pain via ASK1/JNK/NF-κB pathway.
{"title":"Spinal dopamine D1/D2 receptor complex stimulates NGF release to activate astrocytes and promote neuropathic pain","authors":"Yi-Ni Bao , Zi-Meng Zhang , Han Jiang , Rui Wang , Shen Zhang , Dan-Li Zhou , Wen-Ling Dai , Ji-Hua Liu","doi":"10.1016/j.jphs.2025.10.005","DOIUrl":"10.1016/j.jphs.2025.10.005","url":null,"abstract":"<div><h3>Aims</h3><div>Blocking peripheral nerve growth factor (NGF) obviously alleviated neuropathic pain, however, the effect and mechanism of spinal NGF in neuropathic pain are remain controversial. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.</div></div><div><h3>Methods</h3><div>Chronic constriction injury (CCI) of the sciatic nerve was used to instill neuropathic pain. Pain behaviors were assessed using Von Frey filaments and Hargreaves test. For <em>in vitro</em> studies, primary neurons and astrocytes were cultured. RT-PCR, immunofluorescence and Western blot were used to assess the cell signaling pathway.</div></div><div><h3>Results</h3><div>Blocking spinal NGF effectively reduced CCI-induced neuropathic pain and suppressed astrocyte activation both in vivo and <em>in vitro</em>. The trends of changes in spinal NGF and the astrocyte marker matched the trends of changes in pain thresholds in CCI. Moreover, NGF-induced hypersensitivity could be abolished by astrocyte inhibitor. NGF was found mainly expressed in spinal neurons, and that the NGF receptor tropomyosin receptor kinase A (TrkA) but not p75, was widely expressed in spinal astrocytes. Dopamine D1/D2 receptor complex could promote NGF expression in spinal neurons, which bind to TrkA to promote astrocytes activation via ASK1-JNK/NF-κB signaling.</div></div><div><h3>Conclusions</h3><div>These findings imply that D1/D2 receptor complex promotes NGF secretion in spinal neurons, which bind to TrkA to promote astrocyte activation and neuropathic pain via ASK1/JNK/NF-κB pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 1","pages":"Pages 12-22"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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