Pub Date : 2026-01-07DOI: 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.
{"title":"Acetazolamide alleviates motion sickness by inhibiting inner ear carbonic anhydrase 2 and reducing endolymph volume","authors":"Miao-Miao Chen , Chao-Yue Tian , Jian-Gang Ge , Xia Li , Bin Peng , Wei Ji , Lei Cui , Li-Hua Xu , Zheng-Lin Jiang","doi":"10.1016/j.neuropharm.2026.110829","DOIUrl":"10.1016/j.neuropharm.2026.110829","url":null,"abstract":"<div><div>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<sup>+</sup> concentrations in vestibular epithelial cells, inhibition of Na<sup>+</sup>-K<sup>+</sup>-ATPase activity, and modulation of intracellular Na<sup>+</sup> and K<sup>+</sup> 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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110829"},"PeriodicalIF":4.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145940484","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}
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.
{"title":"NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord","authors":"Xiaoyu Zhang, Jiale Sun, Fengtian Zhao, Ting Liu, Shangchen Yu, Wen Zhang, Xuebi Tian","doi":"10.1016/j.neuropharm.2026.110831","DOIUrl":"10.1016/j.neuropharm.2026.110831","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110831"},"PeriodicalIF":4.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934083","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}
Pub Date : 2026-01-02DOI: 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 (AUC0-91), by 36 % (AUC0–91 ratio, 1.36; 95 % CI, 1.0–1.8), increasing the maximum tracer concentration (Cmax) in the intracranial space by 39 % (Cmax ratio, 1.39; 95 % CI, 1.06–1.81), and decreasing the tracer availability in the spinal canal by 25 % (AUC0–91 ratio, 0.75; 95 % CI, 0.66–0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360 % (AUC0–91 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.
{"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}
Pub Date : 2026-01-02DOI: 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 Ih 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.
{"title":"Nose-to-brain delivery of dopamine to the striatum of rats using neurotransmitter-loaded solid lipid nanoparticles: an in vivo study by brain microdialysis","authors":"Laura Dazzi , Giuseppe Talani , Giuseppe Trapani , Luigi Capasso , Annalucia Carbone , Sante Di Gioia , Massimo Conese , Adriana Trapani , Enrico Sanna","doi":"10.1016/j.neuropharm.2026.110830","DOIUrl":"10.1016/j.neuropharm.2026.110830","url":null,"abstract":"<div><div>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 <em>I</em><sub>h</sub> current amplitude. A similar effect was also observed <em>in vitro</em> 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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110830"},"PeriodicalIF":4.6,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891195","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}
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.
{"title":"Spinal Shati/nat8l regulates mechanical hyperalgesia through NAAG-mGluR3 signaling in neuropathic pain","authors":"Keisuke Miyamoto , Kousuke Tatsuta , Kazuyuki Sumi , Kyosuke Uno , Kazuki Tokoro , Shin-ichi Muramatsu , Naotaka Izuo , Kazuhiko Kume , Atsumi Nitta , Masahiro Ohsawa","doi":"10.1016/j.neuropharm.2025.110819","DOIUrl":"10.1016/j.neuropharm.2025.110819","url":null,"abstract":"<div><div><em>Shati/nat8l</em> 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 <em>Shati/nat8l</em> in pain transmission has remained unclear. In this study, we investigated the involvement of spinal <em>Shati/nat8l</em> in mechanical nociceptive processing and neuropathic pain.</div><div>We found that <em>Shati/nat8l</em> 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 <em>Shati/nat8l</em> 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 <em>Shati/nat8l</em> mRNA in the ipsilateral dorsal horn was significantly decreased. Importantly, AAV-mediated restoration of <em>Shati/nat8l</em> expression in the dorsal horn alleviated neuropathic mechanical hyperalgesia and normalized <em>Shati/nat8l</em> mRNA levels.</div><div>These findings suggest that downregulation of spinal <em>Shati/nat8l</em> contributes to mechanical hypersensitivity by impairing the NAAG-mGluR3 signaling pathway. Targeting the <em>Shati/nat8l</em>–NAAG–mGluR3 axis may offer a novel therapeutic strategy for the treatment of neuropathic pain.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110819"},"PeriodicalIF":4.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892969","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}
Pub Date : 2025-12-30DOI: 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.
{"title":"TRPC6 mediates neuronal hyperexcitability in the lateral habenula to drive trigeminal neuralgia-associated anxiety","authors":"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","doi":"10.1016/j.neuropharm.2025.110818","DOIUrl":"10.1016/j.neuropharm.2025.110818","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110818"},"PeriodicalIF":4.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889835","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}
Pub Date : 2025-12-26DOI: 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.
{"title":"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","authors":"Kimberley A. Mount , Hayley M. Kuhn, Eun-Kyung Hwang, Madelyn M. Beutler, Marina E. Wolf","doi":"10.1016/j.neuropharm.2025.110816","DOIUrl":"10.1016/j.neuropharm.2025.110816","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110816"},"PeriodicalIF":4.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850515","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}
Pub Date : 2025-12-24DOI: 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.
{"title":"Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach","authors":"Maria Fiore , Silvia Saltarelli , Laura De Mastro , Enrico D'Ambrosio , Antonia Ianniello , Alessandro Bertolino , Giulio Pergola , Maria Favia , Antonio Rampino","doi":"10.1016/j.neuropharm.2025.110814","DOIUrl":"10.1016/j.neuropharm.2025.110814","url":null,"abstract":"<div><h3>Background</h3><div>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). <em>In vitro</em> 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.</div></div><div><h3>Methods</h3><div>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).</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110814"},"PeriodicalIF":4.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841835","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}
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 (FRRFamide) and a CFamide peptide (FRFamide), 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 FRRFamide peptide was much slower than those of FRFamide 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 FRRFamide 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.
{"title":"Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility","authors":"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","doi":"10.1016/j.neuropharm.2025.110813","DOIUrl":"10.1016/j.neuropharm.2025.110813","url":null,"abstract":"<div><div>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<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide) and a CFamide peptide (FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>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<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide peptide was much slower than those of FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>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<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110813"},"PeriodicalIF":4.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834400","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}
Pub Date : 2025-12-23DOI: 10.1016/j.neuropharm.2025.110815
Cen Yang , Yuting He , Min Cai , Sa Wang , Yuhao Wang , Miao Wang , Huaning Wang , Yanyan Sun , Jiannan Li
Background
Although the dorsal raphe nucleus (DRN) serotonergic neurons—which play a key role in consciousness—send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive.
Methods
Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process.
Results
DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states.
Conclusions
Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.
{"title":"Dorsal raphe serotonergic neurons facilitate arousal from sevoflurane anesthesia by heterogeneously modulating neuronal activity in the basolateral amygdala","authors":"Cen Yang , Yuting He , Min Cai , Sa Wang , Yuhao Wang , Miao Wang , Huaning Wang , Yanyan Sun , Jiannan Li","doi":"10.1016/j.neuropharm.2025.110815","DOIUrl":"10.1016/j.neuropharm.2025.110815","url":null,"abstract":"<div><h3>Background</h3><div>Although the dorsal raphe nucleus (DRN) serotonergic neurons—which play a key role in consciousness—send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive.</div></div><div><h3>Methods</h3><div>Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process.</div></div><div><h3>Results</h3><div>DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states.</div></div><div><h3>Conclusions</h3><div>Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110815"},"PeriodicalIF":4.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834381","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}
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