Demyelination caused by oligodendrocyte death is a key contributor to neurological deficits after spinal cord injury (SCI), highlighting the critical need to promote oligodendrocyte precursor cell (OPC) differentiation and remyelination. The transcription factor Olig2 is a master regulator of this process; however, its activation mechanism remains unclear. Given the marked lactate accumulation in post-SCI ischemic microenvironments, we investigated the role of lactate in SCI as well as its regulation on OPC differentiation. In a rat SCI model, it is found that exogenous lactate administration significantly improves motor recovery, preserves neurons and axons, modulates the glial response. Mechanistically, lactate induces histone H3K27 lactylation (H3K27la), which specifically upregulates Olig2 expression, thereby activating OPC differentiation and remyelination. This study uncovers the lactate-H3K27la-Olig2 metabolic-epigenetic axis as a novel endogenous repair mechanism for SCI, providing a foundation for metabolism-targeted therapeutic strategies.
{"title":"Lactate-driven H3K27 lactylation promotes Olig2-dependent remyelination and motor recovery after spinal cord injury","authors":"Zongxin Zhu , Ximiao Chen , Hanwen Zhang , Ronghui Miao , Huiling Yu , Shiying Zhao , Youli Zhang , Tanxin Yu , Di Zhang , Yifei Zhou , Xiaolei Zhang , Wei Zhang","doi":"10.1016/j.neuropharm.2026.110832","DOIUrl":"10.1016/j.neuropharm.2026.110832","url":null,"abstract":"<div><div>Demyelination caused by oligodendrocyte death is a key contributor to neurological deficits after spinal cord injury (SCI), highlighting the critical need to promote oligodendrocyte precursor cell (OPC) differentiation and remyelination. The transcription factor Olig2 is a master regulator of this process; however, its activation mechanism remains unclear. Given the marked lactate accumulation in post-SCI ischemic microenvironments, we investigated the role of lactate in SCI as well as its regulation on OPC differentiation. In a rat SCI model, it is found that exogenous lactate administration significantly improves motor recovery, preserves neurons and axons, modulates the glial response. Mechanistically, lactate induces histone H3K27 lactylation (H3K27la), which specifically upregulates Olig2 expression, thereby activating OPC differentiation and remyelination. This study uncovers the lactate-H3K27la-Olig2 metabolic-epigenetic axis as a novel endogenous repair mechanism for SCI, providing a foundation for metabolism-targeted therapeutic strategies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110832"},"PeriodicalIF":4.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960024","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 : 2026-01-10DOI: 10.1016/j.neuropharm.2026.110833
Lauren T. Ursich , Amy J. Pearl , Xavier J. Maddern , Andrew J. Lawrence , Leigh C. Walker
Alcohol use is a leading risk factor for premature mortality, yet effective pharmacotherapies remain limited. Neurosteroids, such as allopregnanolone, modulate γ-aminobutyric acid type A (GABAA) receptors and influence alcohol-related behaviours. Zuranolone, an orally bioavailable synthetic analogue of allopregnanolone recently approved for postpartum depression, represents a potential candidate for therapeutic repurposing in alcohol use disorder (AUD). Here, we assessed the effects of acute and daily zuranolone on alcohol-related behaviours in a preclinical binge drinking model, comparing outcomes across sexes and contrasted to the effects of allopregnanolone. Allopregnanolone produced dose-related locomotor responses, characterised by mid dose transient hyperlocomotion and high dose sedation; the mid dose also reduced alcohol intake in both sexes. In contrast, zuranolone produced sex- and dosing schedule-related effects on alcohol consumption: acute high dose administration transiently reduced intake in males in the Latin square design, whereas mid dose administration increased intake under dose escalation in both sexes, particularly in males; however, total intake was unchanged across dosing schedules. Daily zuranolone transiently reduced alcohol intake in males during the first week only. In locomotor assays, acute high dose zuranolone induced sustained hyperactivity in males that was attenuated in females, supporting sex-related differences in sensitivity. Despite its structural similarity to allopregnanolone, zuranolone produced unique behavioural responses, suggesting their pharmacological profiles may differ. Overall, our data do not show robust reductions in alcohol intake following zuranolone administration across dosing schedules in either sex in preclinical models of binge drinking. Future studies are required to explore its potential relevance in comorbid AUD and affective disorders.
{"title":"Assessing the utility of the neurosteroid zuranolone to modify alcohol-related behaviours","authors":"Lauren T. Ursich , Amy J. Pearl , Xavier J. Maddern , Andrew J. Lawrence , Leigh C. Walker","doi":"10.1016/j.neuropharm.2026.110833","DOIUrl":"10.1016/j.neuropharm.2026.110833","url":null,"abstract":"<div><div>Alcohol use is a leading risk factor for premature mortality, yet effective pharmacotherapies remain limited. Neurosteroids, such as allopregnanolone, modulate γ-aminobutyric acid type A (GABA<sub>A</sub>) receptors and influence alcohol-related behaviours. Zuranolone, an orally bioavailable synthetic analogue of allopregnanolone recently approved for postpartum depression, represents a potential candidate for therapeutic repurposing in alcohol use disorder (AUD). Here, we assessed the effects of acute and daily zuranolone on alcohol-related behaviours in a preclinical binge drinking model, comparing outcomes across sexes and contrasted to the effects of allopregnanolone. Allopregnanolone produced dose-related locomotor responses, characterised by mid dose transient hyperlocomotion and high dose sedation; the mid dose also reduced alcohol intake in both sexes. In contrast, zuranolone produced sex- and dosing schedule-related effects on alcohol consumption: acute high dose administration transiently reduced intake in males in the Latin square design, whereas mid dose administration increased intake under dose escalation in both sexes, particularly in males; however, total intake was unchanged across dosing schedules. Daily zuranolone transiently reduced alcohol intake in males during the first week only. In locomotor assays, acute high dose zuranolone induced sustained hyperactivity in males that was attenuated in females, supporting sex-related differences in sensitivity. Despite its structural similarity to allopregnanolone, zuranolone produced unique behavioural responses, suggesting their pharmacological profiles may differ. Overall, our data do not show robust reductions in alcohol intake following zuranolone administration across dosing schedules in either sex in preclinical models of binge drinking. Future studies are required to explore its potential relevance in comorbid AUD and affective disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110833"},"PeriodicalIF":4.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952609","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 : 2026-01-08DOI: 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。
{"title":"Brain-penetrant microtubule-stabilizer epothilone B delays isoflurane-induced unconsciousness in mice","authors":"Yixiang Huang , Zitong Qiu , Xinyue Yu, Sophia Lee, Xiran Zeng, Abbie Chang, Michael C. Wiest","doi":"10.1016/j.neuropharm.2026.110834","DOIUrl":"10.1016/j.neuropharm.2026.110834","url":null,"abstract":"<div><div>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 <em>increased</em> 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.</div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110834"},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948989","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 : 2026-01-07DOI: 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}
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