Pub Date : 2024-05-24DOI: 10.1016/j.neuropharm.2024.110010
Sora Q. Kim , Redin A. Spann , Md Shahjalal H. Khan , Hans-Rudolf Berthoud , Heike Münzberg , Vance L. Albaugh , Yanlin He , David H. McDougal , Paul Soto , Sangho Yu , Christopher D. Morrison
Free-feeding animals navigate complex nutritional landscapes in which food availability, cost, and nutritional value can vary markedly. Animals have thus developed neural mechanisms that enable the detection of nutrient restriction, and these mechanisms engage adaptive physiological and behavioral responses that limit or reverse this nutrient restriction. This review focuses specifically on dietary protein as an essential and independently defended nutrient. Adequate protein intake is required for life, and ample evidence exists to support an active defense of protein that involves behavioral changes in food intake, food preference, and food motivation, likely mediated by neural changes that increase the reward value of protein foods. Available evidence also suggests that the circulating hormone fibroblast growth factor 21 (FGF21) acts in the brain to coordinate these adaptive changes in food intake, making it a unique endocrine signal that drives changes in macronutrient preference in the context of protein restriction.
This article is part of the Special Issue on "Food intake and feeding states".
{"title":"FGF21 as a mediator of adaptive changes in food intake and macronutrient preference in response to protein restriction","authors":"Sora Q. Kim , Redin A. Spann , Md Shahjalal H. Khan , Hans-Rudolf Berthoud , Heike Münzberg , Vance L. Albaugh , Yanlin He , David H. McDougal , Paul Soto , Sangho Yu , Christopher D. Morrison","doi":"10.1016/j.neuropharm.2024.110010","DOIUrl":"10.1016/j.neuropharm.2024.110010","url":null,"abstract":"<div><p>Free-feeding animals navigate complex nutritional landscapes in which food availability, cost, and nutritional value can vary markedly. Animals have thus developed neural mechanisms that enable the detection of nutrient restriction, and these mechanisms engage adaptive physiological and behavioral responses that limit or reverse this nutrient restriction. This review focuses specifically on dietary protein as an essential and independently defended nutrient. Adequate protein intake is required for life, and ample evidence exists to support an active defense of protein that involves behavioral changes in food intake, food preference, and food motivation, likely mediated by neural changes that increase the reward value of protein foods. Available evidence also suggests that the circulating hormone fibroblast growth factor 21 (FGF21) acts in the brain to coordinate these adaptive changes in food intake, making it a unique endocrine signal that drives changes in macronutrient preference in the context of protein restriction.</p><p>This article is part of the Special Issue on \"Food intake and feeding states\".</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141132747","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 : 2024-05-23DOI: 10.1016/j.neuropharm.2024.110007
Susanne E. la Fleur , Aurea S. Blancas-Velazquez , Dirk Jan Stenvers , Andries Kalsbeek
Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master clock is located in the hypothalamic suprachiasmatic nucleus (SCN). Other brain areas and tissues throughout the body also display rhythmic functions and contain the molecular clock mechanism known as peripheral oscillators. To generate the daily feeding rhythm, the SCN signals to different hypothalamic areas with the lateral hypothalamus, paraventricular nucleus and arcuate nucleus being the most prominent. With respect to the rewarding aspects of feeding behavior, the dopaminergic system is also under circadian influence. However the SCN projects only indirectly to the different reward regions, such as the ventral tegmental area where dopamine neurons are located. In addition, high palatable, high caloric diets have the potential to disturb the normal daily rhythms of physiology and have been shown to alter for example meal patterns. Around a meal several hormones and peptides are released that are also under circadian influence. For example, the release of postprandial insulin and glucagon-like peptide following a meal depend on the time of the day. Finally, we review the effect of deletion of different clock genes on feeding behavior. The most prominent effect on feeding behavior has been observed in Clock mutants, whereas deletion of Bmal1 and Per1/2 only disrupts the day-night rhythm, but not overall intake. Data presented here focus on the rodent literature as only limited data are available on the mechanisms underlying daily rhythms in human eating behavior.
{"title":"Circadian influences on feeding behavior","authors":"Susanne E. la Fleur , Aurea S. Blancas-Velazquez , Dirk Jan Stenvers , Andries Kalsbeek","doi":"10.1016/j.neuropharm.2024.110007","DOIUrl":"10.1016/j.neuropharm.2024.110007","url":null,"abstract":"<div><p>Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master clock is located in the hypothalamic suprachiasmatic nucleus (SCN). Other brain areas and tissues throughout the body also display rhythmic functions and contain the molecular clock mechanism known as peripheral oscillators. To generate the daily feeding rhythm, the SCN signals to different hypothalamic areas with the lateral hypothalamus, paraventricular nucleus and arcuate nucleus being the most prominent. With respect to the rewarding aspects of feeding behavior, the dopaminergic system is also under circadian influence. However the SCN projects only indirectly to the different reward regions, such as the ventral tegmental area where dopamine neurons are located. In addition, high palatable, high caloric diets have the potential to disturb the normal daily rhythms of physiology and have been shown to alter for example meal patterns. Around a meal several hormones and peptides are released that are also under circadian influence. For example, the release of postprandial insulin and glucagon-like peptide following a meal depend on the time of the day. Finally, we review the effect of deletion of different clock genes on feeding behavior. The most prominent effect on feeding behavior has been observed in <em>Clock</em> mutants, whereas deletion of <em>Bmal1</em> and <em>Per1/2</em> only disrupts the day-night rhythm, but not overall intake. Data presented here focus on the rodent literature as only limited data are available on the mechanisms underlying daily rhythms in human eating behavior.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002839082400176X/pdfft?md5=e98dadc8fc5292c4aafd3a9e001fa145&pid=1-s2.0-S002839082400176X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.1016/j.neuropharm.2024.110003
Alessia Ricci , Eleonora Rubino , Gian Pietro Serra , Åsa Wallén-Mackenzie
Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms.
One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area.
Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.
深部脑刺激(DBS)等神经调控技术正逐渐成为几种神经和神经精神疾病的临床干预手段,包括帕金森病、肌张力障碍、震颤症和强迫症(OCD)。图雷特综合征和吸毒成瘾是另外两种正在试用或建议使用 DBS 治疗的疾病。然而,仍有一些主要障碍阻碍着这种干预措施充分发挥其治疗潜力。副作用已有报道,而且并非所有接受 DBS 治疗的人都能缓解症状。DBS电极的一个主要靶区是丘脑下核(STN),它在运动、情感和联想功能方面发挥着重要作用,对运动、动机、冲动、强迫以及奖赏和厌恶等都有影响。STN 的多功能性非常复杂。解码 STN 的解剖功能组织可以提高人类患者的战略目标定位能力。STN 紧邻脑内区(zona incerta,ZI)和副丘脑核(para-subthalamic nucleus,pSTN)。STN、pSTN 和 ZI 共同构成了一个高度异质且具有重要临床意义的脑区。以啮齿类动物为基础的实验研究,包括光遗传学、化学遗传学以及病毒遗传束追踪,为我们提供了独特的视角,让我们可以在高空间和时间精度上了解复杂的神经元回路及其对行为的影响。在过去几年中,这一研究领域取得了巨大进步。在此,我们将对临床前研究领域的最新文献进行全面综述,这些文献以实验室小鼠和大鼠的 STN、pSTN 和 ZI 为中心;这三种高度异质且神秘的结构在治疗策略方面具有相关性。特别强调了操纵方法和行为影响。
{"title":"Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents","authors":"Alessia Ricci , Eleonora Rubino , Gian Pietro Serra , Åsa Wallén-Mackenzie","doi":"10.1016/j.neuropharm.2024.110003","DOIUrl":"10.1016/j.neuropharm.2024.110003","url":null,"abstract":"<div><p>Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms.</p><p>One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the <em>para</em>-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area.</p><p>Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824001722/pdfft?md5=f78fa2132e286916ed9ca48ebd579b2a&pid=1-s2.0-S0028390824001722-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-18DOI: 10.1016/j.neuropharm.2024.109989
Shaimaa S. Ibrahim, Omar G. Abo Elseoud, M. Mohamedy, Mohamed M. Amer, Youssef Y. Mohamed, Shehab A. Elmansy, Mohamed M. Kadry, Ahmed A. Attia, Ragy A. Fanous, Mahmoud S. Kamel, Youssef A. Solyman, Mazen S. Shehata, Mina Y. George
{"title":"Corrigendum to “Nose-to-brain delivery of chrysin transfersomal and composite vesicles in doxorubicin-induced cognitive impairment in rats: Insights on formulation, oxidative stress and TLR4/NF-kB/NLRP3 pathways” [Neuropharmacol. (2021) 1, 197, 108738]","authors":"Shaimaa S. Ibrahim, Omar G. Abo Elseoud, M. Mohamedy, Mohamed M. Amer, Youssef Y. Mohamed, Shehab A. Elmansy, Mohamed M. Kadry, Ahmed A. Attia, Ragy A. Fanous, Mahmoud S. Kamel, Youssef A. Solyman, Mazen S. Shehata, Mina Y. George","doi":"10.1016/j.neuropharm.2024.109989","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2024.109989","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962070","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 : 2024-05-18DOI: 10.1016/j.neuropharm.2024.109989
Shaimaa S. Ibrahim , Omar G. Abo Elseoud , Mohamed H. Mohamedy , Mohamed M. Amer , Youssef Y. Mohamed , Shehab A. Elmansy , Mohamed M. Kadry , Ahmed A. Attia , Ragy A. Fanous , Mahmoud S. Kamel , Youssef A. Solyman , Mazen S. Shehata , Mina Y. George
{"title":"Corrigendum to “Nose-to-brain delivery of chrysin transfersomal and composite vesicles in doxorubicin-induced cognitive impairment in rats: Insights on formulation, oxidative stress and TLR4/NF-kB/NLRP3 pathways” [Neuropharmacol. (2021) 1, 197, 108738]","authors":"Shaimaa S. Ibrahim , Omar G. Abo Elseoud , Mohamed H. Mohamedy , Mohamed M. Amer , Youssef Y. Mohamed , Shehab A. Elmansy , Mohamed M. Kadry , Ahmed A. Attia , Ragy A. Fanous , Mahmoud S. Kamel , Youssef A. Solyman , Mazen S. Shehata , Mina Y. George","doi":"10.1016/j.neuropharm.2024.109989","DOIUrl":"10.1016/j.neuropharm.2024.109989","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824001588/pdfft?md5=d2b304b6d01775a0494829f8b0a38cae&pid=1-s2.0-S0028390824001588-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-18DOI: 10.1016/j.neuropharm.2024.110006
Jinyang Wang , Longyuan Du , Tianyun Zhang , Yun Chu , Yue Wang , Yu Wang , Xiaoming Ji , Yunxiao Kang , Rui Cui , Guoliang Zhang , Junyan Liu , Geming Shi
Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to treat acute ischemic stroke, has recently been shown to exert efficacious neuroprotective effects. However, whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of EDB on AD and its potential mechanisms using an AD animal model (male APP/PS1 mice) treated with EDB for 10 weeks starting at 6 months of age. Subsequent analyses revealed that EDB-treated APP/PS1 mice exhibited improved cognitive abilities compared to untreated APP/PS1 mice. Administration of EDB in APP/PS1 mice further alleviated neuropathological alterations of the hippocampus, including Aβ deposition, pyramidal cell karyopyknosis, and oxidative damage, and significantly decreased the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and COX-2 in the hippocampus of APP/PS1 mice. Transcriptome sequencing analysis demonstrated the critical role of the inflammatory reaction in EDB treatment in APP/PS1 mice, indicating that the alleviation of the inflammatory reaction by EDB in the hippocampus of APP/PS1 mice was linked to the action of the TREM2/TLR4/MAPK signaling pathway. Further in vitro investigations showed that EDB suppressed neuroinflammation in LPS-stimulated BV2 cells by inhibiting the TLR4/MAPK signaling pathway and upregulating TREM2 expression. Thus, the findings of the present study demonstrate that EDB is a promising therapeutic agent for AD-related cognitive dysfunction.
{"title":"Edaravone Dexborneol ameliorates the cognitive deficits of APP/PS1 mice by inhibiting TLR4/MAPK signaling pathway via upregulating TREM2","authors":"Jinyang Wang , Longyuan Du , Tianyun Zhang , Yun Chu , Yue Wang , Yu Wang , Xiaoming Ji , Yunxiao Kang , Rui Cui , Guoliang Zhang , Junyan Liu , Geming Shi","doi":"10.1016/j.neuropharm.2024.110006","DOIUrl":"10.1016/j.neuropharm.2024.110006","url":null,"abstract":"<div><p>Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to treat acute ischemic stroke, has recently been shown to exert efficacious neuroprotective effects. However, whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of EDB on AD and its potential mechanisms using an AD animal model (male APP/PS1 mice) treated with EDB for 10 weeks starting at 6 months of age. Subsequent analyses revealed that EDB-treated APP/PS1 mice exhibited improved cognitive abilities compared to untreated APP/PS1 mice. Administration of EDB in APP/PS1 mice further alleviated neuropathological alterations of the hippocampus, including Aβ deposition, pyramidal cell karyopyknosis, and oxidative damage, and significantly decreased the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and COX-2 in the hippocampus of APP/PS1 mice. Transcriptome sequencing analysis demonstrated the critical role of the inflammatory reaction in EDB treatment in APP/PS1 mice, indicating that the alleviation of the inflammatory reaction by EDB in the hippocampus of APP/PS1 mice was linked to the action of the TREM2/TLR4/MAPK signaling pathway. Further <em>in vitro</em> investigations showed that EDB suppressed neuroinflammation in LPS-stimulated BV2 cells by inhibiting the TLR4/MAPK signaling pathway and upregulating TREM2 expression. Thus, the findings of the present study demonstrate that EDB is a promising therapeutic agent for AD-related cognitive dysfunction.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824001758/pdfft?md5=90e81375b34bd7043927d9fb6a39ca28&pid=1-s2.0-S0028390824001758-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuronal voltage-gated KCNQ (Kv7) channels, expressed centrally and peripherally, mediate low-threshold and non-inactivating M-currents responsible for the control of tonic excitability of mammalian neurons. Pharmacological opening of KCNQ channels has been reported to generate analgesic effects in animal models of neuropathic pain. Here, we examined the possible involvement of central KCNQ channels in the analgesic effects of retigabine, a KCNQ channel opener. Behaviorally, intraperitoneally applied retigabine exerted analgesic effects on thermal and mechanical hypersensitivity in male mice developing neuropathic pain after partial sciatic nerve ligation, which was antagonized by the KCNQ channel blocker XE991 preadministered intraperitoneally and intrathecally. Intrathecally applied retigabine also exerted analgesic effects that were inhibited by intrathecally injected XE991. We then explored the synaptic mechanisms underlying the analgesic effects of retigabine in the spinal dorsal horn.
Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult male mice developing neuropathic pain, and the effects of retigabine on miniature and afferent-evoked postsynaptic currents were examined. Retigabine reduced the amplitude of A-fiber-mediated EPSCs without affecting C-fiber-mediated excitatory synaptic transmission. A-fiber-mediated EPSCs remained unaltered by retigabine in the presence of XE991, consistently with the behavioral findings. The frequency and amplitude of mEPSCs were not affected by retigabine. Thus, opening of KCNQ channels in the central terminals of primary afferent A-fibers inhibits excitatory synaptic transmission in the spinal dorsal horn, most likely contributing to the analgesic effect of retigabine.
神经元电压门控 KCNQ(Kv7)通道在中枢和外周表达,介导低阈值和非失活型 M 电流,负责控制哺乳动物神经元的强直兴奋性。据报道,在神经病理性疼痛的动物模型中,药理作用打开 KCNQ 通道可产生镇痛效果。在这里,我们研究了中枢 KCNQ 通道可能参与 KCNQ 通道开放剂瑞替加滨镇痛作用的情况。在行为学上,腹腔注射瑞替加滨对部分坐骨神经结扎后出现神经病理性疼痛的雄性小鼠的热敏和机械过敏有镇痛作用,而腹腔和鞘内预先注射的 KCNQ 通道阻断剂 XE991 可拮抗这种作用。腹腔注射瑞替加滨也能产生镇痛效果,但腹腔注射 XE991 会抑制这种效果。随后,我们探索了瑞替加滨在脊髓背角镇痛作用的突触机制。我们对患有神经病理性疼痛的成年雄性小鼠脊髓切片中附有背根的背角神经元进行了全细胞记录,并考察了瑞替加滨对微型突触后电流和传入突触后电流的影响。瑞替加宾降低了A纤维介导的EPSC的振幅,但不影响C纤维介导的兴奋性突触传递。在有 XE991 存在的情况下,雷替加宾对 A 纤维介导的 EPSC 没有影响,这与行为学研究结果一致。mEPSCs 的频率和振幅不受瑞替加滨的影响。因此,初级传入 A 纤维中央终端的 KCNQ 通道开放抑制了脊髓背角的兴奋性突触传递,这很可能是导致瑞替加滨镇痛效果的原因。
{"title":"Selective inhibition of A-fiber-mediated excitatory transmission underlies the analgesic effects of KCNQ channel opening in the spinal dorsal horn","authors":"Misa Oyama , Shun Watanabe , Takashi Iwai , Mitsuo Tanabe","doi":"10.1016/j.neuropharm.2024.109994","DOIUrl":"10.1016/j.neuropharm.2024.109994","url":null,"abstract":"<div><p>Neuronal voltage-gated KCNQ (Kv7) channels, expressed centrally and peripherally, mediate low-threshold and non-inactivating M-currents responsible for the control of tonic excitability of mammalian neurons. Pharmacological opening of KCNQ channels has been reported to generate analgesic effects in animal models of neuropathic pain. Here, we examined the possible involvement of central KCNQ channels in the analgesic effects of retigabine, a KCNQ channel opener. Behaviorally, intraperitoneally applied retigabine exerted analgesic effects on thermal and mechanical hypersensitivity in male mice developing neuropathic pain after partial sciatic nerve ligation, which was antagonized by the KCNQ channel blocker XE991 preadministered intraperitoneally and intrathecally. Intrathecally applied retigabine also exerted analgesic effects that were inhibited by intrathecally injected XE991. We then explored the synaptic mechanisms underlying the analgesic effects of retigabine in the spinal dorsal horn.</p><p>Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult male mice developing neuropathic pain, and the effects of retigabine on miniature and afferent-evoked postsynaptic currents were examined. Retigabine reduced the amplitude of A-fiber-mediated EPSCs without affecting C-fiber-mediated excitatory synaptic transmission. A-fiber-mediated EPSCs remained unaltered by retigabine in the presence of XE991, consistently with the behavioral findings. The frequency and amplitude of mEPSCs were not affected by retigabine. Thus, opening of KCNQ channels in the central terminals of primary afferent A-fibers inhibits excitatory synaptic transmission in the spinal dorsal horn, most likely contributing to the analgesic effect of retigabine.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945153","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 : 2024-05-14DOI: 10.1016/j.neuropharm.2024.109990
Peng Chen , Yulai Wang , Jing Xie , Jiexin Lei , Benhong Zhou
{"title":"Corrigendum to “Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice”","authors":"Peng Chen , Yulai Wang , Jing Xie , Jiexin Lei , Benhong Zhou","doi":"10.1016/j.neuropharm.2024.109990","DOIUrl":"10.1016/j.neuropharm.2024.109990","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002839082400159X/pdfft?md5=6092ebeb4e588e24c6d2b66420ce8825&pid=1-s2.0-S002839082400159X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.neuropharm.2024.110002
Shelley R. Edwards , Bruce E. Blough , Kristian Cowart , Grace H. Howell , Aaron A. Araujo , Jacob P. Haskell , Sally L. Huskinson , James K. Rowlett , Marcus F. Brackeen , Kevin B. Freeman
Rationale
Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception.
Objectives
The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats.
Methods
Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects.
Results
All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects.
Conclusions
Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.
{"title":"Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP","authors":"Shelley R. Edwards , Bruce E. Blough , Kristian Cowart , Grace H. Howell , Aaron A. Araujo , Jacob P. Haskell , Sally L. Huskinson , James K. Rowlett , Marcus F. Brackeen , Kevin B. Freeman","doi":"10.1016/j.neuropharm.2024.110002","DOIUrl":"10.1016/j.neuropharm.2024.110002","url":null,"abstract":"<div><h3>Rationale</h3><p>Recent studies report that fentanyl analogs with relatively low pK<sub>a</sub> values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception.</p></div><div><h3>Objectives</h3><p>The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pK<sub>a</sub> values in terms of potency and efficacy in male and female Sprague-Dawley rats.</p></div><div><h3>Methods</h3><p>Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects.</p></div><div><h3>Results</h3><p>All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects.</p></div><div><h3>Conclusions</h3><p>Low pK<sub>a</sub> fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pK<sub>a</sub> relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958514","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 : 2024-05-13DOI: 10.1016/j.neuropharm.2024.110001
Xiaoying Tan , Elizabeth M. Neslund , Khawla Fentis , Zheng-Ming Ding
Emerging evidence suggests an important role of astrocytes in mediating behavioral and molecular effects of commonly misused drugs. Passive exposure to nicotine alters molecular, morphological, and functional properties of astrocytes. However, a potential involvement of astrocytes in nicotine reinforcement remains largely unexplored. The overall hypothesis tested in the current study is that astrocytes play a critical role in nicotine reinforcement. Protein levels of the astrocyte marker glial fibrillary acidic protein (GFAP) were examined in key mesocorticolimbic regions following chronic nicotine intravenous self-administration. Fluorocitrate, a metabolic inhibitor of astrocytes, was tested for its effects on behaviors related to nicotine reinforcement and relapse. Effects of fluorocitrate on extracellular neurotransmitter levels, including glutamate, GABA, and dopamine, were determined with microdialysis. Chronic nicotine intravenous self-administration increased GFAP expression in the nucleus accumbens core (NACcr), but not other key mesocorticolimbic regions, compared to saline intravenous self-administration. Both intra-ventricular and intra-NACcr microinjection of fluorocitrate decreased nicotine self-administration. Intra-NACcr fluorocitrate microinjection also inhibited cue-induced reinstatement of nicotine seeking. Local perfusion of fluorocitrate decreased extracellular glutamate levels, elevated extracellular dopamine levels, but did not alter extracellular GABA levels in the NACcr. Fluorocitrate did not alter basal locomotor activity. These results indicate that nicotine reinforcement upregulates the astrocyte marker GFAP expression in the NACcr, metabolic inhibition of astrocytes attenuates nicotine reinforcement and relapse, and metabolic inhibition of astrocytes disrupts extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes play an important role in nicotine reinforcement and relapse, potentially through regulation of extracellular glutamate and dopamine neurotransmission.
{"title":"Fluorocitrate inhibition of astrocytes reduces nicotine self-administration and alters extracellular levels of glutamate and dopamine within the nucleus accumbens in male wistar rats","authors":"Xiaoying Tan , Elizabeth M. Neslund , Khawla Fentis , Zheng-Ming Ding","doi":"10.1016/j.neuropharm.2024.110001","DOIUrl":"10.1016/j.neuropharm.2024.110001","url":null,"abstract":"<div><p>Emerging evidence suggests an important role of astrocytes in mediating behavioral and molecular effects of commonly misused drugs. Passive exposure to nicotine alters molecular, morphological, and functional properties of astrocytes. However, a potential involvement of astrocytes in nicotine reinforcement remains largely unexplored. The overall hypothesis tested in the current study is that astrocytes play a critical role in nicotine reinforcement. Protein levels of the astrocyte marker glial fibrillary acidic protein (GFAP) were examined in key mesocorticolimbic regions following chronic nicotine intravenous self-administration. Fluorocitrate, a metabolic inhibitor of astrocytes, was tested for its effects on behaviors related to nicotine reinforcement and relapse. Effects of fluorocitrate on extracellular neurotransmitter levels, including glutamate, GABA, and dopamine, were determined with microdialysis. Chronic nicotine intravenous self-administration increased GFAP expression in the nucleus accumbens core (NACcr), but not other key mesocorticolimbic regions, compared to saline intravenous self-administration. Both intra-ventricular and intra-NACcr microinjection of fluorocitrate decreased nicotine self-administration. Intra-NACcr fluorocitrate microinjection also inhibited cue-induced reinstatement of nicotine seeking. Local perfusion of fluorocitrate decreased extracellular glutamate levels, elevated extracellular dopamine levels, but did not alter extracellular GABA levels in the NACcr. Fluorocitrate did not alter basal locomotor activity. These results indicate that nicotine reinforcement upregulates the astrocyte marker GFAP expression in the NACcr, metabolic inhibition of astrocytes attenuates nicotine reinforcement and relapse, and metabolic inhibition of astrocytes disrupts extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes play an important role in nicotine reinforcement and relapse, potentially through regulation of extracellular glutamate and dopamine neurotransmission.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945144","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}