Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In...Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.展开更多
BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to asce...BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.展开更多
In the first and second parts of this study,5-hydroxytryptamine(5HT)receptors,including 5-HT3 and 5-HT4 with the highest expression level,were found in clasp and sling fibres of the lower esophageal sphincter(LES).Spe...In the first and second parts of this study,5-hydroxytryptamine(5HT)receptors,including 5-HT3 and 5-HT4 with the highest expression level,were found in clasp and sling fibres of the lower esophageal sphincter(LES).Specific 5-HT3 and 5-HT4 receptor agonists can induce the contraction effect of clasp and sling fibres of the LES while specific 5-HT7 receptor agonists showed no effects.In the study of this part,the in-vitro muscle tension measurement technology and EFS methods were used to detect the effect of the selective 5-HT receptor antagonist on the clasp and sling fibres of the in-vitro LES under the electrical field stimulation(EFS),and further to ensure the effect of 5-HT receptor in the LES neuroregulatory pathway,and deeply explore the effect of 5-HT receptor in the systolic and diastolic function regulation of the LES.展开更多
AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs ...AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B,5-HT3 and 5-HT4 receptor antagonist administration.The force transducers were implanted on the serosal surfaces of the gastric antrum,terminal ileum,ileocecal sphincter and colon.Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state.The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed.RESULTS:5-HT2B,5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum.The 5-HT3 and 5-HT4 receptor antagonists inhibited phaseⅢof the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity.In the proximal colon,the inhibitory effect was dose dependent.Dose dependency,however,was not observed in the distal colon.The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.CONCLUSION:The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity.The5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.展开更多
A rabbit model of traumatic optic nerve injury, established by occlusion of the optic nerve using a vascular clamp, was used to investigate the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep...A rabbit model of traumatic optic nerve injury, established by occlusion of the optic nerve using a vascular clamp, was used to investigate the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist GYKI 52466 on apoptosis of retinal ganglion cells following nerve injury. Hematoxylin-eosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that retinal ganglion cells gradually decreased with increasing time of optic nerve injury, while GYKI 52466 could inhibit this process. The results demonstrate that following acute optic nerve injury, apoptosis of retinal ganglion cells is a programmed process, which can be inhibited by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist.展开更多
In this work, support vector classification （SVC） algorithm was used to build structure-activity relationship （SAR） model of the 5-hydroxytryptamine type 3 （5-HT3 ） receptor antagonists with 26 compounds. In a b...In this work, support vector classification （SVC） algorithm was used to build structure-activity relationship （SAR） model of the 5-hydroxytryptamine type 3 （5-HT3 ） receptor antagonists with 26 compounds. In a benchmark test, SVC was compared with several techniques of machine learning currently used in the field. The prediction performance of the model was discussed on the basis of the leave-one-out cross-validation. The results show that the accuracy of prediction of SVC model was higher than those of back propagation artificial neural network （BP ANN）, K-nearest neighbor （KNN） and Fisher methods.展开更多
This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique...This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.展开更多
Persistent postsurgical pain is a serious issue in public health, which has received increased interest in recent years. Previous studies have reported that psychological factors promote the development of chronic pos...Persistent postsurgical pain is a serious issue in public health, which has received increased interest in recent years. Previous studies have reported that psychological factors promote the development of chronic postsurgical pain. However, it is unclear how chronification of postsurgical pain occurs. The α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor(AMPA) phosphorylation in the central nervous system plays a critical role in synaptic plasticity and contributes to central sensitization and chronic pain development. Here, we discuss the role of AMPA receptor regulation in stress-induced pain chronification after surgery.展开更多
5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated ca...5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated calcium channels(VGCCs),5-HT_(3)R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system(CNS).5-HT_(3)Rs are widely expressed in the medial prefrontal cortex(mPFC),amygdala(AMYG),hippocampus(HIP),periaqueductal gray(PAG),and other brain regions closely associated with anxiety reactions.They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions.5-HT_(3)Rs mediate the activation of the cholecystokinin(CCK)system in the AMYG,and theγ-aminobutyric acid(GABA)“disinhibition”mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons(IINs).In contrast,a 5-HT_(3)R-induced GABA“disinhibition”mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects.5-HT_(2)R-mediated regulation of anxiety reactions are also activated by 5-HT_(3)R-activated 5-HT release in the HIP and PAG.This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT_(3)Rs.However,given the circuit specific modulation of 5-HT_(3)Rs on emotion,systemic use of 5-HT_(3)R agonism or antagonism alone seems unlikely to remedy anxiety,which deeply hinders the current clinical application of 5-HT_(3)R drugs.Therefore,the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.展开更多
目的:从前额叶皮质、海马及下丘脑中5-羟色胺(5-hydroxytryptamine,5-HT)和5-羟色胺受体3(5-hydroxytryptamine receptor3,5-HTR3),5-羟色胺受体4(5-HTR4)角度探讨健脾化湿颗粒改善腹泻型肠易激综合征(diarrhea-predominant irritable b...目的:从前额叶皮质、海马及下丘脑中5-羟色胺(5-hydroxytryptamine,5-HT)和5-羟色胺受体3(5-hydroxytryptamine receptor3,5-HTR3),5-羟色胺受体4(5-HTR4)角度探讨健脾化湿颗粒改善腹泻型肠易激综合征(diarrhea-predominant irritable bowel syndrome,D-IBS)模型大鼠结肠运动和内脏敏感性的作用机制.方法:采用番泻叶灌胃结合束缚应激法建立D-IBS大鼠模型,应用健脾化湿颗粒进行干预,采用酶联免疫法(ELISA)检测大鼠海马中5-HT含量,采用免疫组织化学法检测前额叶皮质、海马及下丘脑中5-HT、5-HTR3、5-HTR4阳性表达,采用逆转录-聚合酶链反应法检测海马中5-H T R3 m R N A和5-H T R4m RNA的表达水平.结果:与正常组相比,模型组海马中5-HT含量(327.30±22.35 vs 265.33±13.60),前额叶皮质、海马、下丘脑中5-HT阳性表达(0.16±0.02 vs 0.08±0.01,0.19±0.02 vs 0.09±0.01,0.17±0.02 vs 0.08±0.01)明显升高(P<0.01);前额叶皮质、海马、下丘脑中5-HTR3阳性表达(0.29±0.02 vs 0.10±0.01,0.23±0.02 vs 0.09±0.01,0.22±0.02 vs 0.09±0.02)及5-HTR4阳性表达(0.25±0.02 vs0.11±0.01,0.28±0.02 vs 0.10±0.02,0.27±0.02 vs 0.11±0.02)明显升高(P<0.01);海马中5-H T R3 m R N A和5-H T R4 m R N A的表达(0.54±0.01 vs 0.17±0.05,0.73±0.08 vs 0.10±0.02)显著升高(P<0.01).与模型组相比,阳性对照组、中、高剂量组海马中5-H T含量(298.92±12.16、286.29±24.43、279.86±20.05 vs 327.30±22.35)显著下降(P<0.05,P<0.01),中、高剂量组前额叶皮质中5-HT表达(0.12±0.01、0.11±0.01 vs 0.16±0.02)显著下降(P<0.01),阳性对照组、中、高剂量组海马、下丘脑中5-H T表达显著下降(P<0.05,P<0.01);各治疗组前额叶皮质、海马、下丘脑中5-H T R3表达及5-H T R4表达下降显著(P<0.05,P<0.01);各治疗组海马中5-H T R3 m R N A表达及5-H T R4 m R N A表达显著降低(P<0.05,P<0.01).结论:健脾化湿颗粒可能通过下调脑中5-HT、5-HTR3、5-HTR4表达来改善D-IBS模型大鼠结肠运动和内脏敏感性.展开更多
基金supported by the Notional Natural Science Foundation of China,Nos.81371213 and 8107098 7the Natural Science Foundation of Shanghai,No.21ZR1468400 (all to QLY)。
文摘Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.
基金The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University of Campania Luigi Vanvitelli(Protocol code 795 on December 23,2019).
文摘BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.
基金Effect of 5-hydroxytryptamine Receptor in the Lower Esophageal Sphincter Regulation Mechanism(Number:18ZF23)。
文摘In the first and second parts of this study,5-hydroxytryptamine(5HT)receptors,including 5-HT3 and 5-HT4 with the highest expression level,were found in clasp and sling fibres of the lower esophageal sphincter(LES).Specific 5-HT3 and 5-HT4 receptor agonists can induce the contraction effect of clasp and sling fibres of the LES while specific 5-HT7 receptor agonists showed no effects.In the study of this part,the in-vitro muscle tension measurement technology and EFS methods were used to detect the effect of the selective 5-HT receptor antagonist on the clasp and sling fibres of the in-vitro LES under the electrical field stimulation(EFS),and further to ensure the effect of 5-HT receptor in the LES neuroregulatory pathway,and deeply explore the effect of 5-HT receptor in the systolic and diastolic function regulation of the LES.
文摘AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B,5-HT3 and 5-HT4 receptor antagonist administration.The force transducers were implanted on the serosal surfaces of the gastric antrum,terminal ileum,ileocecal sphincter and colon.Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state.The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed.RESULTS:5-HT2B,5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum.The 5-HT3 and 5-HT4 receptor antagonists inhibited phaseⅢof the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity.In the proximal colon,the inhibitory effect was dose dependent.Dose dependency,however,was not observed in the distal colon.The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.CONCLUSION:The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity.The5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.
基金The Foundation of Xinjiang Uygur Autonomous Region in China, No. 200821137the National Natural Science Foundation of China, No. 81160153
文摘A rabbit model of traumatic optic nerve injury, established by occlusion of the optic nerve using a vascular clamp, was used to investigate the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist GYKI 52466 on apoptosis of retinal ganglion cells following nerve injury. Hematoxylin-eosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that retinal ganglion cells gradually decreased with increasing time of optic nerve injury, while GYKI 52466 could inhibit this process. The results demonstrate that following acute optic nerve injury, apoptosis of retinal ganglion cells is a programmed process, which can be inhibited by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist.
基金Project supported by National Natural Science Foundation of China（ Grant No. 20373040）
文摘In this work, support vector classification （SVC） algorithm was used to build structure-activity relationship （SAR） model of the 5-hydroxytryptamine type 3 （5-HT3 ） receptor antagonists with 26 compounds. In a benchmark test, SVC was compared with several techniques of machine learning currently used in the field. The prediction performance of the model was discussed on the basis of the leave-one-out cross-validation. The results show that the accuracy of prediction of SVC model was higher than those of back propagation artificial neural network （BP ANN）, K-nearest neighbor （KNN） and Fisher methods.
基金supported by National Natural Science Foundation of China(No.30271500)Science and Tech-nology Research Project Fund from the Department of Edu-cation of Hubei Province of China(No.B20115101)
文摘This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.
基金Supported by The National Institute of Dental and Craniofacial Research Grants,Nos.R01 DE022880 and K02 DE023551
文摘Persistent postsurgical pain is a serious issue in public health, which has received increased interest in recent years. Previous studies have reported that psychological factors promote the development of chronic postsurgical pain. However, it is unclear how chronification of postsurgical pain occurs. The α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor(AMPA) phosphorylation in the central nervous system plays a critical role in synaptic plasticity and contributes to central sensitization and chronic pain development. Here, we discuss the role of AMPA receptor regulation in stress-induced pain chronification after surgery.
基金supported by the National Natural Science Foundation of China(Nos.82071516,32171065,91949105,and 81771227)the Innovation Capability Support Program of Shannxi Province in China(No.2020TD-037)the Fundamental Research Funds for the Central Universities(Nos.GK202105001,GK202205019,and CK202205022),China.
文摘5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated calcium channels(VGCCs),5-HT_(3)R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system(CNS).5-HT_(3)Rs are widely expressed in the medial prefrontal cortex(mPFC),amygdala(AMYG),hippocampus(HIP),periaqueductal gray(PAG),and other brain regions closely associated with anxiety reactions.They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions.5-HT_(3)Rs mediate the activation of the cholecystokinin(CCK)system in the AMYG,and theγ-aminobutyric acid(GABA)“disinhibition”mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons(IINs).In contrast,a 5-HT_(3)R-induced GABA“disinhibition”mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects.5-HT_(2)R-mediated regulation of anxiety reactions are also activated by 5-HT_(3)R-activated 5-HT release in the HIP and PAG.This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT_(3)Rs.However,given the circuit specific modulation of 5-HT_(3)Rs on emotion,systemic use of 5-HT_(3)R agonism or antagonism alone seems unlikely to remedy anxiety,which deeply hinders the current clinical application of 5-HT_(3)R drugs.Therefore,the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.
文摘目的:从前额叶皮质、海马及下丘脑中5-羟色胺(5-hydroxytryptamine,5-HT)和5-羟色胺受体3(5-hydroxytryptamine receptor3,5-HTR3),5-羟色胺受体4(5-HTR4)角度探讨健脾化湿颗粒改善腹泻型肠易激综合征(diarrhea-predominant irritable bowel syndrome,D-IBS)模型大鼠结肠运动和内脏敏感性的作用机制.方法:采用番泻叶灌胃结合束缚应激法建立D-IBS大鼠模型,应用健脾化湿颗粒进行干预,采用酶联免疫法(ELISA)检测大鼠海马中5-HT含量,采用免疫组织化学法检测前额叶皮质、海马及下丘脑中5-HT、5-HTR3、5-HTR4阳性表达,采用逆转录-聚合酶链反应法检测海马中5-H T R3 m R N A和5-H T R4m RNA的表达水平.结果:与正常组相比,模型组海马中5-HT含量(327.30±22.35 vs 265.33±13.60),前额叶皮质、海马、下丘脑中5-HT阳性表达(0.16±0.02 vs 0.08±0.01,0.19±0.02 vs 0.09±0.01,0.17±0.02 vs 0.08±0.01)明显升高(P<0.01);前额叶皮质、海马、下丘脑中5-HTR3阳性表达(0.29±0.02 vs 0.10±0.01,0.23±0.02 vs 0.09±0.01,0.22±0.02 vs 0.09±0.02)及5-HTR4阳性表达(0.25±0.02 vs0.11±0.01,0.28±0.02 vs 0.10±0.02,0.27±0.02 vs 0.11±0.02)明显升高(P<0.01);海马中5-H T R3 m R N A和5-H T R4 m R N A的表达(0.54±0.01 vs 0.17±0.05,0.73±0.08 vs 0.10±0.02)显著升高(P<0.01).与模型组相比,阳性对照组、中、高剂量组海马中5-H T含量(298.92±12.16、286.29±24.43、279.86±20.05 vs 327.30±22.35)显著下降(P<0.05,P<0.01),中、高剂量组前额叶皮质中5-HT表达(0.12±0.01、0.11±0.01 vs 0.16±0.02)显著下降(P<0.01),阳性对照组、中、高剂量组海马、下丘脑中5-H T表达显著下降(P<0.05,P<0.01);各治疗组前额叶皮质、海马、下丘脑中5-H T R3表达及5-H T R4表达下降显著(P<0.05,P<0.01);各治疗组海马中5-H T R3 m R N A表达及5-H T R4 m R N A表达显著降低(P<0.05,P<0.01).结论:健脾化湿颗粒可能通过下调脑中5-HT、5-HTR3、5-HTR4表达来改善D-IBS模型大鼠结肠运动和内脏敏感性.
