大鼠电针镇痛及束缚应激后恢复速度个体差异的基因解析
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摘要
第一部分电针镇痛中个体差异的基因解析
目的:
利用基因芯片技术筛查大鼠下丘脑与电针镇痛相关的候选基因,以期寻找电针镇痛中出现个体差异的分子基础。
方法:
脉冲电流连接电针以1赫兹(Hz)频率刺激大鼠足三里穴位1小时。采用辐射热甩尾法(Tail-Flick Test)测定大鼠甩尾潜伏期(Tail-Flick Latency,TFL),以此作为痛阈指标。根据电针效果(痛阈提高率Pain Threshold Increase Rate,PTIR)将大鼠分为有电针镇痛效果(responder,PTIR大于30%)和无镇痛效果组(non-responder,PTIR小于25%)。利用基因芯片技术分析有电针镇痛效果与无电针镇痛效果大鼠的下丘脑基因表达差异。芯片杂交设计采用等半交换(Half dye-swap)方法,一半有电针镇痛效果与一半无电针镇痛杂交的荧光组合为Cy3比Cy5,另一半为Cy5比Cy3。芯片扫描结果经Significance Analysis of Microarrays(SAM)软件包分析筛选两组间表达存在差异的基因。利用GeneTools在线软件,根据基因的生物学功能将差异表达基因进行功能分类。最后利用实时定量逆转录PCR(real-time quantitativeRT-PCR)方法验证部分差异表达基因。
结果:
(1)实验结果再次证实电针镇痛中存在着个体差异,约有30%的个体在电针后没有镇痛效果。PTIR在对照组平均升高7%,而在电针组平均升高了26%。
(2)在筛选出的两组间存在差异表达的66个基因中,有63个上调,有3个下调,上下调倍数最少为1.54倍。
(3)约半数(34个)差异表达基因可归入9个功能组,分别是离子转运、感知觉、突触发生与传递、信号转导、炎症反应、凋亡、转录、蛋白氨基酸磷酸化和G蛋白信号传导。
(4)钾离子电压门控通道调控的超家族成员H-7基因、γ-氨基丁酸A型受体、参与钠钙离子交换的Solute carrier family 8,member 3、突触囊泡糖蛋白2b、神经生长素1、黑皮质素4型受体和胃促进素前体共7个基因的RT-PCR验证结果与芯片分析结果基本一致。
结论:
本研究结果表明:电针镇痛中存在个体差异,这种个体差异可能与下丘脑的离子转运功能的相关基因、谷氨酸受体和神经生长素1基因的表达差异有关。这些基因有望成为痛觉研究的新靶点,值得进一步深入研究。另外,我们的实验结果提示:黑皮质素4型受体(Melanocortin 4 receptor,MC4R)基因、胃促进素前体(Ghrelin precursor)基因和激素敏感性脂肪酶(Lipase,hormone sensitive)基因有可能是电针疗法治疗肥胖的内在分子靶点,这一发现将有助于阐明电针减肥的具体分子机制。
第二部分束缚应激大鼠恢复速度个体差异的基因解析
目的:
利用基因芯片技术筛选大鼠下丘脑中可能参与束缚应激后恢复过程的差异基因,探讨不同个体对应激反应的差异性。
方法:
在大鼠束缚应激模型上,采用酶联免疫方法(ELISA)和放射免疫方法(RIA)测定应激开始前、应激结束时、恢复1小时后血浆皮质酮及ACTH水平。依据两种激素在应激2小时结束时的水平将试验组分为高反应组与低反应组。在高反应组中,根据应激结束至恢复1小时后血浆皮质酮及ACTH的下降程度分为快速恢复组与慢速恢复组。利用基因芯片技术分析快速恢复组与慢速恢复组大鼠下丘脑的基因表达差异。杂交设计采用了等半交换(half dye swap)的方法,即一半的高反应组对低反应组为Cy3比Cy5,另一半为Cy5比Cy3。根据芯片设计方案,我们采用了一种特殊的均一化(normalization)及固定效应方差分析(fixed effect ANOVA)模型对芯片数据进行了差异表达分析。最后采用实时定量逆转录PCR(real-time quantitative RT-PCR)对芯片分析的部分结果进行验证。
结果:
(1)我们发现束缚应激后血浆皮质酮及ACTH水平在不同个体间存在较大差异,即有的个体对束缚应激反应较强(应激结束时血浆皮质酮及ACTH浓度分别为27.41±3.23ug/dl及499.69±33.73pg/ml),有的个体较弱(应激结束时血浆皮质酮及ACTH浓度分别为12.01±1.91 ug/dl及434.21±31.28 pg/ml)。快速恢复组与慢速恢复组比较发现,应激结束后1小时血浆皮质酮及ACTH水平在两组间存在显著性差异。
(2)芯片分析结果显示快速恢复组与慢速恢复组间大多数基因并无差异表达。有差异表达的8个基因中,与整合素信号通路(integrin signaling pathway)相关的基因如踝蛋白(Talin)、丝氨酸/苏氨酸蛋白磷酸酯酶PP-β催化亚单位(Serine/threonineprotein phosphatase PP1-beta catalytic subunit)、整合素α-6前体(Integrin alpha-6precursor)和肌球蛋白Ⅸb(MyosinⅨb)在快速恢复组均上调1.5倍以上,而接合粘附分子1号(junctional adhesion molecule 1)有1.5倍下调。
(3)踝蛋白、整合素α-6前体等基因的Real-time RT-PCR验证结果与芯片分析结果基本一致。
结论:
本研究结果表明:相同的应激原(stressor)在不同个体可引起不同的应激反应,应激反应的恢复在不同的个体亦不相同,这种个体差异是否与下丘脑的整合素信号通路相关基因有关,本实验目前尚不能确定,有待于进一步研究。
PartⅠ.An individual variation study of electroacupuncture analgesia in rats using microarray
Objective:The aim of the present study is to probe candidate genes which were involved in the electro-acupuncture(EA) analgesia and to understand the molecular basis of the individual difference of EA analgesia in rats.
Methods:EA stimulation at the ST36 acupoints(Zusanli) was applied for 1h at 1Hz and nociceptive sensitivity was assessed by recording the tail-flick latency(TFL) induced by radiant heat.Responders and non-responders were determined by Pain Threshold Increase Rate(PTIR) in which the PTIR of responders is more than 30%while the PTIR of non-responders is less than 25%of control.We compared hypothalamus transcriptional profiles of responders with that of non-responders using oligonucleotide microarray.A half dye-swap design was applied so that half of the responder to non-responder comparisons are Cy3 to Cy5 and the other half are Cy5 to Cy3.Differential expressed genes were filtered using Significance Analysis of Microarrays(SAM) software package.Based on their biological function,the differential expressed genes were classified into different functional groups using GeneTools online software.At last,a real-time quantitative RT-PCR was applied to validate selected differential expressed genes.
Results:First,our results confirmed the individual variation of EA analgesia,there were about 30%animals showed no analgesia effect.Second,we found that 63 and 3 genes were up- and down-regulated in the responder group with the least fold change 1.54, respectively.Third,half of the differentially expressed genes were classified into 9 functional groups which were ion transport,sensory perception,synaptogenesis and synaptic transmission,signal transduction,inflammatory response,apoptosis,transcription, protein amino acid phosphorylation and G-protein signaling.Fourth,Quantitative RT-PCR results confirmed the microarray data.
Conclusion:Our study confirmed the individual difference of EA analgesia,this maybe result from the differential expressions of related genes in rat hypothalamus which were found in our study.These genes may become new targets for nociceptive study and deserve further investigation for developing new acupuncture therapy and intervention of pain modulation.
PartⅡ.An individual variation study of recovery speed from restraint stress in rats using microarray
Objective:The aim of the present study is to search novel genes which maybe involved in the recovery process after restraint(RES) stress in rats.
Methods:Using rat restraint stress model,blood samples were taken just before the exposure to RES,at the end of RES,1h after the termination of RES using tail-nick method. Plasma corticosterone and ACTH were measured using enzyme linked immunosorbent assay(ELISA) and radioimmunoassay(RIA),respectively.Based on the plasma corticosterone and ACTH levels at the end of RES,the RES rats were divided into high response group and low response group.Animals within the high response group were then divided into fast recovery group or slow recovery group which was determined by the decline of plasma ACTH and corticosterone levels during one hour recovery period after stress.We compared hypothalamus transcriptional profiles of two different recovery patterns(fast recovery vs slow recovery) from restraint stress in rats using oligonucleotide microarray.A half dye-swap design was applied so that half of the slow-to-fast recovery comparisons are Cy3 to Cy5 and the other half are Cy5 to Cy3.A special variation customized normalization for this data set was applied.A fixed effect ANOVA model was used for analyzing microarray data.A real-time quantitative RT-PCR was applied to validate the differential expressed genes.
Results:First,our results demonstrated that there is significant difference of plasma corticosterone and ACTH levels after 2h RES stress,that is,some individual had high response while others had low response for stress.Also,a significant difference were found between fast recovery group or slow recovery group concerning plasma ACTH and corticosterone levels during one hour recovery period after stress.Second,analysis of the microarray data showed that most of genes are not differentially expressed between fast VLA-6(integrin alpha-6 precursor) and Myosin IXb were at least 1.5 fold up-regulated in fast recovery group,while junctional adhesion molecule 1(Fllr) was 1.5 fold down-regulated in fast recovery group.Third,quantitative RT-PCR results confirmed the microarray data.
Conclusion:The present study demonstrated that different individual had different stress response even if they experienced same stressor.Meanwhile,the recovery process of restraint stress was also different.As it is not yet proved whether integrin signaling pathway was involved in the recovery from restraint stress in rats,further study will be needed to clarify the integrin signaling pathway-mediated recovery mechanism after stress.
目的:
利用基因芯片技术筛查大鼠下丘脑与电针镇痛相关的候选基因,以期寻找电针镇痛中出现个体差异的分子基础。
方法:
脉冲电流连接电针以1赫兹(Hz)频率刺激大鼠足三里穴位1小时。采用辐射热甩尾法(Tail-Flick Test)测定大鼠甩尾潜伏期(Tail-Flick Latency,TFL),以此作为痛阈指标。根据电针效果(痛阈提高率Pain Threshold Increase Rate,PTIR)将大鼠分为有电针镇痛效果(responder,PTIR大于30%)和无镇痛效果组(non-responder,PTIR小于25%)。利用基因芯片技术分析有电针镇痛效果与无电针镇痛效果大鼠的下丘脑基因表达差异。芯片杂交设计采用等半交换(Half dye-swap)方法,一半有电针镇痛效果与一半无电针镇痛杂交的荧光组合为Cy3比Cy5,另一半为Cy5比Cy3。芯片扫描结果经Significance Analysis of Microarrays(SAM)软件包分析筛选两组间表达存在差异的基因。利用GeneTools在线软件,根据基因的生物学功能将差异表达基因进行功能分类。最后利用实时定量逆转录PCR(real-time quantitativeRT-PCR)方法验证部分差异表达基因。
结果:
(1)实验结果再次证实电针镇痛中存在着个体差异,约有30%的个体在电针后没有镇痛效果。PTIR在对照组平均升高7%,而在电针组平均升高了26%。
(2)在筛选出的两组间存在差异表达的66个基因中,有63个上调,有3个下调,上下调倍数最少为1.54倍。
(3)约半数(34个)差异表达基因可归入9个功能组,分别是离子转运、感知觉、突触发生与传递、信号转导、炎症反应、凋亡、转录、蛋白氨基酸磷酸化和G蛋白信号传导。
(4)钾离子电压门控通道调控的超家族成员H-7基因、γ-氨基丁酸A型受体、参与钠钙离子交换的Solute carrier family 8,member 3、突触囊泡糖蛋白2b、神经生长素1、黑皮质素4型受体和胃促进素前体共7个基因的RT-PCR验证结果与芯片分析结果基本一致。
结论:
本研究结果表明:电针镇痛中存在个体差异,这种个体差异可能与下丘脑的离子转运功能的相关基因、谷氨酸受体和神经生长素1基因的表达差异有关。这些基因有望成为痛觉研究的新靶点,值得进一步深入研究。另外,我们的实验结果提示:黑皮质素4型受体(Melanocortin 4 receptor,MC4R)基因、胃促进素前体(Ghrelin precursor)基因和激素敏感性脂肪酶(Lipase,hormone sensitive)基因有可能是电针疗法治疗肥胖的内在分子靶点,这一发现将有助于阐明电针减肥的具体分子机制。
第二部分束缚应激大鼠恢复速度个体差异的基因解析
目的:
利用基因芯片技术筛选大鼠下丘脑中可能参与束缚应激后恢复过程的差异基因,探讨不同个体对应激反应的差异性。
方法:
在大鼠束缚应激模型上,采用酶联免疫方法(ELISA)和放射免疫方法(RIA)测定应激开始前、应激结束时、恢复1小时后血浆皮质酮及ACTH水平。依据两种激素在应激2小时结束时的水平将试验组分为高反应组与低反应组。在高反应组中,根据应激结束至恢复1小时后血浆皮质酮及ACTH的下降程度分为快速恢复组与慢速恢复组。利用基因芯片技术分析快速恢复组与慢速恢复组大鼠下丘脑的基因表达差异。杂交设计采用了等半交换(half dye swap)的方法,即一半的高反应组对低反应组为Cy3比Cy5,另一半为Cy5比Cy3。根据芯片设计方案,我们采用了一种特殊的均一化(normalization)及固定效应方差分析(fixed effect ANOVA)模型对芯片数据进行了差异表达分析。最后采用实时定量逆转录PCR(real-time quantitative RT-PCR)对芯片分析的部分结果进行验证。
结果:
(1)我们发现束缚应激后血浆皮质酮及ACTH水平在不同个体间存在较大差异,即有的个体对束缚应激反应较强(应激结束时血浆皮质酮及ACTH浓度分别为27.41±3.23ug/dl及499.69±33.73pg/ml),有的个体较弱(应激结束时血浆皮质酮及ACTH浓度分别为12.01±1.91 ug/dl及434.21±31.28 pg/ml)。快速恢复组与慢速恢复组比较发现,应激结束后1小时血浆皮质酮及ACTH水平在两组间存在显著性差异。
(2)芯片分析结果显示快速恢复组与慢速恢复组间大多数基因并无差异表达。有差异表达的8个基因中,与整合素信号通路(integrin signaling pathway)相关的基因如踝蛋白(Talin)、丝氨酸/苏氨酸蛋白磷酸酯酶PP-β催化亚单位(Serine/threonineprotein phosphatase PP1-beta catalytic subunit)、整合素α-6前体(Integrin alpha-6precursor)和肌球蛋白Ⅸb(MyosinⅨb)在快速恢复组均上调1.5倍以上,而接合粘附分子1号(junctional adhesion molecule 1)有1.5倍下调。
(3)踝蛋白、整合素α-6前体等基因的Real-time RT-PCR验证结果与芯片分析结果基本一致。
结论:
本研究结果表明:相同的应激原(stressor)在不同个体可引起不同的应激反应,应激反应的恢复在不同的个体亦不相同,这种个体差异是否与下丘脑的整合素信号通路相关基因有关,本实验目前尚不能确定,有待于进一步研究。
PartⅠ.An individual variation study of electroacupuncture analgesia in rats using microarray
Objective:The aim of the present study is to probe candidate genes which were involved in the electro-acupuncture(EA) analgesia and to understand the molecular basis of the individual difference of EA analgesia in rats.
Methods:EA stimulation at the ST36 acupoints(Zusanli) was applied for 1h at 1Hz and nociceptive sensitivity was assessed by recording the tail-flick latency(TFL) induced by radiant heat.Responders and non-responders were determined by Pain Threshold Increase Rate(PTIR) in which the PTIR of responders is more than 30%while the PTIR of non-responders is less than 25%of control.We compared hypothalamus transcriptional profiles of responders with that of non-responders using oligonucleotide microarray.A half dye-swap design was applied so that half of the responder to non-responder comparisons are Cy3 to Cy5 and the other half are Cy5 to Cy3.Differential expressed genes were filtered using Significance Analysis of Microarrays(SAM) software package.Based on their biological function,the differential expressed genes were classified into different functional groups using GeneTools online software.At last,a real-time quantitative RT-PCR was applied to validate selected differential expressed genes.
Results:First,our results confirmed the individual variation of EA analgesia,there were about 30%animals showed no analgesia effect.Second,we found that 63 and 3 genes were up- and down-regulated in the responder group with the least fold change 1.54, respectively.Third,half of the differentially expressed genes were classified into 9 functional groups which were ion transport,sensory perception,synaptogenesis and synaptic transmission,signal transduction,inflammatory response,apoptosis,transcription, protein amino acid phosphorylation and G-protein signaling.Fourth,Quantitative RT-PCR results confirmed the microarray data.
Conclusion:Our study confirmed the individual difference of EA analgesia,this maybe result from the differential expressions of related genes in rat hypothalamus which were found in our study.These genes may become new targets for nociceptive study and deserve further investigation for developing new acupuncture therapy and intervention of pain modulation.
PartⅡ.An individual variation study of recovery speed from restraint stress in rats using microarray
Objective:The aim of the present study is to search novel genes which maybe involved in the recovery process after restraint(RES) stress in rats.
Methods:Using rat restraint stress model,blood samples were taken just before the exposure to RES,at the end of RES,1h after the termination of RES using tail-nick method. Plasma corticosterone and ACTH were measured using enzyme linked immunosorbent assay(ELISA) and radioimmunoassay(RIA),respectively.Based on the plasma corticosterone and ACTH levels at the end of RES,the RES rats were divided into high response group and low response group.Animals within the high response group were then divided into fast recovery group or slow recovery group which was determined by the decline of plasma ACTH and corticosterone levels during one hour recovery period after stress.We compared hypothalamus transcriptional profiles of two different recovery patterns(fast recovery vs slow recovery) from restraint stress in rats using oligonucleotide microarray.A half dye-swap design was applied so that half of the slow-to-fast recovery comparisons are Cy3 to Cy5 and the other half are Cy5 to Cy3.A special variation customized normalization for this data set was applied.A fixed effect ANOVA model was used for analyzing microarray data.A real-time quantitative RT-PCR was applied to validate the differential expressed genes.
Results:First,our results demonstrated that there is significant difference of plasma corticosterone and ACTH levels after 2h RES stress,that is,some individual had high response while others had low response for stress.Also,a significant difference were found between fast recovery group or slow recovery group concerning plasma ACTH and corticosterone levels during one hour recovery period after stress.Second,analysis of the microarray data showed that most of genes are not differentially expressed between fast VLA-6(integrin alpha-6 precursor) and Myosin IXb were at least 1.5 fold up-regulated in fast recovery group,while junctional adhesion molecule 1(Fllr) was 1.5 fold down-regulated in fast recovery group.Third,quantitative RT-PCR results confirmed the microarray data.
Conclusion:The present study demonstrated that different individual had different stress response even if they experienced same stressor.Meanwhile,the recovery process of restraint stress was also different.As it is not yet proved whether integrin signaling pathway was involved in the recovery from restraint stress in rats,further study will be needed to clarify the integrin signaling pathway-mediated recovery mechanism after stress.
引文
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15.Wang Q,Mao L,J.Han.The arcuate nucleus of hypothalamus mediates low but not high frequency electroacupuncture analgesia in rats.Brain Res.1990;513:60-6.
16.Yu LC,Han JS.Involvement of arcuate nucleus of hypothalamus in the descending pathway from nucleus accumbens to periaqueductal grey subserving an antinociceptive effect.Int J Neurosci.1989;48:71-8.
17.Hsieh JC,Tu CH,Chen FP,Chen MC,Yeh TC,Cheng HC,Wu YT,Liu RS,Ho LT.Activation of the hypothalamus characterizes the acupuncture stimulation at the analgesic point in human:a positron emission tomography study.Neurosci Lett.2001;307:105-8.
18.华兴邦,周浩良.大鼠穴位图谱的研制.实验动物与动物实验.1991;20:1-3.
19.Grossman ML,Basbaum AI,Fields HL.Afferent and efferent connections of the rat tail flick reflex:a model used to analyse pain control mechanism.J.Comp.Neurol.1982;206:9-16.
20.Takeshige C,Tanaka M,Sato T,Hishida F.Mechanism of individual variation in effectiveness of acupuncture analgesia based on animal experiments.Eur J Pain.1990;110:109-13.
21.Reyes TM,Walker JR,DeCino C,Hogenesch JB,Sawchenko PE.Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus.J Neurosci.2003;23:5607-16.
22.Bueno Filho JS,Gilmour SG,Rosa GJ.Design of microarray experiments for genetical genomics studies.Genetics 2006;174:45-57.
23.Lee GS.Han JB.Shin MK.Hong MC.Kim SW.Min BI.Bae H.Enhancement of electroacupuncture-induced analgesic effect in cholecystokinin-A receptor deficient rats. Brain Res Bull. 2003;62:161-4.
24. Lee Y, Lee CH, Oh U. Painful channels in sensory neurons. Mol Cells. 2005; 20:315-24.
25. Ekberg J, Adams DJ. Neuronal voltage-gated sodium channel subtypes: key roles in inflammatory and neuropathic pain. Int J Biochem Cell Biol. 2006; 38:2005-10.
26. Gadotti VM, Tibola D, Flavia Paszcuk A, Rodrigues AL, Calixto JB, Santos AR. Contribution of spinal glutamatergic receptors to the antinociception caused by agmatine in mice. Brain Res. 2006; 1093:116-22.
27. Haghparast A, Gheitasi IP, Lashgari R. Involvement of glutamatergic receptors in the nucleus cuneiformis in modulating morphine-induced antinociception in rats. Eur J Pain. 2007 (MEDLINE查得) .
28. Song JY, Ichtchenko K, Sudhof TC, Brose N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci U S A. 1999; 96:1100-5.
29. Cabioglu MT, Ergene N. Electroacupuncture therapy for weight loss reduces serum total cholesterol, triglycerides, and LDL cholesterol levels in obese women. Am J Chin Med. 2005;33:525-33.
30. Lacey JM, Tershakovec AM, Foster GD. Acupuncture for the treatment of obesity: a review of the evidence. Int J Obes Relat Metab Disord. 2003; 27:419-27.
31. Nargund RP, Strack AM, Fong TM. Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem. 2006; 49:4035-43.
32. Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol. 2003; 457:213-35.
33. Fong TM, Van der Ploeg LH. A melanocortin agonist reduces neuronal firing rate in rat hypothalamic slices. Neurosci Lett. 2000; 283:5-8.
34. Vivenza D, Rapa A, Castellino N, Bellone S, Petri A, Vacca G, Aimaretti G, Broglio F, Bona G. Ghrelin gene polymorphisms and ghrelin, insulin, IGF-I, leptin and anthropometric data in children and adolescents. Eur J Endocrinol. 2004; 151:127-33.
35. Wren AM, Bloom SR. Gut hormones and appetite control. Gastroenterology. 2007;132: 2116-30.
1. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005 6:463-75.
2. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005; 67: 259-84.
3. Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 1992; 267: 1244-52.
4. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005;4:141-94.
5. Phillips DI, Jones A. Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses? J Physiol. 2006; 572:45-50.
6. Mayer EA, Fanselow MS. Dissecting the components of the central response to stress. Nat Neurosci. 2003; 10:1011-2.
7. Garcia A, Marti O, Valles A, Dal-Zotto S, Armario A. Recovery of the hypothalamic-pituitary-adrenal response to stress. Effect of stress intensity, stress duration and previous stress exposure. Neuroendocrinology. 2000; 72:114-25.
8. Linden W, Earle TL, Gerin W, Christenfeld N. Physiological stress reactivity and recovery: conceptual siblings separated at birth? J Psychosom Res. 1997; 42:117-35.
9. Garcia A, Armario A. Individual differences in the recovery of the hypothalamic-pituitary-adrenal axis after termination of exposure to a severe stressor in outbred male Sprague-Dawley rats. Psychoneuroendocrinology. 2001; 26:363-74.
10. Mormede P, Courvoisier H, Ramos A. Molecular genetic approaches to investigate individual variations in behavioral and neuroendocrine stress responses.Psychoneuroendocrinology. 2002; 27:563-83.
11. Bowman RE. Stress-induced changes in spatial memory are sexually differentiated and vary across the lifespan. J Neuroendocrinol. 2005; 17:526-35.
12. Lee HC, Chang DE, Yeom M, Kim GH, Choi KD, Shim I, Lee HJ, Hahm DH. Gene expression profiling in hypothalamus of immobilization-stressed mouse using cDNA microarray. Brain Res Mol Brain Res. 2005; 135: 293-300.
13. Tanaka T, Horikawa Y, Kawamoto T, Kabe-Sakurai N, Takeda J, Mikuni M. Expression profile of mRNAs from rat hippocampus and its application to microarray. Brain Res Mol Brain Res. 2004; 129:20-32.
14. Bueno Filho JS, Gilmour SG, Rosa GJ. Design of microarray experiments for genetical genomics studies. Genetics 2006; 174: 45-57.
15. Cui X, Churchill GA. Statistical tests for differential expression in cDNA microarray experiments. Genome Biol 2003; 4: 210.
16. Cui X, Hwang JT, Qiu J, Blades NJ, Churchill GA. Improved statistical tests for differential gene expression by shrinking variance components estimates. Biostatistics 2005; 6: 59-75.
17. Keller-Wood ME, Shinsako J, Keil LC, Dallman MR Insulin-induced hypoglycemia in conscious dogs: I. dose-related pituitary and adrenal responses. Endocrinology 1981; 109: 818-24.
18. Bertok L. Stress and nonspecific resistance. Ann NY Acad Sci, 1998; 851:1-2.
1.万德森.临床肿瘤学.北京:科学出版社,1999.112.
2.吴在德.外科学.第五版.北京:人民卫生出版社,2001.147-8.
3.Ulett GA,Han J,Hart S.Traditional and evidence-based acupuncture:history,mechanisms,and present status.South Med J.1998;91:1115-20.
4.韩济生.针刺镇痛及其相关神经通路和神经介质.生理科学进展.1984;15:294-9.
5.刘乡.以痛治痛.针刺镇痛的基本神经机制.科学通报.2001;46:609-15.
6.韩济生.内源性镇痛系统.生理科学进展.生理科学进展.1981;12:104-8.
7.矫勇益,端木肇夏,俞光第,印其章.刺激下丘脑弓状核或垂体前叶对丘脑束旁核神经元伤害性反应的抑制.生理学报.1995;47:423-8.
8.陈其亮,李金华,周志菁,印其章.损毁或刺激垂体和下丘脑弓状核对大鼠痛觉调 制的影响.生理学报.1995;47:505-9.
9.张难,印其章.大鼠蓝斑参与下丘脑弓状核区注射谷氨酸单钠的镇痛效应.生理学报.1988;40:529-38.
10.Cabyoglu MT,Ergene N,Tan U.The mechanism of acupuncture and clinical applications.Int J Neurosci.2006;116:115-25.
11.Hart JS.Acupuncture and endorphins.Neurosci Lett.2004;361:258-61.
12.Weigent DA,Blalock JE.Associations between the neuroendocrine and immune systems.J Leukoe Biol.1995;58:137-50.
13.Cooper PE,Martin JB.Neuroendoerinology and brain peptides.n Neurol.1980;8:551-7.
14.鞠大宏,杨介宾,宋开源.针刺镇痛的神经内分泌免疫调节环路的实验研究.中国中医基础医学杂志.1998;4:29-32.
15.Cho ZH,Hwang SC,Wong EK,Son YD,Kang CK,Park TS,Bai S J,Kim YB,Lee YB,Sung KK,Lee BH,Shepp LA,Min KT.Neural substrates,experimental evidences and functional hypothesis of acupuncture mechanisms.Acta Neurol Stand.2006;113:370-7.
16.Wang H,Yu M,Ochani M,Amella CA,Tanovic M,Susarla S,Li JH,Wang H,Yang H,Ulloa L,AI-Abed Y,Czura C J,Tracey KJ.Nicotinic acetylcholine receptor alpha7subunit is an essential regulator of inflammation.Nature.2003;421:384-8.
17.Son YS,Park HJ,Kwon OB,Jung SC,Shin HC,Lim S.Antipyretie effects of acupuncture on the lipopolysaccharide-indueed fever and expression of interleukin-6and interleukin-I beta mRNAs in the hypothalamus of rats.Neurosci Lett.2002;319:45-8.
18.Mori H,Nishijo K,Kawamura H,Abo T.Unique immunomodulation by electro-acupuncture in humans possibly via stimulation of the autonomic nervous system.Neurosci Lett.2002;320:21-4.
19.Hahrn ET,Lee J J,Lee WK,Bae HS,Min BI,Cho YW.Electroaeupuneture enhancement of natural killer cell activity suppressed by anterior hypothalarnic lesions in rats.Neuroimmunomodulation.2004;11:268-72.
20.Maier SF,Goehler LE,Fleshner M,Watkins LR.The role of the vagus nerve in cytokine-to-brain communication.Ann N Y Acad Sci 1998;840:289-300.
21.Tracey KJ.The inflammatory reflex.Nature 2002;420:853-9
22. Tian N, Wang F, Tian DR, Zou Y, Wang SW, Guan LL, Shi YS, Chang JK, Yang J, Han JS. Electroacupuncture suppresses expression of gastric ghrelin and hypothalamic NPY in chronic food restricted rats. Peptides. 2006; 27:2313-20.
23. Liu JH, Yan J, Yi SX, Chang XR, Lin YP, Hu JM. Effects of electroacupuncture on gastric myoelectric activity and substance P in the dorsal vagal complex of rats. Neurosci Lett. 2004; 356:99-102.
24. Xiong LZ, Yang J, Wang Q, Lu ZH. Involvement of delta-and mu-opioid receptors in the delayed cerebral ischemic tolerance induced by repeated electroacupuncture preconditioning in rats. Chin Med J (Engl). 2007; 120:394-9.
25. Wu LZ, Cui CL, Tian JB, Ji D, Han JS. Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and kappa-opioid receptor implicated. Brain Res. 1999 ;851:290-6.
26. Fu X, Wang YQ, Wu GC. Involvement of nociceptin/orphanin FQ and its receptor in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation. Brain Res. 2006; 1078:212-8.
27. Han JS. Cholecystokinin octapeptide (CCK-8): a negative feedback control mechanism for opioid analgesia. Prog Brain Res. 1995; 105:263-71.
28. Bai B, Wang H, Liu WY, Song CY. Effect of anti-opioid peptide sera on the enhancement of electroacupuncture analgesia induced by neurotensin in PAG of rats. Sheng Li Xue Bao. 1999; 51:224-8.
29. Wang XL, Zhang TF, Zhang HX, Mao HR, Huang GF. Therapeutic effects of acupoint injection at cervical Jiaji points and effects on ET and CGRP in the patient of ischemic stroke. Zhongguo Zhen Jiu. 2007;27:93-5.
30. Yi SX, Yang RD, Yan J, Chang XR, Ling YP. Effect of electro-acupuncture at Foot-Yangming Meridian on somatostatin and expression of somatostatin receptor genes in rabbits with gastric ulcer. World J Gastroenterol. 2006;12:1761-5.
31. Yang J, Liu WY, Song CY, Lin BC. Only arginine vasopressin, not oxytocin and endogenous opiate peptides, in hypothalamic paraventricular nucleus play a role in acupuncture analgesia in the rat. Brain Res Bull. 2006; 68:453-8.
32. Yang J, Liu WY, Song CY, Lin BC. Through central arginine vasopressin, not oxytocin and endogenous opiate peptides, glutamate sodium induces hypothalamic paraventricular nucleus enhancing acupuncture analgesia in the rat. Neurosci Res. 2006; 54:49-56.
33. Uvnas-Moberg K, Bruzelius G, Alster P, Lundeberg T. The antinociceptive effect of non-noxious sensory stimulation is mediated partly through oxytocinergic mechanisms. Acta Physiol Scand. 1993; 149:199-204.
34. Pan B, Castro-Lopes JM, Coimbra A. Activation of anterior lobe corticotrophs by electroacupuncture or noxious stimulation in the anaesthetized rat, as shown by colocalization of Fos protein with ACTH and beta-endorphin and increased hormone release. Brain Res Bull. 1996;40:175-82.
35. Tsuchiya M, Sato EF, Inoue M, Asada A. Acupuncture enhances generation of nitric oxide and increases local circulation. Anesth Analg. 2007; 104:301-7.
36. Jung JY, Yang HR, Jeong YJ, Vang MS, Park SW, Oh WM, Kim SH, Youn DH, Na CS, Kim WJ. Effects of acupuncture on c-Fos expression in brain after noxious tooth stimulation of the rat. Am J Chin Med. 2006; 34:989-1003.
37. Wang TT, Yuan WL, Ke Q, Song XB, Zhou X, Kang Y, Zhang HT, Lin Y, Hu YL, Feng ZT, Wu LL, Zhou XF. Effects of electro-acupuncture on the expression of c-jun and c-fos in spared dorsal root ganglion and associated spinal laminae following removal of adjacent dorsal root ganglia in cats. Neuroscience. 2006; 140:1169-76.
38. Petti FB, Liguori A, Ippoliti F. Study on cytokines IL-2, IL-6, IL-10 in patients of chronic allergic rhinitis treated with acupuncture. J Tradit Chin Med. 2002; 22:104-11.
39. Yang QG, Hang YN, Sun DJ, Chen XM, Wang XR, Xu CR, Yao JL. Changes of IFN-gamma, IL-2, IL-6 and IL-10 in the patient with cardiac surgery under combined acupuncture anesthesia. Zhongguo Zhen Jiu. 2006; 26:503-6.
40. Stener-Victorin E, Lundeberg T, Waldenstrom U, Manni L, Aloe L, Gunnarsson S, Janson PO. Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced Polycystic ovaries. Biol Reprod. 2000;63:1497-503.
2.王跃秀.针刺镇痛机制的研究进展.北京中医.2004;23:52-5.
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4.Takeshige C,Murai M,Tanaka M,Hachisu M.Parallel individual variations in the effectiveness of acupuncture,morphine analgesia,and dorsal PAG-SPA and their abolition by D-phenylalanine.Adv.Pain.Res.Ther.1983;5:563-9.
5.Takeshige C,Oka K,Mizuno T,Hisamitsu T,Luo CP,Kobori M,Mera H,Fang TQ.The acupuncture point and its connecting central pathway for producing acupuncture analgesia.Brain Res Bull.1993;30:53-67.
6.Sudakov SK,Borisova EV,Lyupina YV.Influence of inheritance and fostering on sensitivity to effects of morphine on nocieeption and locomotor activity in two inbred rat strains.Neuropharmacology.1996;35:1131-4.
7.李有田,柏玉萍,富琦.针刺后溪穴治疗面肌抽搐的临床研究.针刺研究.1999;2:90-2.
8.姜俊,严振国,邰浩清,刘俭喧,高维汉.针刺治疗原发性青光眼的临床与实验研究.针刺研究.1999;2:95-7.
9.Chae Y,Park HJ,Hahm DH,Yi SH,Lee H.Individual differences of acupuncture analgesia in humans using cDNA microarray.J Physiol Sci.2006;56:425-31.
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11.ShenWX,Yin WP,Yin QZ.The role of dorsal raphe nucleus in the effect of hypothalamic arcuate nucleus stimulation and electroacupuncture on the nociceptive responses of locus coeruleus neurons.Selection from article abstracts on acupuncture and moxibustion.1987;500-1.
12.Shao LR,Zhang HQ,Duanmu ZX,Yin QZ.Involvement of pituitary β-endorphin in the antinociception induced by hypothalamic arcuate nucleus stimulation.Chin.J Physiol Sci.1995;11:97-100.
13.Gu F,Guo SY,Yin QZ.Influence of lateral ventricle injection of anti-endorphin serum on analgesia produced by hypothalamic arcuate nucleus stimulation in rats.Chin J Physiol Sci.1986;2:385-7.
14.闫丽萍,马骋,项晓人,何崇,刘志诚,王玲玲.电针对大鼠丘脑背内侧核痛敏神经元放电的影响.中国中医药科技.2003;3:129-31.
15.Wang Q,Mao L,J.Han.The arcuate nucleus of hypothalamus mediates low but not high frequency electroacupuncture analgesia in rats.Brain Res.1990;513:60-6.
16.Yu LC,Han JS.Involvement of arcuate nucleus of hypothalamus in the descending pathway from nucleus accumbens to periaqueductal grey subserving an antinociceptive effect.Int J Neurosci.1989;48:71-8.
17.Hsieh JC,Tu CH,Chen FP,Chen MC,Yeh TC,Cheng HC,Wu YT,Liu RS,Ho LT.Activation of the hypothalamus characterizes the acupuncture stimulation at the analgesic point in human:a positron emission tomography study.Neurosci Lett.2001;307:105-8.
18.华兴邦,周浩良.大鼠穴位图谱的研制.实验动物与动物实验.1991;20:1-3.
19.Grossman ML,Basbaum AI,Fields HL.Afferent and efferent connections of the rat tail flick reflex:a model used to analyse pain control mechanism.J.Comp.Neurol.1982;206:9-16.
20.Takeshige C,Tanaka M,Sato T,Hishida F.Mechanism of individual variation in effectiveness of acupuncture analgesia based on animal experiments.Eur J Pain.1990;110:109-13.
21.Reyes TM,Walker JR,DeCino C,Hogenesch JB,Sawchenko PE.Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus.J Neurosci.2003;23:5607-16.
22.Bueno Filho JS,Gilmour SG,Rosa GJ.Design of microarray experiments for genetical genomics studies.Genetics 2006;174:45-57.
23.Lee GS.Han JB.Shin MK.Hong MC.Kim SW.Min BI.Bae H.Enhancement of electroacupuncture-induced analgesic effect in cholecystokinin-A receptor deficient rats. Brain Res Bull. 2003;62:161-4.
24. Lee Y, Lee CH, Oh U. Painful channels in sensory neurons. Mol Cells. 2005; 20:315-24.
25. Ekberg J, Adams DJ. Neuronal voltage-gated sodium channel subtypes: key roles in inflammatory and neuropathic pain. Int J Biochem Cell Biol. 2006; 38:2005-10.
26. Gadotti VM, Tibola D, Flavia Paszcuk A, Rodrigues AL, Calixto JB, Santos AR. Contribution of spinal glutamatergic receptors to the antinociception caused by agmatine in mice. Brain Res. 2006; 1093:116-22.
27. Haghparast A, Gheitasi IP, Lashgari R. Involvement of glutamatergic receptors in the nucleus cuneiformis in modulating morphine-induced antinociception in rats. Eur J Pain. 2007 (MEDLINE查得) .
28. Song JY, Ichtchenko K, Sudhof TC, Brose N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci U S A. 1999; 96:1100-5.
29. Cabioglu MT, Ergene N. Electroacupuncture therapy for weight loss reduces serum total cholesterol, triglycerides, and LDL cholesterol levels in obese women. Am J Chin Med. 2005;33:525-33.
30. Lacey JM, Tershakovec AM, Foster GD. Acupuncture for the treatment of obesity: a review of the evidence. Int J Obes Relat Metab Disord. 2003; 27:419-27.
31. Nargund RP, Strack AM, Fong TM. Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem. 2006; 49:4035-43.
32. Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol. 2003; 457:213-35.
33. Fong TM, Van der Ploeg LH. A melanocortin agonist reduces neuronal firing rate in rat hypothalamic slices. Neurosci Lett. 2000; 283:5-8.
34. Vivenza D, Rapa A, Castellino N, Bellone S, Petri A, Vacca G, Aimaretti G, Broglio F, Bona G. Ghrelin gene polymorphisms and ghrelin, insulin, IGF-I, leptin and anthropometric data in children and adolescents. Eur J Endocrinol. 2004; 151:127-33.
35. Wren AM, Bloom SR. Gut hormones and appetite control. Gastroenterology. 2007;132: 2116-30.
1. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005 6:463-75.
2. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005; 67: 259-84.
3. Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 1992; 267: 1244-52.
4. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005;4:141-94.
5. Phillips DI, Jones A. Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses? J Physiol. 2006; 572:45-50.
6. Mayer EA, Fanselow MS. Dissecting the components of the central response to stress. Nat Neurosci. 2003; 10:1011-2.
7. Garcia A, Marti O, Valles A, Dal-Zotto S, Armario A. Recovery of the hypothalamic-pituitary-adrenal response to stress. Effect of stress intensity, stress duration and previous stress exposure. Neuroendocrinology. 2000; 72:114-25.
8. Linden W, Earle TL, Gerin W, Christenfeld N. Physiological stress reactivity and recovery: conceptual siblings separated at birth? J Psychosom Res. 1997; 42:117-35.
9. Garcia A, Armario A. Individual differences in the recovery of the hypothalamic-pituitary-adrenal axis after termination of exposure to a severe stressor in outbred male Sprague-Dawley rats. Psychoneuroendocrinology. 2001; 26:363-74.
10. Mormede P, Courvoisier H, Ramos A. Molecular genetic approaches to investigate individual variations in behavioral and neuroendocrine stress responses.Psychoneuroendocrinology. 2002; 27:563-83.
11. Bowman RE. Stress-induced changes in spatial memory are sexually differentiated and vary across the lifespan. J Neuroendocrinol. 2005; 17:526-35.
12. Lee HC, Chang DE, Yeom M, Kim GH, Choi KD, Shim I, Lee HJ, Hahm DH. Gene expression profiling in hypothalamus of immobilization-stressed mouse using cDNA microarray. Brain Res Mol Brain Res. 2005; 135: 293-300.
13. Tanaka T, Horikawa Y, Kawamoto T, Kabe-Sakurai N, Takeda J, Mikuni M. Expression profile of mRNAs from rat hippocampus and its application to microarray. Brain Res Mol Brain Res. 2004; 129:20-32.
14. Bueno Filho JS, Gilmour SG, Rosa GJ. Design of microarray experiments for genetical genomics studies. Genetics 2006; 174: 45-57.
15. Cui X, Churchill GA. Statistical tests for differential expression in cDNA microarray experiments. Genome Biol 2003; 4: 210.
16. Cui X, Hwang JT, Qiu J, Blades NJ, Churchill GA. Improved statistical tests for differential gene expression by shrinking variance components estimates. Biostatistics 2005; 6: 59-75.
17. Keller-Wood ME, Shinsako J, Keil LC, Dallman MR Insulin-induced hypoglycemia in conscious dogs: I. dose-related pituitary and adrenal responses. Endocrinology 1981; 109: 818-24.
18. Bertok L. Stress and nonspecific resistance. Ann NY Acad Sci, 1998; 851:1-2.
1.万德森.临床肿瘤学.北京:科学出版社,1999.112.
2.吴在德.外科学.第五版.北京:人民卫生出版社,2001.147-8.
3.Ulett GA,Han J,Hart S.Traditional and evidence-based acupuncture:history,mechanisms,and present status.South Med J.1998;91:1115-20.
4.韩济生.针刺镇痛及其相关神经通路和神经介质.生理科学进展.1984;15:294-9.
5.刘乡.以痛治痛.针刺镇痛的基本神经机制.科学通报.2001;46:609-15.
6.韩济生.内源性镇痛系统.生理科学进展.生理科学进展.1981;12:104-8.
7.矫勇益,端木肇夏,俞光第,印其章.刺激下丘脑弓状核或垂体前叶对丘脑束旁核神经元伤害性反应的抑制.生理学报.1995;47:423-8.
8.陈其亮,李金华,周志菁,印其章.损毁或刺激垂体和下丘脑弓状核对大鼠痛觉调 制的影响.生理学报.1995;47:505-9.
9.张难,印其章.大鼠蓝斑参与下丘脑弓状核区注射谷氨酸单钠的镇痛效应.生理学报.1988;40:529-38.
10.Cabyoglu MT,Ergene N,Tan U.The mechanism of acupuncture and clinical applications.Int J Neurosci.2006;116:115-25.
11.Hart JS.Acupuncture and endorphins.Neurosci Lett.2004;361:258-61.
12.Weigent DA,Blalock JE.Associations between the neuroendocrine and immune systems.J Leukoe Biol.1995;58:137-50.
13.Cooper PE,Martin JB.Neuroendoerinology and brain peptides.n Neurol.1980;8:551-7.
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