抗感2号解热镇痛作用及其解热机制的实验研究
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摘要
前言
中药是中华民族的宝贵财富，前人早已发现中药有药效可靠平缓、副作用小的特点。近年不断有新药开发出来。抗感2号就是新近开发的中药复方制剂，其主要成份有葛根、连翘、穿心莲、藿香等。在国内申报新药之前，我们运用生理学和药理学方法对其进行了解热、镇痛、抗炎、体外抑菌等方面的药效学研究。本论文主要研究抗感2号在解热、镇痛方面作用并从中枢发热介质的角度探讨其解热的化学信息传递机制。为抗感2号的临床应用和进一步开发利用提供实验依据和理论基础。
实验材料
1．实验对象：健康雄性Wistar系大鼠、健康昆明种小鼠
2．实验试剂及用药：抗感2号粉剂；干酵母；2，4-二硝基苯酚；巴米尔；液氮及氮气；cAMP放免测定药盒
3．实验仪器：数字型温度计(SY-2型)；热板测痛仪(GS-840型)；液体闪烁计数仪(LS6500型)
实验方法
1．酵母发热实验：实验动物分六组：正常对照组、模型组、阳性药组(200m／kg)、中药三个剂量组(217mg／kg、435mg／kg、870mg／kg)。用干酵母复制发热动物模型，用三种剂量抗感2号观察其对发热的影响，并用阳性药物作对照。
2．2，4-二硝基苯酚发热实验：动物分组同上，阳性药组(100mg／kg)，中药三个剂量(109mg／kg、217mg／kg、435mg／kg)。与上一实验不同的是，造模前各组做预防给药连续灌胃三天。
3．醋酸致痛扭体实验：小鼠随机分成六组：正常对照组、阳性对照组、中药四个剂量组(742mg／kg、1484mg／kg、2968mg／kg、5936mg／kg)。向小鼠
腹腔注射醋酸溶液复制疼痛模型，观察抗感2号对疼痛的影响。
4.热板致痛实验:动物分组同前，通过测量小鼠痛闭值的变化，观察其
对疼痛的影响。
5.大鼠下丘脑组织cAMP含量测定实验:发热实验部分同实验1，动物
分四组:正常对照组、模型组、中药两组(217m扩kg、435m群kg)。测温至6h
断头处死动物，取出下丘脑组织投人液氮中固定，按试剂盒说明书进行
cAMP含量的测定。
结果
在酵母性发热实验中，模型组与正常组相比体温变化值P<0.001，中
药组与模型组相比，温差有统计学意义，抗感2号能显著抑制大鼠体温升高
(P<0.01)。其中中剂量组(435m扩kg)效果最好(P<0.001)。该药还能
预防2，4一二硝基苯酚所致大鼠发热。药物镇痛方面，其对醋酸致痛小鼠扭
体反应有明显的抑制作用(P<0.001)，对热板法致痛有明显提高痛阑值作
用(P<0.01)，且呈量效关系。模型组下丘脑组织cAMP含量升高(P<0.
05)，中药组与模型组相比，抗感2号能抑制cAMP含量的升高(P<0.05)。
结论
1.本实验证明了中药抗感2号对酵母和2，4一二硝基苯酚性发热大鼠有
明显的解热作用，并有一定量效关系。
.抗感2号对醋酸致小鼠扭体和热板致痛都有明显抑制和镇痛作用。
.抗感2号可明显抑制酵母性发热时下丘脑组织中cAMP含量的升
局。
4.实验结果提示:抗感2号可通过抑制下丘脑组织中cAMP含量的升
高，而发挥其解热作用。
The Chinese traditional medicine is our precious treasure. Recently more and more new herbs have been impoldered. The anti-fever 2 whose main components are Puerariae Eordythia Andrographis Paniculata and Agastache is just a new compound agent. Before reporting it to a higher authority, we take physiological and pharmacological methods to observe its antipyretic analgesic anti-inflammatory in vitro bacterisostatic effects. This paper mainly talk over the antipyretic and analgesic effects of anti-fever 2 on laboratory animals and how it brings into full play. Our purpose is to introduce experimental thereunder and theoretic base for clinical use and further usage.
Materials
1. Animal; male Wistar rats^KunMing mice
2. Drug: anti-fever 2 powder dry yeast Dinitrophenol Aspirin liguid nitro-gon Nitrogen gas cAMP radioimmunoassay Test Kit
3. Instrument: digital thermometer ( SY-2 ) pain threshold detector ( GS-840) Jiquid scintillator(LS6500)
Methods
1. Fever induced by yeast: The animals were divided into six groups: control group, model group, positive drug group (200mg/kg) , three herb groups (217mg/kg, 435mg/kg, 870mg/kg). The experiment was carried out on rat
models by using dry-yeast as pyretogenic agent. We choose three dosage of herb to observe the antipyretic effect of anti-fever 2 and aspirin as control.
2. Fever induced by dinitrophenol; Group dividing is as same as experiment 1. Drugs were administered continuously for three days as follows: positive drug (100mg/kg) , three herb groups (109mg/kg, 217mg/kg, 435mg/kg) , control group (salt water) , model group (salt water). Then we began to make models. 3. Writhing test: The mice were divided into six groups randomly: control group, positive drug group ( 300mg/kg) , four herb groups ( 742mg/kg, 1484mg/kg, 2986mg/kg, 5936mg/kg). The analgesic effect was determined with mouse writhing method of celiac acetum injecting.
4. Hot plat test; Group dividing is as same as experiment 3. Through measuring the changes of pain threshold, we observed analgesic effect of anti-fever 2.
5. Assay of cAMP content in hypothalamus of rats: Model building is the same as experiment 1. There were total four groups: control group, model group, two herb groups (217mg/kg, 435mg/kg). After 6 hours of yeast injection, rats were decapitated quickly and hypothalamus tissues were taken out and put into liquid nitrogen for fixation. Then we began to assay the cAMP content in hypothalamus according to specification of the Test Kit.
Results
In the yeast inducing fever test compared with control group the changes of rats'temperature in model group are obvious (P <0. 001) . Compared with model group the changes of temperature in herb groups have statistical significance. Anti-fever 2 can significantly inhibit uprise of temperature in rats induced by yeast (P<0.01). The medial dosage (435mg/kg) has the best effect (P<0. 001). The durg can also prevent fever induced by dinitrophenol. In analgesic studies using hot plat test and writhing test on mice anti-fever 2 has obvious inhibition of ache induced by acetum(P <0. 001) and can raise pain threshold of mice on hot plat evidently ( P <0.01). Compared with control group the anti-fever can inhibit the rise of cAMP content in the hypothalamus of rats ( P < 0. 05).
Conclusion
1. Our test has proved that anti-fever 2 has significant antipyretic effect on fevered rats induced by dry-yeast and dinitrophenol.
2. In Writhing test and hot plat test anti-fever 2 has significant analgesic effect on model mice.
3. Anti-fever 2 can distinctly inhibit the rise of cAMP content in hypothala-mus tissues of fevered rats.
4. These facts suggest that anti-fever 2 possesses obvious antipyretic effect on fever rats and its action may be mediated by lowering cAMP level in hypothal-amus.
中药是中华民族的宝贵财富，前人早已发现中药有药效可靠平缓、副作用小的特点。近年不断有新药开发出来。抗感2号就是新近开发的中药复方制剂，其主要成份有葛根、连翘、穿心莲、藿香等。在国内申报新药之前，我们运用生理学和药理学方法对其进行了解热、镇痛、抗炎、体外抑菌等方面的药效学研究。本论文主要研究抗感2号在解热、镇痛方面作用并从中枢发热介质的角度探讨其解热的化学信息传递机制。为抗感2号的临床应用和进一步开发利用提供实验依据和理论基础。
实验材料
1．实验对象：健康雄性Wistar系大鼠、健康昆明种小鼠
2．实验试剂及用药：抗感2号粉剂；干酵母；2，4-二硝基苯酚；巴米尔；液氮及氮气；cAMP放免测定药盒
3．实验仪器：数字型温度计(SY-2型)；热板测痛仪(GS-840型)；液体闪烁计数仪(LS6500型)
实验方法
1．酵母发热实验：实验动物分六组：正常对照组、模型组、阳性药组(200m／kg)、中药三个剂量组(217mg／kg、435mg／kg、870mg／kg)。用干酵母复制发热动物模型，用三种剂量抗感2号观察其对发热的影响，并用阳性药物作对照。
2．2，4-二硝基苯酚发热实验：动物分组同上，阳性药组(100mg／kg)，中药三个剂量(109mg／kg、217mg／kg、435mg／kg)。与上一实验不同的是，造模前各组做预防给药连续灌胃三天。
3．醋酸致痛扭体实验：小鼠随机分成六组：正常对照组、阳性对照组、中药四个剂量组(742mg／kg、1484mg／kg、2968mg／kg、5936mg／kg)。向小鼠
腹腔注射醋酸溶液复制疼痛模型，观察抗感2号对疼痛的影响。
4.热板致痛实验:动物分组同前，通过测量小鼠痛闭值的变化，观察其
对疼痛的影响。
5.大鼠下丘脑组织cAMP含量测定实验:发热实验部分同实验1，动物
分四组:正常对照组、模型组、中药两组(217m扩kg、435m群kg)。测温至6h
断头处死动物，取出下丘脑组织投人液氮中固定，按试剂盒说明书进行
cAMP含量的测定。
结果
在酵母性发热实验中，模型组与正常组相比体温变化值P<0.001，中
药组与模型组相比，温差有统计学意义，抗感2号能显著抑制大鼠体温升高
(P<0.01)。其中中剂量组(435m扩kg)效果最好(P<0.001)。该药还能
预防2，4一二硝基苯酚所致大鼠发热。药物镇痛方面，其对醋酸致痛小鼠扭
体反应有明显的抑制作用(P<0.001)，对热板法致痛有明显提高痛阑值作
用(P<0.01)，且呈量效关系。模型组下丘脑组织cAMP含量升高(P<0.
05)，中药组与模型组相比，抗感2号能抑制cAMP含量的升高(P<0.05)。
结论
1.本实验证明了中药抗感2号对酵母和2，4一二硝基苯酚性发热大鼠有
明显的解热作用，并有一定量效关系。
.抗感2号对醋酸致小鼠扭体和热板致痛都有明显抑制和镇痛作用。
.抗感2号可明显抑制酵母性发热时下丘脑组织中cAMP含量的升
局。
4.实验结果提示:抗感2号可通过抑制下丘脑组织中cAMP含量的升
高，而发挥其解热作用。
The Chinese traditional medicine is our precious treasure. Recently more and more new herbs have been impoldered. The anti-fever 2 whose main components are Puerariae Eordythia Andrographis Paniculata and Agastache is just a new compound agent. Before reporting it to a higher authority, we take physiological and pharmacological methods to observe its antipyretic analgesic anti-inflammatory in vitro bacterisostatic effects. This paper mainly talk over the antipyretic and analgesic effects of anti-fever 2 on laboratory animals and how it brings into full play. Our purpose is to introduce experimental thereunder and theoretic base for clinical use and further usage.
Materials
1. Animal; male Wistar rats^KunMing mice
2. Drug: anti-fever 2 powder dry yeast Dinitrophenol Aspirin liguid nitro-gon Nitrogen gas cAMP radioimmunoassay Test Kit
3. Instrument: digital thermometer ( SY-2 ) pain threshold detector ( GS-840) Jiquid scintillator(LS6500)
Methods
1. Fever induced by yeast: The animals were divided into six groups: control group, model group, positive drug group (200mg/kg) , three herb groups (217mg/kg, 435mg/kg, 870mg/kg). The experiment was carried out on rat
models by using dry-yeast as pyretogenic agent. We choose three dosage of herb to observe the antipyretic effect of anti-fever 2 and aspirin as control.
2. Fever induced by dinitrophenol; Group dividing is as same as experiment 1. Drugs were administered continuously for three days as follows: positive drug (100mg/kg) , three herb groups (109mg/kg, 217mg/kg, 435mg/kg) , control group (salt water) , model group (salt water). Then we began to make models. 3. Writhing test: The mice were divided into six groups randomly: control group, positive drug group ( 300mg/kg) , four herb groups ( 742mg/kg, 1484mg/kg, 2986mg/kg, 5936mg/kg). The analgesic effect was determined with mouse writhing method of celiac acetum injecting.
4. Hot plat test; Group dividing is as same as experiment 3. Through measuring the changes of pain threshold, we observed analgesic effect of anti-fever 2.
5. Assay of cAMP content in hypothalamus of rats: Model building is the same as experiment 1. There were total four groups: control group, model group, two herb groups (217mg/kg, 435mg/kg). After 6 hours of yeast injection, rats were decapitated quickly and hypothalamus tissues were taken out and put into liquid nitrogen for fixation. Then we began to assay the cAMP content in hypothalamus according to specification of the Test Kit.
Results
In the yeast inducing fever test compared with control group the changes of rats'temperature in model group are obvious (P <0. 001) . Compared with model group the changes of temperature in herb groups have statistical significance. Anti-fever 2 can significantly inhibit uprise of temperature in rats induced by yeast (P<0.01). The medial dosage (435mg/kg) has the best effect (P<0. 001). The durg can also prevent fever induced by dinitrophenol. In analgesic studies using hot plat test and writhing test on mice anti-fever 2 has obvious inhibition of ache induced by acetum(P <0. 001) and can raise pain threshold of mice on hot plat evidently ( P <0.01). Compared with control group the anti-fever can inhibit the rise of cAMP content in the hypothalamus of rats ( P < 0. 05).
Conclusion
1. Our test has proved that anti-fever 2 has significant antipyretic effect on fevered rats induced by dry-yeast and dinitrophenol.
2. In Writhing test and hot plat test anti-fever 2 has significant analgesic effect on model mice.
3. Anti-fever 2 can distinctly inhibit the rise of cAMP content in hypothala-mus tissues of fevered rats.
4. These facts suggest that anti-fever 2 possesses obvious antipyretic effect on fever rats and its action may be mediated by lowering cAMP level in hypothal-amus.
引文
1．范书铎，孙丽华，梁强等．葛根素对发热兔解热作用的实验研究．中国医科大学学报．1991，20(4)：250-252，256
2．范书铎，孙丽华，吴玉环等．葛根素、生石膏配伍对致热原作用下猫POAH温敏神经元放电的影响．中国应用生理学杂志．1997，13(1)：71-74
3．刘自明．中药退热灵合剂的解热作用分析．北京中医．1999(2)：51-52
4. Dinaraello CA, Cannon JG, Wolff SM. New concepts on the pathogenesis of fever. Rev Infect Dis,1988,10( 1 ) :168-189
5. Steiner AA, Branco LGS. Role of the preoptic carbon monoxide pathway in endotoxin fever in rats. Brain Research,2002,927 (1) :27-34
6. Kluger MJ. Fever:Role of pyrogens and cryogens. Physiol Rev, 1991,71 (1) :93-127
7．李楚杰．发热机制研究的新进展．中国病理生理杂志．1990，6(5)：375-380
8. Bligh J. Effects on temperature of monoamines injected into the lateral ventricles of sleep. J Phsiol, 1966,185:46
9．方剑乔，陈海英，刘金洪等．电针对致热大鼠脑和血清中前列腺素E_2水平的影响．中国中医基础医学杂志．1999，5(8)：55-58
10．刘阳，文涛，冯煜等．丁香酚对致热家兔弓状核及PO/AH区脑组织中PGE_2和cAMP含量的影响．中国应用生理学杂志．2002，18(2)：113，178
11．王琳，焦红军．发热机制的研究进展．中医研究．2000，13(2)：57-61
12．张俊荣，李育浩，吴清和等．海芋不同提取部位对大鼠酵母性发热的抑制作用及对下丘脑中PGE_2含量的影响．1999，31(5)：40-41
13．赵红艳，张璠，范书铎等．黄芩甙对发热大鼠下丘脑PGE_2和cAMP含量的影响．中国应用生理学杂志．2002，18(2)：139-141
14．徐方云，李楚杰．家免EP性发热时血浆、脑脊液和不同脑区组织cAMP含量的变化．中国病理生理杂志．1997，13(1)：52-56
15．王彦平，王华东，陈小琳等．异丙嗪对家兔EGTA性发热的解热作用
及其机制研究．中国病理生理杂志．1999，15(3)：222-224
16．张永和，杜葵琴，计国仪等．大鼠LP和ET发热时不同脑区β-EN含量变化及其作用机理的探讨．中国病理生理杂志．1994，10(4)：370-373
17．李文，杜葵琴，张永和等．大鼠内生致热原性发热时不同脑区精氨酸加压素和亮氨酸脑啡肽含量的变化．中国病理生理杂志．1994，10(3)：249-253
18．霍海如，谭余庆，李晓芹等．桂枝汤有效部位A对体温双向调节作用机理研究——对下丘脑和隔区AVP及下丘脑NT含量的影响．中国实验方剂学杂志．1999，5(1)：33-36
19．邢德君，杜葵琴，计国义等．大鼠内毒素性发热时不同脑区cAMP含量和腺苷酸环化酶活性的变化．中国病理生理杂志．1992，8(2)：147-150
20．齐云，霍海如，郭淑英等．发热及低体温大鼠下丘脑腺苷酸环化酶和磷酸二酯酶活性的经时变化．中国病理生理杂志．2001，17(12)：1202-1204
21．齐云，霍海如，郭淑英等．发热及低体温大鼠下丘脑中腺苷酸环化酶活性与环一磷酸腺苷含量的变化．中国病理生理杂志．2002，18(4)：371-373
22．王达安，胡巢凤，杨皓庄等．α-促黑素细胞激素对IL-1β刺激家兔离体下丘脑释放cAMP的抑制作用．中国病理生理杂志．1997，13(4)：360-363
23．王华东，屈洋，王彦平等．中枢CRH在大鼠应激性体温升高和LPS性发热机制中的作用．中国病理生理杂志．2001，17(2)：124-127
24. Milton AS, Wendlandt S. Effects on body temperature of prostaglandins of the A. E and F series on injection into the third ventricle of unanaestheized cat and rabbits. J Physiol Lond,1971,218(2) :325-336
25. Bernheim HA, Gilbert TM, Stitt JT. Prostaglandin E levels in third ventricalar cerebrospinal fluid of rabbits during fever and changes in body temperature. J Physiol, 1980,301:69-78
26. Coceani F, Lees J, Bishai I. Further evidence implicationing pmstaglandin E_2 in the genesis of pyrogen fever. Am J Physiol,1988,254(3 Pt 2) :463-469
27. Andrei Ⅱ, Pero RS,.Scheck AC et al. Prostaglandin E_2-synthesizing enzymes in fever: differential transcriptional regulation. Am J Physiol,2002,283(5) :1104-1117
28. Imai-Matsumura K, Matsumura K, Terao A et al. Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE_2. Am J Physiol,2002,283 (6) : 1346-1353
29. Sathaqiva B, Williams BA. Central effects on dibutyryl cyclic AMP and GMP on the temperature in conscious rabbits. Brain Res, 1983,277 (2) :311-320
30．齐云，霍海如，田甲丽等．桂枝汤对发热及低体温大鼠下丘脑中腺苷酸环化酶和磷酸二酯酶活性的影响．中国中西医结合杂志．2001，21(3)：203-205
31．齐云，霍海如，周军等．桂枝汤对体温双向调节作用机理探讨——对下丘脑中腺苷酸环化酶活性及环一磷酸腺苷含量的影响．中国实验方剂学杂志．2001，7(2)：25-28
32．张丹卉，蒋玉凤，黄启福等．解热醒神注射液对内毒素性发热家兔下丘脑cAMP、IL-1β含量的影响．中国病理生理杂志．2002，18(8)：956-958
33．蓝肇熙，张进淘，张发荣等．抗高热Ⅰ号合剂对肺炎双球茵所致发热家免脑脊液PGE、cAMP含量的影响．华西药学杂志．2001，16(2)：81-83
34，马翔，杨雁，陈慧敏等．抗退饮对LP性发热家兔的下丘脑cAMP含量及脑腹中隔区AVP含量的影响．中国病理生理杂志．1999，15(8)：753-755
35．张丹卉，蒋玉凤，黄启福等．清开灵对内毒素性发热家免下丘脑cAMP及腹中隔区AVP含量的影响．中国病理生理杂志．2001，17(4)：340-342
36．蒋玉凤，黄启福，严京等．清开灵液对家兔白细胞致热原性发热和脑脊液cAMP含量的影响。中国病理生理杂志．1995，11(1)：54-57
37．赵红艳，张璠，李守拙等．野黄芩甙对发热家兔下丘脑及脑脊液中环磷腺苷含量的影响．中国医科大学学报．2003，32(2)：115-116，119
38．蔡群，李楚杰．cAMP热限及其与致热原热限的关系研究．中国病理生
理杂志．1988，4(1)：18-20
39. Siegert R, Philipp-Dormston WK, Radsak K. Mechanism of fever induction in rabbits. Infect Immun, 1976,14 ( 5 ) : 1130-1137
40．关新民．医学神经生物学．北京：人民卫生出版社，2002：229-40
41．[德]H．G．沃格尔等著，杜冠华等译．药理学实验指南．新药发现和药理学评价．北京：科学出版社，2001：507-08，491-492
42．王华东，李楚杰，屈洋等。下丘脑[Ca~(2+)]_i、cAMP在家兔EGTA性发热机制中的作用．中国病理生理杂志．1996，12(4)：402-405
2．范书铎，孙丽华，吴玉环等．葛根素、生石膏配伍对致热原作用下猫POAH温敏神经元放电的影响．中国应用生理学杂志．1997，13(1)：71-74
3．刘自明．中药退热灵合剂的解热作用分析．北京中医．1999(2)：51-52
4. Dinaraello CA, Cannon JG, Wolff SM. New concepts on the pathogenesis of fever. Rev Infect Dis,1988,10( 1 ) :168-189
5. Steiner AA, Branco LGS. Role of the preoptic carbon monoxide pathway in endotoxin fever in rats. Brain Research,2002,927 (1) :27-34
6. Kluger MJ. Fever:Role of pyrogens and cryogens. Physiol Rev, 1991,71 (1) :93-127
7．李楚杰．发热机制研究的新进展．中国病理生理杂志．1990，6(5)：375-380
8. Bligh J. Effects on temperature of monoamines injected into the lateral ventricles of sleep. J Phsiol, 1966,185:46
9．方剑乔，陈海英，刘金洪等．电针对致热大鼠脑和血清中前列腺素E_2水平的影响．中国中医基础医学杂志．1999，5(8)：55-58
10．刘阳，文涛，冯煜等．丁香酚对致热家兔弓状核及PO/AH区脑组织中PGE_2和cAMP含量的影响．中国应用生理学杂志．2002，18(2)：113，178
11．王琳，焦红军．发热机制的研究进展．中医研究．2000，13(2)：57-61
12．张俊荣，李育浩，吴清和等．海芋不同提取部位对大鼠酵母性发热的抑制作用及对下丘脑中PGE_2含量的影响．1999，31(5)：40-41
13．赵红艳，张璠，范书铎等．黄芩甙对发热大鼠下丘脑PGE_2和cAMP含量的影响．中国应用生理学杂志．2002，18(2)：139-141
14．徐方云，李楚杰．家免EP性发热时血浆、脑脊液和不同脑区组织cAMP含量的变化．中国病理生理杂志．1997，13(1)：52-56
15．王彦平，王华东，陈小琳等．异丙嗪对家兔EGTA性发热的解热作用
及其机制研究．中国病理生理杂志．1999，15(3)：222-224
16．张永和，杜葵琴，计国仪等．大鼠LP和ET发热时不同脑区β-EN含量变化及其作用机理的探讨．中国病理生理杂志．1994，10(4)：370-373
17．李文，杜葵琴，张永和等．大鼠内生致热原性发热时不同脑区精氨酸加压素和亮氨酸脑啡肽含量的变化．中国病理生理杂志．1994，10(3)：249-253
18．霍海如，谭余庆，李晓芹等．桂枝汤有效部位A对体温双向调节作用机理研究——对下丘脑和隔区AVP及下丘脑NT含量的影响．中国实验方剂学杂志．1999，5(1)：33-36
19．邢德君，杜葵琴，计国义等．大鼠内毒素性发热时不同脑区cAMP含量和腺苷酸环化酶活性的变化．中国病理生理杂志．1992，8(2)：147-150
20．齐云，霍海如，郭淑英等．发热及低体温大鼠下丘脑腺苷酸环化酶和磷酸二酯酶活性的经时变化．中国病理生理杂志．2001，17(12)：1202-1204
21．齐云，霍海如，郭淑英等．发热及低体温大鼠下丘脑中腺苷酸环化酶活性与环一磷酸腺苷含量的变化．中国病理生理杂志．2002，18(4)：371-373
22．王达安，胡巢凤，杨皓庄等．α-促黑素细胞激素对IL-1β刺激家兔离体下丘脑释放cAMP的抑制作用．中国病理生理杂志．1997，13(4)：360-363
23．王华东，屈洋，王彦平等．中枢CRH在大鼠应激性体温升高和LPS性发热机制中的作用．中国病理生理杂志．2001，17(2)：124-127
24. Milton AS, Wendlandt S. Effects on body temperature of prostaglandins of the A. E and F series on injection into the third ventricle of unanaestheized cat and rabbits. J Physiol Lond,1971,218(2) :325-336
25. Bernheim HA, Gilbert TM, Stitt JT. Prostaglandin E levels in third ventricalar cerebrospinal fluid of rabbits during fever and changes in body temperature. J Physiol, 1980,301:69-78
26. Coceani F, Lees J, Bishai I. Further evidence implicationing pmstaglandin E_2 in the genesis of pyrogen fever. Am J Physiol,1988,254(3 Pt 2) :463-469
27. Andrei Ⅱ, Pero RS,.Scheck AC et al. Prostaglandin E_2-synthesizing enzymes in fever: differential transcriptional regulation. Am J Physiol,2002,283(5) :1104-1117
28. Imai-Matsumura K, Matsumura K, Terao A et al. Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE_2. Am J Physiol,2002,283 (6) : 1346-1353
29. Sathaqiva B, Williams BA. Central effects on dibutyryl cyclic AMP and GMP on the temperature in conscious rabbits. Brain Res, 1983,277 (2) :311-320
30．齐云，霍海如，田甲丽等．桂枝汤对发热及低体温大鼠下丘脑中腺苷酸环化酶和磷酸二酯酶活性的影响．中国中西医结合杂志．2001，21(3)：203-205
31．齐云，霍海如，周军等．桂枝汤对体温双向调节作用机理探讨——对下丘脑中腺苷酸环化酶活性及环一磷酸腺苷含量的影响．中国实验方剂学杂志．2001，7(2)：25-28
32．张丹卉，蒋玉凤，黄启福等．解热醒神注射液对内毒素性发热家兔下丘脑cAMP、IL-1β含量的影响．中国病理生理杂志．2002，18(8)：956-958
33．蓝肇熙，张进淘，张发荣等．抗高热Ⅰ号合剂对肺炎双球茵所致发热家免脑脊液PGE、cAMP含量的影响．华西药学杂志．2001，16(2)：81-83
34，马翔，杨雁，陈慧敏等．抗退饮对LP性发热家兔的下丘脑cAMP含量及脑腹中隔区AVP含量的影响．中国病理生理杂志．1999，15(8)：753-755
35．张丹卉，蒋玉凤，黄启福等．清开灵对内毒素性发热家免下丘脑cAMP及腹中隔区AVP含量的影响．中国病理生理杂志．2001，17(4)：340-342
36．蒋玉凤，黄启福，严京等．清开灵液对家兔白细胞致热原性发热和脑脊液cAMP含量的影响。中国病理生理杂志．1995，11(1)：54-57
37．赵红艳，张璠，李守拙等．野黄芩甙对发热家兔下丘脑及脑脊液中环磷腺苷含量的影响．中国医科大学学报．2003，32(2)：115-116，119
38．蔡群，李楚杰．cAMP热限及其与致热原热限的关系研究．中国病理生
理杂志．1988，4(1)：18-20
39. Siegert R, Philipp-Dormston WK, Radsak K. Mechanism of fever induction in rabbits. Infect Immun, 1976,14 ( 5 ) : 1130-1137
40．关新民．医学神经生物学．北京：人民卫生出版社，2002：229-40
41．[德]H．G．沃格尔等著，杜冠华等译．药理学实验指南．新药发现和药理学评价．北京：科学出版社，2001：507-08，491-492
42．王华东，李楚杰，屈洋等。下丘脑[Ca~(2+)]_i、cAMP在家兔EGTA性发热机制中的作用．中国病理生理杂志．1996，12(4)：402-405