Ghrelin对C75抑制小鼠胃排空和胃肠通过量的影响及RIY对吗啡镇痛作用的影响
|
摘要
C75是脂肪酸合酶(FAS)的抑制剂。脂肪酸合酶是乙酰辅酶A合成脂肪酸过程中的关键酶。C75能抑制脂肪酸合酶的活性。已经有很多文献报道,C75在抑制肿瘤、糖尿病和减肥等都有很好的作用。C75能抑制小鼠的摄食,增加能量代谢的消耗,因此能使小鼠减肥。胃促生长素(Ghrelin)作为C75功能性拮抗剂研究。Ghrelin主要功能有刺激垂体前叶释放生长激素、增加食欲、调节能量平衡、促进胃酸分泌、增强机体免疫力与抗应激能力等作用。由于胃肠运动会对小鼠的摄食产生影响,因此我们的实验目的就是研究C75是否对小鼠的胃排空和胃肠通过量有影响,这种作用是否与Ghrelin相关。采用低压冷冻干燥法测量小鼠的胃排空量,通过营养性碳糊法测量小鼠的胃肠通过量。实验结果表明Ghrelin能明显减弱C75对小鼠胃排空的未通过量的抑制作用。
本文的第二部分是研究RIY对吗啡镇痛作用的影响。RIY是从油菜籽中提取的有活性的三肽。已经有人证明,RIY能降低自发性高血压小鼠的血压。还有人报道说,RIY能抑制摄食和胃排空,并且这个作用是通过刺激内源性CCK分泌,通过CCKA受体途径起到作用,CCKA受体拮抗剂氯戊米特能拮抗RIY抑制摄食和胃排空的作用。由于内源性CCK和内源性阿片受体在焦虑,学习记忆和镇痛作用中有相互拮抗的作用,本文研究了RIY是否影响吗啡的镇痛作用。侧脑室给药RIY,5分钟后,皮下给药吗啡,吗啡给药后10min、20min、30min、40min、50min、60min、70min、80min、90min、120min,通过热甩尾法测小鼠的甩尾值。实验结果表明,RIY能剂量依赖的影响吗啡的镇痛作用。高剂量RIY(200nmol/mouse, i. c. v.)在吗啡给药10min时能明显能增强吗啡的镇痛作用,而低剂量RIY(100nmol/mouse, i. c. v.)能抑制吗啡的镇痛作用。
C75 was synthesed as an inhibitor of fatty acid synhase(FAS).FAS is the key enzyme which catalyzes the condensation of acetyl-CoA and malony-CoA to generate long chain fatty acids in the cytoplam。FAS was inhibited by the C75. It was reported that C75 can inhibit tumor, diabetes and lose weight. C75 can lose weight of mice for it can reduce food intake and increase the energe consumed. Ghrelin was studied as a C75 inhibitor, which can stimulate the growth hormone release, enhance appetite, balance the energe, insicrete the acid and so on. For the food intake and gastrointestinal mobility are closely related, the present study was designed to investigate the effects and mechanisms of C75 on gastric emptying and gastrointestinal transit.The gastric emptying and gastrointestinal transit were measured by lyophilization method and charcoal meal test method, respectively. Our data showed that ghrelin can attenuate the function of C75 to decrease gastrointestinal mobility.
In the second section we studied that RIY influenced the antinociceptive effects of morphine. The tripeptide Arg-Ile-Tyr(RIY) was from subtilisin digest of rapeseed protein, which was the residue of rapeseed after extraction of oil. Previous studies indicated that RIY decreased blood pressure after oral administration in spontaneously hypertensive rats(SHR), this tripeptide also inhibited food intake and gastric emptying after peripheral adimnistration in mice via CCKA receptors, and this function of RIY can be inhibited by the CCKA antagonist lorglumide. In this study,we want to found if RIY and morphine have any interaction in the antinociceptive action. RIY was administrative by intracerebroventricular(i.c.v.) before 5min the subcutaneous(s.c) morphine. The latency time was tested by the warm water tail immersion test. after morphine administrative 10min,20min,30min,40min,50min,60min,70min,80min, 90min,120min. The result showed that high dose of RIY(200nmol/mouse,i.c.v.)enhanced the morphine's antinociceptive after 10min administration morphine, while the low dose of RIY(100nmol/mouse, i.c.v.)can inhibit the morphine's antinociceptive.
本文的第二部分是研究RIY对吗啡镇痛作用的影响。RIY是从油菜籽中提取的有活性的三肽。已经有人证明,RIY能降低自发性高血压小鼠的血压。还有人报道说,RIY能抑制摄食和胃排空,并且这个作用是通过刺激内源性CCK分泌,通过CCKA受体途径起到作用,CCKA受体拮抗剂氯戊米特能拮抗RIY抑制摄食和胃排空的作用。由于内源性CCK和内源性阿片受体在焦虑,学习记忆和镇痛作用中有相互拮抗的作用,本文研究了RIY是否影响吗啡的镇痛作用。侧脑室给药RIY,5分钟后,皮下给药吗啡,吗啡给药后10min、20min、30min、40min、50min、60min、70min、80min、90min、120min,通过热甩尾法测小鼠的甩尾值。实验结果表明,RIY能剂量依赖的影响吗啡的镇痛作用。高剂量RIY(200nmol/mouse, i. c. v.)在吗啡给药10min时能明显能增强吗啡的镇痛作用,而低剂量RIY(100nmol/mouse, i. c. v.)能抑制吗啡的镇痛作用。
C75 was synthesed as an inhibitor of fatty acid synhase(FAS).FAS is the key enzyme which catalyzes the condensation of acetyl-CoA and malony-CoA to generate long chain fatty acids in the cytoplam。FAS was inhibited by the C75. It was reported that C75 can inhibit tumor, diabetes and lose weight. C75 can lose weight of mice for it can reduce food intake and increase the energe consumed. Ghrelin was studied as a C75 inhibitor, which can stimulate the growth hormone release, enhance appetite, balance the energe, insicrete the acid and so on. For the food intake and gastrointestinal mobility are closely related, the present study was designed to investigate the effects and mechanisms of C75 on gastric emptying and gastrointestinal transit.The gastric emptying and gastrointestinal transit were measured by lyophilization method and charcoal meal test method, respectively. Our data showed that ghrelin can attenuate the function of C75 to decrease gastrointestinal mobility.
In the second section we studied that RIY influenced the antinociceptive effects of morphine. The tripeptide Arg-Ile-Tyr(RIY) was from subtilisin digest of rapeseed protein, which was the residue of rapeseed after extraction of oil. Previous studies indicated that RIY decreased blood pressure after oral administration in spontaneously hypertensive rats(SHR), this tripeptide also inhibited food intake and gastric emptying after peripheral adimnistration in mice via CCKA receptors, and this function of RIY can be inhibited by the CCKA antagonist lorglumide. In this study,we want to found if RIY and morphine have any interaction in the antinociceptive action. RIY was administrative by intracerebroventricular(i.c.v.) before 5min the subcutaneous(s.c) morphine. The latency time was tested by the warm water tail immersion test. after morphine administrative 10min,20min,30min,40min,50min,60min,70min,80min, 90min,120min. The result showed that high dose of RIY(200nmol/mouse,i.c.v.)enhanced the morphine's antinociceptive after 10min administration morphine, while the low dose of RIY(100nmol/mouse, i.c.v.)can inhibit the morphine's antinociceptive.
引文
1. Minokoshi Y, et al. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428(6982):569-574.
2. Kuhajda F, et al. (2000) Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proceedings of the National Academy of Sciences 97(7):3450.
3. Loftus T, et al. (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288(5475):2379.
4. Tu Y, et al. (2005) C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology 146(1):486.
5. Hu Z, Cha S, Chohnan S,& Lane M (2003) Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proceedings of the National Academy of Sciences of the United States of America 100(22):12624.
6. Lane M, et al. (2005) Role of malonyl-CoA in the hypothalamic control of food intake and energy expenditure. Biochemical Society Transactions 33:1063-1067.
7. Price N, et al. (2002) A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics 80(4):433-442.
8. Wolfgang M & Lane M (2006) The role of hypothalamic malonyl-CoA in energy homeostasis. Journal of Biological Chemistry 281(49):37265.
9. Kumar M, Shimokawa T, Nagy T,& Lane M (2002) Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice. Proceedings of the National Academy of Sciences 99(4):1921.
10. Kim E, et al. (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. Journal of Biological Chemistry 279(19):19970.
11. Kuhajda F, Landree L,& Ronnett G (2005) The connections between C75 and obesity drug-target pathways. Trends in pharmacological sciences 26(11):541-544.
12. Jensen V, Ladekarl M, Holm-Nielsen P, Melsen F,& Soerensen F (2005) The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-I in node-negative breast cancer. The Journal of pathology 176(4):343-352.
13. Alo P, et al. (1998) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77(3):474-482.
14. Epstein J, Carmichael M,& Partin A (1995) OA-519 (fatty acid synthase) as an independent predictor of pathologic stage in adenocarcinoma of the prostate. Urology 45(1):81-86.
15. Shurbaji M, Kalbfleisch J,& Thurmond T (1996) Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer* 1. Human pathology 27(9):917-921.
16. Rashid A, et al. (1997) Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. The American journal of pathology 150(1):201.
17. Pizer E, Chrest F, DiGiuseppe J,& Han W (1998) Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer research 58(20):4611.
18. Gansler T & Hardman W (1997) Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival* 1. Human pathology 28(6):686-692.
19. Kuhajda FP (2000) Fatty-acid synthase and human cancer:new perspectives on its role in tumor biology. Nutrition 16(3):202-208.
20. Menendez J, Vellon L, Colomer R,& Lupu R (2005) Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. International Journal of Cancer 115(1):19-35.
21. Kojima M, et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762):656-660.
22. Sun Y, Wang P, Zheng H,& Smith R (2004) Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proceedings of the National Academy of Sciences of the United States of America 101 (13):4679.
23. Goto M, et al. (2006) Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Endocrinology 147(11):5102.
24. Gil-Campos M, Aguilera C, Ca ete R,& Gil A (2007) Ghrelin:a hormone regulating food intake and energy homeostasis. British Journal of Nutrition 96(02):201-226.
25. Kaiya H, Furuse M, Miyazato M,& Kangawa K (2009) Current knowledge of the roles of ghrelin in regulating food intake and energy balance in birds. General and comparative endocrinology 163(1-2):33-38.
26. Toshinai K, et al. (2003) Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 144(4):1506.
27. Ishii S, et al. (2002) Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 143(12):4934.
28. Date Y, et al. (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. GASTROENTEROLOGY-BALTIMORE THEN PHILADELPHIA-123(4):1120-1128.
29. Cummings D, Frayo R, Marmonier C, Aubert R,& Chapelot D (2004) Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time-and food-related cues. American Journal of Physiology-Endocrinology And Metabolism 287(2):E297.
30. Otto B, et al. (2001) Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. European Journal of Endocrinology 145(5):669.
31. Edholm T, Levin F, Hellstr m P,& Schmidt P (2004) Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regulatory peptides 121(l-3):25-30.
32. Tack J, et al. (2006) Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 55(3):327.
33. INUI A, et al. (2004) Ghrelin, appetite, and gastric motility:the emerging role of the stomach as an endocrine organ. The FASEB Journal 18(3):439.
34. Xing J & Chen J (2004) Alterations of gastrointestinal motility in obesity. Obesity 12(11):1723-1732.
35. Xie D, et al. (2002) Effect of areca on contraction of colonic muscle strips in rats. World Journal of Gastroenterology 8(2):350-352.
36. De Smet B, Thijs T, Peeters T,& Depoortere I (2007) Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents. Neurogastroenterology and Motility 19(3):211-217.
37. Li L-F, Lu Y-Y, Xiong W, Liu J-Y,& Chen Q (2008) Effect of centrally administered C75, a fatty acid synthase inhibitor, on gastric emptying and gastrointestinal transit in mice. European Journal of Pharmacology 595(1-3):90-94.
38. Horowitz M, Jones K, Edelbroek M, Smout A,& Read N (1993) The effect of posture on gastric emptying and intragastric distribution of oil and aqueous meal components and appetite. Gastroenterology 105(2):382-390.
39. Ford M, Camilleri M, Wiste J,& Hanson R (1995) Differences in colonic tone and phasic response to a meal in the transverse and sigmoid human colon. Gut 37(2):264.
40. Marczak ED, et al. (2003) New antihypertensive peptides isolated from rapeseed. Peptides 24(6):791-798.
41. Marczak ED, Ohinata K, Lipkowski AW,& Yoshikawa M (2006) Arg-Ile-Tyr (RIY) derived from rapeseed protein decreases food intake and gastric emptying after oral administration in mice. Peptides 27(9):2065-2068.
42. Noble F & Roques BP (1999) CCK-B receptor:chemistry, molecular biology, biochemistry and pharmacology. Progress in Neurobiology 58(4):349-379.
43. Hill DR, Shaw, T.M. and Woodruff, G.N., (1987) Species differences in the localization of "peripheral" type CCK receptors in rodent brain.. Neurosci. Lett.79:286-298.
44. Bradwejn J, Koszycki, D. and Shriqui, C., (1991) Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Arch. Gen. Psychiat.88(603-610).
45. Wank SA (1995) Cholecystokinin receptors, pp G628-646.
46. Berridge MJ & Irvine RF (1989) Inositol phosphates and cell signalling. Nature 341(6239):197-205.
47. Roche S, Bali, J.P., Galleyrand, J.C. and Magous, R., (1991) Characterization of a gastrin-type receptor on rabbit gastric parietal cells using L-365,260 and L-364,718. Am. J. Physiol.260:G182-G188
48. Berna MJ, Tapia JA, Sancho V,& Jensen RT (2007) Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. Current Opinion in Pharmacology 7(6):583-592.
49. Kosterlitz H (1979) The best laid schemes o'mice an'men gang aft agley. Annual Review of Pharmacology and Toxicology 19(1):1-13.
50. H. W K (1979) The best laid schemes o'mice an'men gang aft agley. Annu Rev Pharmacol Toxicol 19:1-12.
51. Corbett A, Paterson S,& Kosterlitz H (1993) Selectivity of ligands for opioid receptors. Handbook of experimental pharmacology 104:645-679.
52. Henderson G & McKnight A (1997) The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ. Trends in pharmacological sciences 18(4):293-300.
53. Corbett A, Henderson G, McKnight A,& Paterson S (2006) 75 years of opioid research:the exciting but vain quest for the Holy Grail. British journal of pharmacology 147(S1):S153.
54. Pasternak G (2005) Molecular biology of opioid analgesia. Journal of pain and symptom management 29(5):2-9.
55. Traynor JR & Elliott J (1993) [delta]-Opioid receptor subtypes and cross-talk with [mu]-receptors. Trends in pharmacological sciences 14(3):84-86.
56. Traynor J (1989) Subtypes of the kappa-opioid receptor:fact or fiction? Trends in pharmacological sciences 10(2):52.
57. Jaffe J & Martin W(1985) Opioid analgesics and antagonists. The pharmacological basis of therapeutics:491-531.
58. Houde R (1979) Analgesic effectiveness of the narcotic agonist-antagonists. British Journal of Clinical Pharmacology 7(Suppl 3):297S.
59. Von Voigtlander PF & Lewis RA (1982) U-50,488, a selective kappa opioid agonist:Comparison to other reputed kappa agonists. Progress in Neuro-Psychophannacology and Biological Psychiatry 6(4-6):467-470.
60. Broom D, Jutkiewicz E, Rice K, Traynor J,& Woods J (2002) Behavioral Effects of δ-Opioid Receptor Agonists: Potential Antidepressants? The Japanese Journal of Pharmacology 90(1):1-6.
61. Mansour A, Khachaturian H, Lewis ME, Akil H, & Watson SJ (1988) Anatomy of CNS opioid receptors. Trends in Neurosciences 11(7):308-309, IN302-IN303,310-314.
62. Mansour A, Fox CA, Akil H,& Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS:anatomical and functional implications. Trends in Neurosciences 18(1):22-29.
63. H. Fink AR, M. Voits and J.P. Voigt (1998) Voigt, Major biological actions of CCK—a critical evaluation of research findings. Exp. Brain Res. (123 (1998)):77-83.
64. Baber NS, Dourish CT,& Hill DR (1989) The role of CCK, caerulein, and CCK antagonists in nociception. Pain 39(3):307-328.
65. Harro J & Oreland L (1993) Cholecystokinin receptors and memory:A radial maze study. Pharmacology Biochemistry and Behavior 44(3):509-517.
66. Bradwejn J & de Montigny C (1984) Benzodiazepines antagonize cholecystokinin-induced activation of rat hippocampal neurones. Nature 312(5992):363-364.
67. Hebb ALO, Poulin J-F, Roach SP, Zacharko RM,& Drolet G (2005) Cholecystokinin and endogenous opioid peptides: Interactive influence on pain, cognition, and emotion. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29(8):1225-1238.
68. Beinfeld MC, Meyer DK,& Brownstein MJ (1981) Cholecystokinin in the central nervous system. Peptides 2(Supplement 2):77-79.
69. Lindefors N, Lind 閚 A, Bren S, Sedvall G,& Persson H (1993) CCK peptides and mRNA in the human brain. Progress in Neurobiology 40(6):671-690.
70. Rezvani A, Stokes K, Rhoads D,& Way E (1987) Proglumide exhibits delta opioid agonist properties. Alcohol and drug research 7(3):135.
71. Jurna I & Zetler G (1981) Antinociceptive effect of centrally administered caerulein and cholecystokinin octapeptide (CCK-8). Eur J Pharmacol 73:323-331.
72. Wang X & Han J (2006) Modification by Cholecystokinin Octapeptide of the Binding of I-,A-,and K-Opioid Receptors.Journal of neurochemistry 55(4):1379-1382.
73. Harro J & Vasar E (1991) Cholecystokinin-induced anxiety:How is it reflected in studies on exploratory behaviour? Neuroscience & Biobehavioral Reviews 15(4):473-477.
74. Sebret A, et al. (1999) Rat Hippocampal Neurons Are Critically Involved in Physiological Improvement of Memory Processes Induced by Cholecystokinin-B Receptor Stimulation, pp 7230-7237.
75. B. Pommier FB, A. Simon, M. Pophillat, T. Matsui, V. Dauge, B.P. Roques and F. Noble (2002) Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. J. Neurosci 22 (2002)(22):2005-2011.
76. Koks S, et al. (2001) Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system. Psychopharmacology 158(2):198.
77. Przewlocka B, Sumova A,& Lason W (1990) The influence of conditioned fear-induced stress on the opioid systems in the rat. Pharmacology Biochemistry and Behavior 37(4):661-666.
78. Levine J, Feldmesser M, Tecott L, Lane S,& Gordon N (1984) The role of stimulus intensity and stress in opioid-mediated analgesia. Brain research 304(2):265-269.
79. Baker DQ et al. (1997) Cerebrospinal fluid and plasma [beta]-endorphin in combat veterans with post-traumatic stress disorder. Psychoneuroendocrinology 22(7):517-529.
80. Van der Kolk B, Greenberg M, Orr S,& Pitman R (1989) Endogenous opioids, stress induced analgesia, and posttraumatic stress disorder. Psychopharmacology Bulletin 25(3):417.
81. Rubinstein M, et al. (1996) Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis. Proceedings of the National Academy of Sciences 93(9):3995.
82. Jurna I & Zetler G (1981) Antinociceptive effect of centrally administered caerulein and cholecystokinin octapeptide (CCK-8). European Journal of Pharmacology 73(4):323-331.
83. Itoh S, Katsuura G,& Maeda Y (1982) Caerulein and cholecystokinin suppress [beta]-endorphin-induced analgesia in the rat. European Journal of Pharmacology 80(4):421-425.
84. Wiertelak E, Maier S,& Watkins L (1992) Cholecystokinin antianalgesia:safety cues abolish morphine analgesia. Science 256(5058):830-833.
85. Fu C-Y, et al. (2006) Rat/mouse hemokinin-1, a mammalian tachykinin peptide, markedly potentiates the antinociceptive effects of morphine administered at the peripheral and supraspinal level. Behavioural brain research 170(2):293-301.
86. Hill RG, Hughes J,& Pittaway KM (1987) Antinociceptive action of cholecystokinin octapeptide (CCK 8) and related peptides in rats and mice:Effects of naloxone and peptidase inhibitors. Neuropharmacology 26(4):289-300.
87. Baber N, Dourish C,& Hill D (1989) The role of CCK, caerulein, and CCK antagonists in nociception. Pain 39(3):307-328.
88. Rezayat M, Rahnavard A,& Zarrindast M (2008) Role of cholecystokinin receptors in induction of antinociception in hot-plate test. Pharmacology & toxicology 87(2):58-62.
89. 韩济生(1994)八肽胆囊收缩素(CCK 8)抗阿片作用及其机理研究.中国神经科学杂志1(1)：1-6.
90. Pommier B, et al. (2002) Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. Journal of Neuroscience 22(5):2005.
91. Faris P (1985) Opiate antagonistic function of cholecystokinin in analgesia and energy balance systems. Annals of the New York Academy of Sciences 448:437.
2. Kuhajda F, et al. (2000) Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proceedings of the National Academy of Sciences 97(7):3450.
3. Loftus T, et al. (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288(5475):2379.
4. Tu Y, et al. (2005) C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology 146(1):486.
5. Hu Z, Cha S, Chohnan S,& Lane M (2003) Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proceedings of the National Academy of Sciences of the United States of America 100(22):12624.
6. Lane M, et al. (2005) Role of malonyl-CoA in the hypothalamic control of food intake and energy expenditure. Biochemical Society Transactions 33:1063-1067.
7. Price N, et al. (2002) A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics 80(4):433-442.
8. Wolfgang M & Lane M (2006) The role of hypothalamic malonyl-CoA in energy homeostasis. Journal of Biological Chemistry 281(49):37265.
9. Kumar M, Shimokawa T, Nagy T,& Lane M (2002) Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice. Proceedings of the National Academy of Sciences 99(4):1921.
10. Kim E, et al. (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. Journal of Biological Chemistry 279(19):19970.
11. Kuhajda F, Landree L,& Ronnett G (2005) The connections between C75 and obesity drug-target pathways. Trends in pharmacological sciences 26(11):541-544.
12. Jensen V, Ladekarl M, Holm-Nielsen P, Melsen F,& Soerensen F (2005) The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-I in node-negative breast cancer. The Journal of pathology 176(4):343-352.
13. Alo P, et al. (1998) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77(3):474-482.
14. Epstein J, Carmichael M,& Partin A (1995) OA-519 (fatty acid synthase) as an independent predictor of pathologic stage in adenocarcinoma of the prostate. Urology 45(1):81-86.
15. Shurbaji M, Kalbfleisch J,& Thurmond T (1996) Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer* 1. Human pathology 27(9):917-921.
16. Rashid A, et al. (1997) Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. The American journal of pathology 150(1):201.
17. Pizer E, Chrest F, DiGiuseppe J,& Han W (1998) Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer research 58(20):4611.
18. Gansler T & Hardman W (1997) Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival* 1. Human pathology 28(6):686-692.
19. Kuhajda FP (2000) Fatty-acid synthase and human cancer:new perspectives on its role in tumor biology. Nutrition 16(3):202-208.
20. Menendez J, Vellon L, Colomer R,& Lupu R (2005) Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. International Journal of Cancer 115(1):19-35.
21. Kojima M, et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762):656-660.
22. Sun Y, Wang P, Zheng H,& Smith R (2004) Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proceedings of the National Academy of Sciences of the United States of America 101 (13):4679.
23. Goto M, et al. (2006) Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Endocrinology 147(11):5102.
24. Gil-Campos M, Aguilera C, Ca ete R,& Gil A (2007) Ghrelin:a hormone regulating food intake and energy homeostasis. British Journal of Nutrition 96(02):201-226.
25. Kaiya H, Furuse M, Miyazato M,& Kangawa K (2009) Current knowledge of the roles of ghrelin in regulating food intake and energy balance in birds. General and comparative endocrinology 163(1-2):33-38.
26. Toshinai K, et al. (2003) Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 144(4):1506.
27. Ishii S, et al. (2002) Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 143(12):4934.
28. Date Y, et al. (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. GASTROENTEROLOGY-BALTIMORE THEN PHILADELPHIA-123(4):1120-1128.
29. Cummings D, Frayo R, Marmonier C, Aubert R,& Chapelot D (2004) Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time-and food-related cues. American Journal of Physiology-Endocrinology And Metabolism 287(2):E297.
30. Otto B, et al. (2001) Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. European Journal of Endocrinology 145(5):669.
31. Edholm T, Levin F, Hellstr m P,& Schmidt P (2004) Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regulatory peptides 121(l-3):25-30.
32. Tack J, et al. (2006) Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 55(3):327.
33. INUI A, et al. (2004) Ghrelin, appetite, and gastric motility:the emerging role of the stomach as an endocrine organ. The FASEB Journal 18(3):439.
34. Xing J & Chen J (2004) Alterations of gastrointestinal motility in obesity. Obesity 12(11):1723-1732.
35. Xie D, et al. (2002) Effect of areca on contraction of colonic muscle strips in rats. World Journal of Gastroenterology 8(2):350-352.
36. De Smet B, Thijs T, Peeters T,& Depoortere I (2007) Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents. Neurogastroenterology and Motility 19(3):211-217.
37. Li L-F, Lu Y-Y, Xiong W, Liu J-Y,& Chen Q (2008) Effect of centrally administered C75, a fatty acid synthase inhibitor, on gastric emptying and gastrointestinal transit in mice. European Journal of Pharmacology 595(1-3):90-94.
38. Horowitz M, Jones K, Edelbroek M, Smout A,& Read N (1993) The effect of posture on gastric emptying and intragastric distribution of oil and aqueous meal components and appetite. Gastroenterology 105(2):382-390.
39. Ford M, Camilleri M, Wiste J,& Hanson R (1995) Differences in colonic tone and phasic response to a meal in the transverse and sigmoid human colon. Gut 37(2):264.
40. Marczak ED, et al. (2003) New antihypertensive peptides isolated from rapeseed. Peptides 24(6):791-798.
41. Marczak ED, Ohinata K, Lipkowski AW,& Yoshikawa M (2006) Arg-Ile-Tyr (RIY) derived from rapeseed protein decreases food intake and gastric emptying after oral administration in mice. Peptides 27(9):2065-2068.
42. Noble F & Roques BP (1999) CCK-B receptor:chemistry, molecular biology, biochemistry and pharmacology. Progress in Neurobiology 58(4):349-379.
43. Hill DR, Shaw, T.M. and Woodruff, G.N., (1987) Species differences in the localization of "peripheral" type CCK receptors in rodent brain.. Neurosci. Lett.79:286-298.
44. Bradwejn J, Koszycki, D. and Shriqui, C., (1991) Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Arch. Gen. Psychiat.88(603-610).
45. Wank SA (1995) Cholecystokinin receptors, pp G628-646.
46. Berridge MJ & Irvine RF (1989) Inositol phosphates and cell signalling. Nature 341(6239):197-205.
47. Roche S, Bali, J.P., Galleyrand, J.C. and Magous, R., (1991) Characterization of a gastrin-type receptor on rabbit gastric parietal cells using L-365,260 and L-364,718. Am. J. Physiol.260:G182-G188
48. Berna MJ, Tapia JA, Sancho V,& Jensen RT (2007) Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. Current Opinion in Pharmacology 7(6):583-592.
49. Kosterlitz H (1979) The best laid schemes o'mice an'men gang aft agley. Annual Review of Pharmacology and Toxicology 19(1):1-13.
50. H. W K (1979) The best laid schemes o'mice an'men gang aft agley. Annu Rev Pharmacol Toxicol 19:1-12.
51. Corbett A, Paterson S,& Kosterlitz H (1993) Selectivity of ligands for opioid receptors. Handbook of experimental pharmacology 104:645-679.
52. Henderson G & McKnight A (1997) The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ. Trends in pharmacological sciences 18(4):293-300.
53. Corbett A, Henderson G, McKnight A,& Paterson S (2006) 75 years of opioid research:the exciting but vain quest for the Holy Grail. British journal of pharmacology 147(S1):S153.
54. Pasternak G (2005) Molecular biology of opioid analgesia. Journal of pain and symptom management 29(5):2-9.
55. Traynor JR & Elliott J (1993) [delta]-Opioid receptor subtypes and cross-talk with [mu]-receptors. Trends in pharmacological sciences 14(3):84-86.
56. Traynor J (1989) Subtypes of the kappa-opioid receptor:fact or fiction? Trends in pharmacological sciences 10(2):52.
57. Jaffe J & Martin W(1985) Opioid analgesics and antagonists. The pharmacological basis of therapeutics:491-531.
58. Houde R (1979) Analgesic effectiveness of the narcotic agonist-antagonists. British Journal of Clinical Pharmacology 7(Suppl 3):297S.
59. Von Voigtlander PF & Lewis RA (1982) U-50,488, a selective kappa opioid agonist:Comparison to other reputed kappa agonists. Progress in Neuro-Psychophannacology and Biological Psychiatry 6(4-6):467-470.
60. Broom D, Jutkiewicz E, Rice K, Traynor J,& Woods J (2002) Behavioral Effects of δ-Opioid Receptor Agonists: Potential Antidepressants? The Japanese Journal of Pharmacology 90(1):1-6.
61. Mansour A, Khachaturian H, Lewis ME, Akil H, & Watson SJ (1988) Anatomy of CNS opioid receptors. Trends in Neurosciences 11(7):308-309, IN302-IN303,310-314.
62. Mansour A, Fox CA, Akil H,& Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS:anatomical and functional implications. Trends in Neurosciences 18(1):22-29.
63. H. Fink AR, M. Voits and J.P. Voigt (1998) Voigt, Major biological actions of CCK—a critical evaluation of research findings. Exp. Brain Res. (123 (1998)):77-83.
64. Baber NS, Dourish CT,& Hill DR (1989) The role of CCK, caerulein, and CCK antagonists in nociception. Pain 39(3):307-328.
65. Harro J & Oreland L (1993) Cholecystokinin receptors and memory:A radial maze study. Pharmacology Biochemistry and Behavior 44(3):509-517.
66. Bradwejn J & de Montigny C (1984) Benzodiazepines antagonize cholecystokinin-induced activation of rat hippocampal neurones. Nature 312(5992):363-364.
67. Hebb ALO, Poulin J-F, Roach SP, Zacharko RM,& Drolet G (2005) Cholecystokinin and endogenous opioid peptides: Interactive influence on pain, cognition, and emotion. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29(8):1225-1238.
68. Beinfeld MC, Meyer DK,& Brownstein MJ (1981) Cholecystokinin in the central nervous system. Peptides 2(Supplement 2):77-79.
69. Lindefors N, Lind 閚 A, Bren S, Sedvall G,& Persson H (1993) CCK peptides and mRNA in the human brain. Progress in Neurobiology 40(6):671-690.
70. Rezvani A, Stokes K, Rhoads D,& Way E (1987) Proglumide exhibits delta opioid agonist properties. Alcohol and drug research 7(3):135.
71. Jurna I & Zetler G (1981) Antinociceptive effect of centrally administered caerulein and cholecystokinin octapeptide (CCK-8). Eur J Pharmacol 73:323-331.
72. Wang X & Han J (2006) Modification by Cholecystokinin Octapeptide of the Binding of I-,A-,and K-Opioid Receptors.Journal of neurochemistry 55(4):1379-1382.
73. Harro J & Vasar E (1991) Cholecystokinin-induced anxiety:How is it reflected in studies on exploratory behaviour? Neuroscience & Biobehavioral Reviews 15(4):473-477.
74. Sebret A, et al. (1999) Rat Hippocampal Neurons Are Critically Involved in Physiological Improvement of Memory Processes Induced by Cholecystokinin-B Receptor Stimulation, pp 7230-7237.
75. B. Pommier FB, A. Simon, M. Pophillat, T. Matsui, V. Dauge, B.P. Roques and F. Noble (2002) Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. J. Neurosci 22 (2002)(22):2005-2011.
76. Koks S, et al. (2001) Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system. Psychopharmacology 158(2):198.
77. Przewlocka B, Sumova A,& Lason W (1990) The influence of conditioned fear-induced stress on the opioid systems in the rat. Pharmacology Biochemistry and Behavior 37(4):661-666.
78. Levine J, Feldmesser M, Tecott L, Lane S,& Gordon N (1984) The role of stimulus intensity and stress in opioid-mediated analgesia. Brain research 304(2):265-269.
79. Baker DQ et al. (1997) Cerebrospinal fluid and plasma [beta]-endorphin in combat veterans with post-traumatic stress disorder. Psychoneuroendocrinology 22(7):517-529.
80. Van der Kolk B, Greenberg M, Orr S,& Pitman R (1989) Endogenous opioids, stress induced analgesia, and posttraumatic stress disorder. Psychopharmacology Bulletin 25(3):417.
81. Rubinstein M, et al. (1996) Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis. Proceedings of the National Academy of Sciences 93(9):3995.
82. Jurna I & Zetler G (1981) Antinociceptive effect of centrally administered caerulein and cholecystokinin octapeptide (CCK-8). European Journal of Pharmacology 73(4):323-331.
83. Itoh S, Katsuura G,& Maeda Y (1982) Caerulein and cholecystokinin suppress [beta]-endorphin-induced analgesia in the rat. European Journal of Pharmacology 80(4):421-425.
84. Wiertelak E, Maier S,& Watkins L (1992) Cholecystokinin antianalgesia:safety cues abolish morphine analgesia. Science 256(5058):830-833.
85. Fu C-Y, et al. (2006) Rat/mouse hemokinin-1, a mammalian tachykinin peptide, markedly potentiates the antinociceptive effects of morphine administered at the peripheral and supraspinal level. Behavioural brain research 170(2):293-301.
86. Hill RG, Hughes J,& Pittaway KM (1987) Antinociceptive action of cholecystokinin octapeptide (CCK 8) and related peptides in rats and mice:Effects of naloxone and peptidase inhibitors. Neuropharmacology 26(4):289-300.
87. Baber N, Dourish C,& Hill D (1989) The role of CCK, caerulein, and CCK antagonists in nociception. Pain 39(3):307-328.
88. Rezayat M, Rahnavard A,& Zarrindast M (2008) Role of cholecystokinin receptors in induction of antinociception in hot-plate test. Pharmacology & toxicology 87(2):58-62.
89. 韩济生(1994)八肽胆囊收缩素(CCK 8)抗阿片作用及其机理研究.中国神经科学杂志1(1)：1-6.
90. Pommier B, et al. (2002) Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. Journal of Neuroscience 22(5):2005.
91. Faris P (1985) Opiate antagonistic function of cholecystokinin in analgesia and energy balance systems. Annals of the New York Academy of Sciences 448:437.