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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33000完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱麗珠(Lih-Chu Chiou) | |
| dc.contributor.author | Chia-ju Kuo | en |
| dc.contributor.author | 郭佳茹 | zh_TW |
| dc.date.accessioned | 2021-06-13T04:21:31Z | - |
| dc.date.available | 2006-08-02 | |
| dc.date.copyright | 2006-08-02 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-07-22 | |
| dc.identifier.citation | Anton B, Fein J, To T, Li X, Silberstein L, Evans CJ (1996) Immunohistochemical localization of ORL-1 in the central nervous system of the rat. J Comp Neurol 368:229-251.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33000 | - |
| dc.description.abstract | 在1994年的時候，發現了第四種屬於鴉片類受體家族的類鴉片孤兒受體 (opioid receptor-like, ORL-1) ，這使我們對鴉片的研究有了一個新的方向。因為雖然這個新的G蛋白耦合受體是屬於鴉片類受體的一員，但是它和鴉片類受體結合劑卻沒有很強的親合力。一年之後，有兩個團體幾乎同時地發現這個受體的內生性結合劑，這個含有17個胺基酸序列的神經肽 (neuropeptide) 被兩個團體各自命名為nociceptin和orphanin FQ。在2002年的時候，這個類鴉片孤兒受體被國際藥理學會依照它的內生性致效劑正式命名為NOP受體。NOP受體和N/OFQ廣泛地分布在中央神經系統，在週邊也有很廣泛的分布。很多的研究指出NOP受體和N/OFQ可以調控許多生理功能，比如疼痛、焦慮、學習、記憶、食物攝取、利尿以及藥物上癮。然而NOP受體和N/OFQ在疼痛上到底是扮演什麼角色還不是十分清楚。N/OFQ不像傳統的嗎啡類藥物一樣具有止痛的功能，N/OFQ會產生止痛和增加痛覺兩種反應。所以為了要了解N/OFQ在止痛的生理功能上到底是扮演什麼樣的角色，就必須發展出NOP受體的結合劑；包括了致效劑和拮抗劑。
UFP-102 ([(pF)Phe4, Arg14, Lys15]N/OFQ-NH2) 是一個良好的選擇性NOP受體致效劑；它的合成是將N/OFQ-NH2作兩種化學修飾：將第14和第15的胺基酸用Arg和Lys取代，以及接上一個[pF(Phe4)]。以前有報告指出這兩種化學修飾可以分別增加NOP受體致效劑的效果及對NOP受體的親合力。本篇論文是要在老鼠的中腦環導水管灰質區的腦切片中，利用盲補綴箝制的實驗方法，看UFP-102活化NOP受體的定量性研究；中腦環導水管灰質區是一個研究N/OFQ抑制嗎啡類藥物止痛效果非常重要的地方。 在大鼠的中腦環導水管灰質區腦切片中，UFP-102在靜止膜電位的時候會濃度相依地引起一個向外的電流，並且能夠增加在-60到-140 mV hyperpolarization ramp下所誘發的膜電流。根據Nernst equation此電流的反轉電位接近鉀離子的平衡電位，且此細胞膜電流具有向內整流的性質。顯示UFP-102可以活化一個向內整流性鉀離子通道。且UFP-102和N/OFQ有一樣的作用效果，但是UFP-102卻比N/OFQ更加有效。 UFP-101是一個選擇性的競爭型NOP受體拮抗劑，它可以濃度相依地降低UFP-102所誘導出的鉀離子電流，且UFP-101的抑制作用不會改變此電流的反轉電位。UFP-101是使UFP-102的濃度反應曲線向右平行移動，但是不會改變UFP-102所能引起的最大反應。如果增加UFP-102的濃度就可以克服UFP-101的抑制效果。然而，沒有選擇性的嗎啡類受體抑制劑，naloxone，並無法抑制UFP-102所誘導出的鉀電流。UFP101對抗UFP-102的pIC50為6.52。 此篇論文的結論是，在大鼠的中腦環導水管灰質區腹側神經細胞：(1) UFP-102是一個NOP受體的選擇性致效劑，它的EC50是11±2 (2) 雖然UFP-102和N/OFQ所能引起的最大反應很相似，但是它的效果比N/OFQ好了4~5倍左右。 | zh_TW |
| dc.description.abstract | Abstract
The discovery of a fourth member of the opioid receptor family, opioid receptor-like (ORL-1) recptor in 1994 gave rise to a new camp in opioid research, since this new G-protein coupled receptor though being in logically homogenous to classical opioid receptors’ did not bind opiates with high affinity. A year later, two groups independently identified the endogenous ligand of this receptor, a 17 amino acid neuropeptide named nociceptin or orphanin FQ. This receptor family was officially renamed after its endogenous ligand as nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) receptor in IUPHAR2002. The NOP receptor and N/OFQ are widely distributed in the central nervous system (CNS), and the periphery. Several studies have implicated the N/OFQ-NOP receptor plays an important role system in pain, anxiety, learning, memory, food intake, diuresis, and drug addition. However, N/OFQ modulation of pain pathways is yet to be completely understood. N/OFQ, unlike traditional opioids which display analgesia effect, elicited both analgesia and hyperalgesia. It has great benefit in understanding the physiological role(s) of N/OFQ in pain regulation by developing NOP receptor ligands, including agonists and antagonists. A novel ligand for the receptor (NOP), [(pF)Phe4, Arg14, Lys15] N/OFQ-NH2 (UFP-102), has been generated by combining in the N/OFQ-NH2 sequence two chemical modifications, [Arg14, Lys15] and [(pF)Phe4], that have been previously demonstrated to increase potency and ability lasting, respectively. The present study, quantitatively investigated the potency of UFP-102 at NOP receptors of rat brain slices containing the midbrain ventrolateral periaquaductal gray (vlPAG), a crucial site for N/OFQ-induced reversal of opioid algesia, using the blind patch-clamp whole cell recording technique. UFP-102 concentration-dependently induced an outward current at resting membrane potential and increased the membrane current elicited by hyperpolarization ramps from -60 to -140 mV in ventrolateral PAG neurons. The current induced by UFP-102 is characterized with inward rectification and has reversal potential near the equilibrium potential of K+ ions according to the Nernst equation. Therefore, UFP-102 activates inwardly rectifying K+ channels. UFP-102 showed similar maximal effects (35 ± 3% and 40 ± 4%, respectively) but higher potency (4- to 5-fold) relative to N/OFQ. UFP-101, a novel selective and competitive antagonist of NOP receptors, concentration-dependently attenuated of K+ current induced by UFP-102 but did not change its reversal potential. It produced a parallel right-shift of the concentration-response curve of UFP-102 but did not alter the extent of UFP-102 induced maximal response. The antagonistic effect of UFP-101 on UFP-102 induced K+ current was surmountable by increasing the UFP-102 concentrations. However, the nonselective opioid receptor antagonist, naloxone, did not attenuated of K+ current induced by UFP-102. The pIC50 of UFP-101 against UFP-102 was 6.52. It is concluded that, in ventrolateral PAG, (1) UFP-102 is a selective agonist of NOP receptor with an EC50 value of 11±2 nM. (2) UFP-102 showed similar maximal effects but higher potency (about 4- to 5-fold) relative to N/OFQ. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T04:21:31Z (GMT). No. of bitstreams: 1 ntu-95-R93443012-1.pdf: 480042 bytes, checksum: 91ad4975d437feea608dad2db26ee56b (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | 目錄
頁次 一、縮寫表 …………………………………………...Ⅰ 二、英文摘要 …………………………………………Ⅱ 三、中文摘要 …………………………………………Ⅴ 四、緒論 ……………………………………………….1 五、實驗材料及方法 ………………………………..38 六、實驗結果………………………………………….46 七、討論……………………………………………….52 八、結論……………………………………………….62 九、圖表……………………………………………….63 十、參考文獻………………………………………….75 | |
| dc.language.iso | zh-TW | |
| dc.subject | 大鼠環導水管灰質區 | zh_TW |
| dc.subject | 類鴉片受體 | zh_TW |
| dc.subject | Periaqueductal Gray Slices of Rats | en |
| dc.subject | UFP-102 | en |
| dc.title | [(pF)Phe4, Arg14, Lys15]N/OFQ-NH2 (UFP-102) 活化大鼠環導水管灰質N/OFQ受體之定量性研究 | zh_TW |
| dc.title | A Quantitative Study of the Effect of [(pF)Phe4, Arg14, Lys15] N/OFQ-NH2 (UFP-102) on Activating N/OFQ Receptors in Periaqueductal Gray Slices of Rats | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 簡伯武(Po-Wu Gean),王鴻利(Hung-Li Wang),黃玲玲(Lin-Lin Huang) | |
| dc.subject.keyword | 類鴉片受體,大鼠環導水管灰質區, | zh_TW |
| dc.subject.keyword | UFP-102,Periaqueductal Gray Slices of Rats, | en |
| dc.relation.page | 88 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-07-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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