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研究生:廖彥昱
研究生(外文):Yan-Yu Liao
論文名稱:新NOP受體拮抗劑UFP-101及NOP功能性拮抗劑Nocistatin,在大鼠環導水管灰質腦切片影響Nociceptin活化鉀離子通道之研究
論文名稱(外文):Effects of UFP-101, a novel NOP antagonist, and nocistatin, a NOP functional antagonist on nociceptin-induced K+ channel activation in rat periaqueductal gray slices.
指導教授:邱麗珠邱麗珠引用關係
指導教授(外文):Lih-Chu Chiou
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:95
中文關鍵詞:向內整流性鉀離子通道環導水管灰質NocistatinNociceptinUFP-101NOP受體
外文關鍵詞:GIRKNociceptinPAGUFP-101Nocistatin
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1994年一種新的類鴉片孤兒受體(ORL1)被發現,其結構相似於傳統鴉片類受體,不過卻對傳統鴉片致效劑缺乏親和力。它的內生性致效劑一年後被發現,並命名為nociceptin或orphanin FQ(N/OFQ)。在2002年國際藥理學聯合會以其內生性致效劑之名正式將ORL1受體命名為NOP受體(nociceptin/orphanin FQ peptide receptor)。N/OFQ和NOP受體在中樞神經系統有廣泛的分布。研究顯示N/OFQ媒介許多生理功能,如痛覺、記憶、焦慮及攝食等。尤其在痛覺調控方面有廣泛的研究,N/OFQ與傳統鴉片呈現的止痛作用不同,它會造成止痛及加強痛覺二極相反的作用。研究發展NOP受體的致效劑與拮抗劑有助於了解N/OFQ在疼痛調節上的角色。
UFP-101([Nphe1,Arg14,Lys15]Nociceptin-NH2)是由NOP受體致效劑[Arg14,Lys15]N/OFQ及NOP受體拮抗劑[Nphe1]N/OFQ(1-13)-NH2修飾而來的具選擇性新NOP受體拮抗劑。本篇論文利用盲補綴全細胞的電生理學記錄方式在N/OFQ反轉嗎啡止痛的重要區域—中腦環導水管灰質腹側區的神經細胞定量性研究UFP-101對N/OFQ的作用。
當PAG腹側區神經細胞處於靜止膜電位時,N/OFQ會誘發細胞膜電流向外流,並隨著N/OFQ濃度的提高而增加在-60到-140 mV hyperpolarization ramp下所誘發的膜電流。此種N/OFQ所誘導出的細胞膜電流具有向內整流的性質,且此電流的反轉電位接近於鉀離子的平衡電位。顯示N/OFQ可以活化向內整流性鉀離子通道。
UFP-101可以濃度相依地抑制由N/OFQ誘導出的鉀離子電流,但不改變其反轉電位。在UFP-101存在下,會使得N/OFQ誘導鉀離子電流作用的濃度-反應曲線平行右移,不過並不影響N/OFQ所能達到的最大效用,且增加N/OFQ的濃度可以克服UFP-101所產生的拮抗效果。利用此濃度反應曲線作出UFP-101的Schild plot,可以求得UFP-101的pA2值為6.92,斜率為0.79。這些結果顯示UFP-101對N/OFQ是競爭性拮抗作用。
給予UFP-101濃度高達1 μM不影響PAG腹側區神經細胞由voltage ramp所引起的膜電流,但在膜電流不受UFP-101影響的同一細胞,加入GABAB致效劑baclofen仍然可以活化向內整流性鉀離子通道。另一方面,在PAG腹側區神經細胞,MOP受體致效劑DAMGO也可活化向內整流性鉀離子通道。然而,給予1 μM高濃度的UFP-101對於DAMGO所引發的向內整流性鉀離子電流並無拮抗作用。顯示UFP-101對NOP受體的拮抗作用具選擇性。
Nocistatin是一個內生性的胜肽,來自於和N/OFQ相同的前驅蛋白, pre-pro N/OFQ,nocistatin並不會與NOP受體結合,但卻是N/OFQ的功能性抗拮劑CNocistatin已被發現可以拮抗數種N/OFQ的作用,包括脊髓止痛、抗鴉片止痛、痛覺過敏、學習與記憶能力減退以及抑制baroreceptor reflex等。在本論文我們也研究nocistatin在大鼠PAG腦切片對於N/OFQ打開鉀離子通道作用的影響。雖然在大多數PAG腹側區神經細胞Nocistatin濃度高達1 μM不影響由300 nM N/OFQ所誘導的向內整流性鉀離子通道活性,但在某些PAG腹側區神經細胞Nocistatin是可以抑制由N/OFQ所誘導的向內整流性鉀離子電流。
本論文結論在PAG腹側區神經細胞:(1)UFP-101是具選擇性及競爭性的NOP受體拮抗劑,其pA2值為6.92。(2)UFP-101對NOP受體不具有內在致效劑的活性。(3)在少數細胞Nocistatin能抑制由N/OFQ所誘導的鉀離子電流。
In 1994, a novel opioid receptor family, opioid receptor like 1(ORL1)orphan receptors, was identified to be structurally similar to classical opioid receptors, but insensitive to traditional opioids. Its endogenous ligand was later identified to be a heptadecapeptide and termed 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. N/OFQ and NOP receptors were widely distributed in the CNS. It had been reported to modulate many biological functions, such as nociception, memory, anxiety and feeding. Among these, its effects on pain regulation were actively explored, N/OFQ, unlike tranditional 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.
UFP-101([Nphe1,Arg14,Lys15]Nociceptin-NH2),a novel selective and competitive antagonist of NOP receptors, modified from the NOP receptor agonist, [Arg14,Lys15]N/OFQ, and the NOP receptor antagonist, [Nphe1]N/OFQ(1-13)-NH2. The present study, quantitatively investigated the interaction of UFP-101 and N/OFQ at NOP receptors of rat brain slices containing the midbrain ventrolateral periaqueductal gray(vlPAG), a crucial site for N/OFQ-induced reversal of opioid analgesia, using the blind patch-clamp whole cell recording technique.
N/OFQ 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 N/OFQ is characterized with inward rectification and has the reversal potential near the equilibrium potential of K+ ions according to the Nernst equation. Therefore, N/OFQ activates inwardly rectifying K+ channels.
UFP-101 concentration-dependently attenuated the K+ current induced by N/OFQ but did not change its reversal potential. It produced a parallel right-shift of the concentration-response curve of N/OFQ but did not alter the extent of N/OFQ-induced maximal response. The antagonistic effect of UFP-101 on N/OFQ-induced K+ current was surmountable by increasing the N/OFQ concentrations. Schild plot analysis yielded a pA2 value of 6.92 and a slope of 0.79. These results indicate that UFP-101 is a competitive type of antagonist of native NOP receptors in vlPAG neurons.
UFP-101 alone, at concentrations up to 1μM, had no effect on the membrane current elicited by voltage ramp. However, in the same ventrolateral PAG neuron, baclofen, a GABAB receptor agonist that is also an activator of inwardly rectifying K+ channels, did activate the K+ conductance. On the other hand, UFP-101, at concentrations up to 1μM, did not reverse the effect of DAMGO,.which is an MOP (mu-opioid) receptor agonist that also activates inwardly rectifying K+ channels in the ventrolateral PAG. This indicates that UFP-101 is specific for NOP receptors.
Nocistatin, a endogenous peptide produced from the same precursor of N/OFQ, pre-pro N/OFQ, does not bind to the NOP receptors, but acts as a functional antagonist of N/OFQ-induced actions, such as spinal analgesia, anti-opioid analgesia, hyperalgesia, learning and memory impairment, and baroreceptor reflex inhibition. In the present study, we also investigated the effect of nocistatin on N/OFQ-induced K+ channel activation in rat periaqueductal gray slices. In most vlPAG neurons, nocistatin, at concentrations up to 1μM, did not affect N/OFQ(300 nM)-induced inwardly retifying K+ channel activations, but in some vlPAG neurons, nocistatin inhibited N/OFQ-induced inwardly retifying K+ current.
It is concluded that, in ventrolateral PAG neurons, (1)UFP-101 is a selective and competitive antagonist of NOP with a pA2 value of 6.92.(2)UFP-101 had no intrinsic activity on NOP.(3)Nocistatin inhibited N/OFQ-induced K+ current in some neurons.
一、縮寫表 ………………………………………………… 1
二、英文摘要 ……………………………………………… 2
三、中文摘要 ……………………………………………… 5
四、緒論 …………………………………………………… 8
五、實驗材料及方法 ……………………………………… 35
六、實驗結果 ……………………………………………… 43
七、討論 …………………………………………………… 51
八、結論 …………………………………………………… 64
九、圖表 …………………………………………………… 66
十、參考文獻 ……………………………………………… 83
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