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研究生:陳姿吟
研究生(外文):Tzu-Yin Chen
論文名稱:類鴉片與腎臟感覺功能
論文名稱(外文):Opioids and Renal Sensory Function
指導教授:陳朝峰陳朝峰引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
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:106
中文關鍵詞:物質P單側輸尿管阻塞傳出性腎神經活性腎臟腎臟反射腎神經類鴉片
外文關鍵詞:substance P (SP)unilateral ureteral occlusion (UUO)renorenal reflexrenal nerveopioidafferent renal nerve activity (ARNA)
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釵h腎臟疾病都與腎臟感覺反應的不全有關,由此可知腎臟感覺弁鄐妣垠n性。在電生理的研究下,有兩類的腎臟感覺受體被發現,分別為:(a)感應腎臟內壓力的腎壓力性受體(renal mechanoreceptors);及(b)感應腎臟缺血及腎內化學環境改變的腎化學性受體(renal chemoreceptors)。在大鼠中,藉由刺激含有物質P的神經纖維而活化腎臟感覺神經元,可以引發一抑制性的腎臟腎臟反射(inhibitory renorenal reflex)來調控體液的平衡。
內生性類鴉片系統(endogenous opioid system)被廣泛的發現在中樞及周邊神經系統,其傳統的受體主要可分為μ、κ、δ等三大亞型。而類鴉片受體的基因表現,也被發現存在釵h周邊組織,其中包括有腎臟,故推測其可能在調控腎臟弁鄐之篝t重要角色。雖然過去有證據指出,類鴉片會經由活化腎交感神經的活性來改變腎弁遄A此在調控腎臟血液動力學及排泄弁鄐W扮演重要角色,但對於類鴉片是否調控腎臟感覺弁遄A則須更進一步的研究。此外,類鴉片亦被發現會抑制物質P的釋放。因此本論文,將探討類鴉片是否會經由影響腎盂內物質P的釋放,來參與腎感覺弁鄋瑤梇情A以及其在單側輸尿管阻塞的腎臟所扮演的角色。
結果顯示,經由免疫墨漬法發現δ型類鴉片受體蛋白質(δ-opioid receptor, DOR)在腎盂壁上有表現,且表現量在單側輸尿管阻塞後的腎臟較多。若從腎盂內灌注類鴉片胜肽, Leu-enkephalin、β-endorphin及dynorphin A (0.1mg/ml, 20μl/min),則會增加傳入性腎神經活性(afferent renal nerve activity, ARNA);尤其在UUO的大鼠中,增加更明顯。此外,從腎盂灌注類鴉片致效劑DADLE([D-Ala2, D-Leu5]-enkephalin),則會有一濃度依存性的增加ARNA的活性,但卻不會影響腎盂內物質P的釋放及對側腎臟尿液流速(urine flow rate, UV)和鈉離子排泄率(urinary sodium excretion, UNaV);而此ARNA的增加並不會因預先給予NK-1受體拮抗劑spantide I (0.1mg/ml, 20μl/min)而有所減少。另外也發現,由腎盂灌注類鴉片拮抗劑,並不會改變因腎盂內壓力增加而活化的腎壓力性受體時ARNA的增加;而灌注DADLE也不會改變因腎盂灌注高張食鹽水(600mM NaCl)而活化腎化學性受體時ARNA的增加。
DOR蛋白確實存在於腎盂中,尤其在UUO病態下表現更多。綜觀以上結果,類鴉片與腎臟腎臟反射的感覺傳遞路徑不同,其可能經由其他未被發現的路徑來調控腎臟的感覺弁遄A尤其在腎臟病態時。而類鴉片生理意義及調節的機制,均有待進一步的研究。
An impaired renal sensory response associated with various kidney disorders has been demonstrated in rats, which suggests the important role of renal afferents in the reflex control of renal function. Two classes of renal sensory receptors have been identified neurophysiologically: (a) renal mechanoreceptors responding to increases in intrarenal pressure and (b) renal chemoreceptors responding to renal ischemia and/or changes in the chemical environment of the renal interstitium. In rats, activation of renal sensory neurons by substance P (SP)-containing nerve fibers elicits an inhibitory renorenal reflex, which may involve in the regulation of body fluid homeostasis.
The endogenous opioid system present in the central nervous and peripheral organ system consists of three classes of opioid receptors, μ-, κ- and δ-opioid receptors. The gene expression of opioid receptors has been demonstrated in various peripheral tissues of rats, including kidneys, suggesting that endogenous opioid peptides might also work in the regulation of kidneys. Although evidence suggests that opioids change renal function via altering the renal sympathetic nerve activity, this being an important modulation of renal hemodynamics and excretory function, however, whether opioids mediate renal sensory function needs to be further study. Opioids may inhibit the release of substance P (SP). Therefore, we examined whether opioids stimulate the renal sensory function via affecting the release of SP and involve in the alteration of kidneys after 24-hr of unilateral ureteral occlusion (UUO).
In the immunoblotting studies, expression of the δ-opioid receptor protein was demonstrated, especially more prominent in the postobstructive kidneys. The intrarenal pelvic infusion of endogenous opioid peptides, leu-enkephalin, β-endophin and dynorphin A, (0.1mg/ml, 20μl/min), produced a significant increase in the afferent renal nerve activity (ARNA), especially in UUO rats. The infusion of DADLE, a δ-opioid receptor agonist, produced a dose-dependent increase of ARNA without affecting renal pelvic substance P release, urine flow rate, and urinary sodium excretion. The increased ARNA produced by intrapelvic infusion of DADLE was unaffected by pretreatment of rats with the NK-1 receptor antagonist, spantide I (0.1mg/ml, 20μl/min). Infusion of naloxone did not affect the response to stimulation of mechanoreceptors. In addition, intrarenal pelvic infusion of DADLE increased ARNA, but failed to alter the magnitude of ARNA response produced by stimulating chemoreceptor with infusion of hypertonic saline solution (600mM NaCl).
Taken together, our study suggests that opioids stimulate the renal sensory function, especially in rats with UUO, but do not participate in the response to the stimulation of mechano- and chemo- receptors. Opioids may act through another mechanism to mediate the renal sensory function.
縮寫表....................................................I
中文摘要.................................................II
英文摘要.................................................IV
一、文獻回顧
1、腎弁鄋滲姜g調控
1-1、前言................................................01
1-2、腎臟的神經分布......................................02
1-2-1、外源的神經分布....................................02
1-2-2、內在的神經分布....................................03
(A)、傳出性的神經分布....................................03
(B)、傳入性的神經分布....................................04
1-3、腎臟腎臟反射........................................05
1-3-1、腎壓力性受體......................................06
1-3-2、腎化學性受體......................................06
1-3-3、傳入性腎神經的活性................................07
1-3-4、生理意義..........................................08
1-3-5、作用機制..........................................08
(A)、傳遞路徑............................................08
(B)、傳遞路徑的調節......................................09
1-4、腎感覺神經與腎病變..................................10
1-4-1、體液不平衡........................................10
1-4-2、肝硬化引起的腎衰竭................................10
1-4-3、缺血性腎衰竭......................................11
1-4-4、單側輸尿管阻塞....................................11
2、類鴉片
2-1、前言................................................12
2-2、類鴉片受體..........................................12
2-3、內生性類鴉片胜肽....................................13
2-4、細胞內訊息傳遞機制..................................14
2-4-1、cyclic AMP的調節..................................15
2-4-2、離子通道的調節....................................15
2-4-3、次級信差的調節....................................15
2-5、分布................................................16
2-6、作用................................................17
2-6-1、對中樞的作用......................................17
2-6-2、對周邊的作用......................................17
(A)、周邊止痛............................................17
(B)、免疫系統的調控......................................18
(C)、呼吸道的調控........................................18
(D)、肝臟保護............................................18
(E)、腸胃道的調控........................................19
(F)、缺血預先處理的參與..................................20
(F-1)、心臟保護..........................................20
2-6-3、抑制神經傳導物質的釋放............................21
3、類鴉片與腎弁?
3-1、類鴉片影響尿液輸出量................................22
3-1-1、作用位置..........................................23
3-1-1-1、周邊............................................23
3-1-1-2、腎臟............................................23
3-1-1-3、中樞............................................24
3-1-2、作用機制..........................................25
3-1-2-1、μ型類鴉片的抗利尿及利尿機制.....................25
3-1-2-2、κ型類鴉片的利尿機制.............................25
3-2、類鴉片影響鈉離子排泄................................25
3-2-1、作用機制..........................................26
二、研究目的.............................................27
三、研究材料及方法
1、實驗動物之準備
1-1、實驗動物的飼養......................................29
1-2、單側輸尿管阻塞的誘導................................29
2、免疫組織化學染色之研究................................30
3、西方墨漬分析法之研究..................................31
4、一般手術..............................................31
5、傳入腎神經活性(ARNA)的研究
5-1、傳入性腎神經之記錄方法..............................32
5-2、類鴉片對傳入性腎神經之反應..........................33
6、活化腎壓力性與化學性受體對ARNA反應之研究
6-1、類鴉片對刺激腎壓力性受體之研究......................34
6-1-1、刺激腎壓力性受體之方法............................34
6-1-2、類鴉片對刺激腎壓力性受體之反應....................35
6-2、類鴉片對刺激腎化學性受體之研究......................35
6-2-1、刺激腎化學性受體之方法............................35
6-2-2、類鴉片對刺激腎化學性受體之反應....................35
7、腎盂內物質P釋放量之研究
7-1、腎盂流出物的檢體收集................................36
7-2、類鴉片對腎盂內物質P釋放之反應.......................36
7-3、檢體中物質P含量的測定...............................36
8、腎臟腎臟反射之研究
8-1、腎臟腎臟反射之實驗方法..............................37
8-2、類鴉片對腎臟腎臟反射之反應..........................38
9、化學分析..............................................38
10、資料處理及統計方法...................................38
11、藥品.................................................39
四、結果
1、腎盂內類鴉片受體:免疫組織化學染色....................40
2、腎盂內DOR蛋白:西方墨漬分析...........................40
3、類鴉片對傳入性腎神經活性之影響
3-1、類鴉片受體拮抗劑對ARNA之影響........................41
3-2、類鴉片受體致效劑對ARNA之影響........................41
3-3、給予類鴉片受體拮抗劑後,類鴉片對ARNA之影響..........42
3-4、類鴉片致效劑在UUO大鼠中,對ARNA之影響...............42
4、類鴉片對刺激腎壓力性受體及化學性受體之影響
4-1、類鴉片對刺激腎壓力性受體之影響......................43
4-2、類鴉片對刺激腎化學性受體之影響......................44
5、類鴉片對腎盂內物質P釋放之影響
5-1、類鴉片對腎盂內物質P釋放之影響.......................44
5-2、給予神經激肽-1受體拮抗劑後,類鴉片對ARNA之影響......45
6、類鴉片對腎臟腎臟反射之影響
6-1、類鴉片對腎臟腎臟反射的尿液流速之影響................46
6-2、類鴉片對腎臟腎臟反射的鈉離子排泄率之影響............46
五、討論
1、腎盂內類鴉片受體之免疫墨漬法分析......................47
2、類鴉片對傳入性腎神經活性之影響
2-1、類鴉片拮抗劑對ARNA之影響............................48
2-2、類鴉片致效劑對ARNA之影響............................48
2-3、給予類鴉片受體拮抗劑後,類鴉片對ARNA之影響..........49
3、類鴉片對刺激腎壓力性及化學性受體之影響
3-1、類鴉片對刺激腎壓力性受體之影響......................50
3-2、類鴉片對刺激腎化學性受體之影響......................51
4、類鴉片對腎盂內物質P釋放之影響.........................51
5、類鴉片對腎臟腎臟反射之影響............................51
6、UUO下,類鴉片對腎臟之影響
6-1、DOR蛋白的表現.......................................52
6-2、類鴉片致效劑對ARNA之影響............................53
7、未來研究方向..........................................53
六、結論.................................................55
七、參考文獻.............................................93
八、附錄................................................105
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