臺灣博碩士論文加值系統

臨床上，使用嗎啡和其他鴉片類的止痛劑，被發現會造成病人膀胱功能障礙並有尿液滯留的問題。這種副作用被認為是經由鴉片類delta及mu受體所造成，而且在上脊髓部位和脊髓部位所引發的機制不同。因此，在治療尿失禁的病患時，似乎可以利用藥物介入的方式來調節內嗎啡系統，使過度的排尿反射受到抑制，以達到治療的效果。本研究之主要目的是探討兩種非胜類鴉片樣delta受體促效劑 (SNC-80，BW373U86) 及一種鴉片樣d受體拮抗劑 (naltrindole) 對大白鼠排尿反射影響之作用機制，並提供一些資訊作為臨床上治療尿失禁方面的參考。本實驗以尿胺麻醉之大白鼠為實驗材料，並以持續性生理食鹽水灌流引起自發性膀胱收縮之方法，測試其對排尿反射之影響，除紀錄膀胱壓外，並同時紀錄骨盆傳入 (PANA) 及傳出神經之活性 (PENA)，以及尿道外括約肌之肌電圖 (EUS-EMG)。結果發現，當注射SNC-80或BW373U86至側腦室中，會使排尿反射受到抑制，延長排尿間隔 (40~95%)，但是對於EUS-EMG、PANA及PENA並無影響。若注射SNC-80及BW373U86至脊髓硬膜下腔，會使排尿反射受到短期而完全的抑制 (約5分鐘)，當排尿反射出現後，仍會降低PANA (5~41%) 及PENA (5~44%)。另一方面，注射naltrindole至側腦室中，會使排尿頻率增加，降低PMP (8~11%)，若注射到脊髓硬膜下腔，則在給藥後的第一次排尿反射出現之前，會造成膀胱震盪型的收縮但不排尿，然後會使排尿時PMP (8~9%) 及PANA增強 (18~32%)。至於局部給予SNC-80及BW373U86至膀胱壁上，則會縮短排尿間隔 (17~25%)，降低排尿時PMP、PANA、PENA，以及EUS-EMG。局部給予naltrindole則有相反的效果，但是在高劑量時會降低排尿時PMP。結果顯示，不論是促效劑或拮抗劑注射到側腦室中，皆不會對骨盆神經之活性造成影響，因此推論上脊髓部位的內嗎啡系統，並不會直接影響副交感神經節前神經元之活性，其作用可能在中間神經元或膀胱的輸入神經。然而，當促效劑直接作用在脊髓部位時，卻會直接影響到副交感神經節前神經元之活性，因此對骨盆神經之活性造成抑制。根據結果，腦部之內嗎啡系統的抑制作用，主要和排尿反射閾值之調控有關，而脊髓部位的內嗎啡系統則可直接對副交感神經節前神經元造成抑制性作用。因此本研究的結論是，鴉片樣delta受體促效劑SNC-80對尿失禁病患的治療可能一個較好的選擇。

Morphine and a number of other opioid analgesics produce urinary retention in clinical use. This action appears to involve the activation of delta and mu opioid receptors in both supraspinal and spinal levels. Thus, Pharmacologic manipulation of endogenous opioid mechanisms may be clinically useful in treating neurogenic bladder dysfunction, such as urinary incontinence. The purpose of this study is to investigate the action mechanisms of two non-peptide opioid delta-receptor-selective agonists (SNC-80, BW373U86) and an antagonist (naltrindole) involved in the micturition reflex. They were tested by the spontaneous volume-induced contraction of the urinary bladder in the urethane-anesthetized rats. The intravesical pressure, the pelvic afferent activity (PANA) and efferent activities (PENA) as well as the EMG of external urethral sphincter (EUS-EMG) were recorded simultaneously. The intracerebroventricular administration of SNC-80 or BW373U86 caused inhibition of the micturition reflex, and BW373U86 also induced a reduction in peak micturition pressure (PMP) and EUS-EMG. The intrathecal infusion of SNC-80 or BW373U86 produced a complete short-lasting inhibition of micturition reflex. The inhibition of the EUS-EMG, PANA and PENA were persisted when the micturition reappeared. On the other hand, the intracerebroventricular administration of naltrindole, the micturition reflex was facilitated but the PMP was inhibited. Whereas intrathecal infusion of naltrindole produced a series of ineffective bladder contractions before the first micturition started. In local application of SNC-80 or BW373U86, however, the micturition interval, PMP, EUS-EMG, PANA, and PENA were all inhibited. Local application of naltrindole produced the effects just opposite to the agonist stated above, except the PMP, which was reduced in a high dose. The opioid delta receptor agonists and antagonist at the supraspinal site failed to alter the pelvic nerve activity suggest that supraspinal endogenous opioid system does not act directly on the sacral preganglionic neurons, but indirectly through descending fibers on the interneuron at the level of afferent inputs in the sacral spinal cord. However, these agonists at the spinal site may cause direct inhibition of the sacral preganglionic neuron discharge, and then inhibit the pelvic nerve activity. These results indicate that the brain endogenous opioid system seems to play a major role in the modulation of the micturition threshold and the frequency, whereas in the spinal region, enkephalinergic neurons seem to control the activity of sacral preganglionic neurons. It is concluded that the opioid d-receptor agonist, SNC-80, but not BW373U86, may be a good candidate for the treatment of the patient with urinary incontinence.

目錄
頁
圖次 ………………………………………………………III
中文摘要 …………………………………………………V
英文摘要…………………………………………………VII
緒論…………………………………………………………1
材料與方法 ………………………………………………10
結果 ………………………………………………………17
討論 ………………………………………………………26
結論 ………………………………………………………36
附圖 ………………………………………………………37
參考文獻 ………………………………………...………71
附錄 ………………………………………………………77

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