臺灣博碩士論文加值系統

　　下泌尿道(the lower urinary tract)儲尿及間歇性排尿的功能受腦部及脊髓複雜的神經系統所支配。在正常狀況下膀胱及出口(包括膀胱頸及外尿道括約肌)呈現協調的互動關係，當儲存尿液時，膀胱呈靜止狀態而外尿道括約肌則為活化狀況;但排尿時¸逼尿肌強力收縮而括約肌活性受到抑制。

　　膀胱傳入纖維藉由骨盆神經傳入腰薦神經叢，而尿道傳入纖維是經由會陰神經傳入中樞。本研究的目的在於藉由膀胱漲縮來調控外尿道擴約肌反射路徑，分為骨盆神經傳入纖維到外尿道擴約肌與會陰神經之反射路徑，各稱之為骨盆神經-外尿道擴約肌反射(pelvic-EUS reflex)與骨盆神經-會陰神經反射(pelvic-pudendal reflex)，以及會陰神經傳入纖維到對側會陰神經與外尿道擴約肌之反射路徑，各稱之為會陰神經-會陰神經反射(pudendal-pudendal reflex)與會陰神經-外尿道擴約肌反射(pudendal-EUS reflex)。此外，MK801 (NMDA antagonist)與LY215490 (AMPA antagonist)被用來評估穀氨基酸在這些反射路經中傳遞的角色為何，目前MK801是能夠抑制骨盆神經-外尿道擴約肌反射與會陰神經-會陰神經反射，而LY215490的抑制效果並不顯著。

　　鼠於儲尿時期其外尿道擴約肌活動為tonic activity，在排尿瞬間轉成bursting加速尿液的排空。此實驗建立多種急性與慢性脊髓損傷模型，包括急性與慢性胸椎第八節，腰椎第三節及腰椎第六節的脊髓完全切斷，來評估tonic activity與bursting的控制機轉所在。此外，5HT-1A receptors agonist (8-OH-DPAT) 在上述反射機制與外尿道擴約肌中扮演了誘發與增強的角色，反之antagonist (WAY100635) 則可以反轉8-OH-DPAT的效果，讓反射訊號幾乎回復到未用藥前的狀態。

　　骨盆神經-外尿道擴約肌與會陰神經-會陰神經反射在膀胱漲尿時其反射訊號被抑制，會陰神經-外尿道擴約肌反射改變卻不顯著，因此認為外尿道擴約肌並不完全由會陰神經支配，應該另有神經分支連至此肌肉而導致反應不同。穀氨基酸與血清素機制對於膀胱活動和外尿道擴約肌佔有相當程度的影響力，尤其是5HT-1A receptors agonist可以誘發外尿道擴約肌活動。另外，此實驗中證明tonic activity的控制機轉大約位於脊髓胸椎第八節與腰椎第六節之間，而bursting的控制機轉位於脊髓胸椎第八節與腰椎第三節之間。此研究進一步結合骨盆神經與會陰神經兩種電刺激模式探討骨盆神經傳入纖維與會陰神經傳入纖維對外尿道擴約肌的關係，結果指出兩神經電刺激區間介於180-300 ms時，電刺激會陰神經可以顯著抑制骨盆神經-外尿道擴約肌反射，抑制效果在膀胱漲尿期間更加顯著。

　Normal lower urinary tract function involves spinal and supraspinal pathways that control urine storage and release. In rats, urine release is mediated by contraction of the bladder detrusor accompanied coordinated activation of two types (tonic activity and bursting) of external urethral sphincter (EUS). This study used cystometry, EUS electromyography and nerve activity to examine the origin of EUS bursting and EUS activity as well as pudendal nerve evoked by electrical stimulation at pudendal and pelvic nerves (pudendal-EUS, pudendal-pudendal nerve and pelvic-EUS reflexes). Furthermore, the changes in the reflexes induced by bladder distension and by administration of agonists or antagonists for glutamatergic or serotonergic receptors were examined in rats with intact spinal cord (SC) rats or spinal cord injury (SCI) following administration of glutamatergic antagonist receptors (MK801 or LY215490) or 5HT-1A receptor agonist (8-OH-DPAT) and antagonist (WAY100635).

　In intact-SC rats, stimulation of the entire pudendal nerve elicited short latency (8-12 ms) responses in the EUS and short (3-8 ms) and long latency responses (16-20 ms) in contralateral pudendal nerve. The long latency pudendal-pudendal reflex was reduced by 36.7 % in area during bladder distension. However, there was no significant change in the area of pudendal-EUS reflex during bladder distension. Peak amplitudes of both reflexes were reduced 32% by bladder distension. The effects of glutamatergic receptor antagonists on the reflexes were also examined. MK801 (0.3-5 mg/kg, i.v.) markedly depressed the pudendal-pudendal reflex, but LY215490 (3 mg/kg, i.v.) had a minimal inhibitory effect. Both glutamatergic receptor antagonists significantly suppressed the pudendal-EUS reflex.

　The pelvic-EUS reflex consisted of an early response (ER, latency, 18-22 ms) and a late, long duration response (LR, latency greater than 100 ms) that consisted of bursts of activity at 20-160 ms inter-burst intervals in intact-SC rats. The LR was markedly enhanced when the bladder was distended. The ER and LR was significantly decreased 75% and 35%, respectively, by MK801 (0.3 mg/kg, i.v.), but only decreased 18% and 14%, respectively, by LY215490 (3 mg/kg, i.v.). 8-OH-DPAT (1 mg/kg, i.v.) enhanced spontaneous EUS activity and the pelvic-EUS reflexes. WAY100635 (0.3-1 mg/kg, i.v.) reversed the effect of 8-OH-DPAT and suppressed EUS activity and the pelvic-EUS reflex.

　The effects of 8-OH-DPAT and WAY100635 were examined in the rats following acute and chronic (2-5 weeks) SCI. Tonic EUS activity remained but bursting was abolished during bladder distension in the rats with acute T8-9 or L3-4 and chronic L3-4 SCI. Both tonic and bursting EUS activity were completely abolished in acute and chronic L6-S1 SCI rats. Only the ER remained in acute and chronic T8-9 and L3-4 SCI rats, but was absent in L6-S1 rats. 8-OH-DPAT (1 mg/kg, i.v.) facilitated tonic activity, EUS bursting and LR in T8-9 chronic SCI rats. However, only tonic activity was enhanced (5-10%) by 8-OH-DPAT in T8-9 acute SCI rats. WAY100635 (1 mg/kg, i.v.) reversed the effect of 8-OH-DPAT. Neither drug had any effect in acute or chronic L3-4 or L6-S1 SCI rats.

These results indicate that the EUS is innervated by multiple pathways and that glutamatergic excitatory transmission is important in the neural mechanisms underlying bladder-sphincter coordination in the rat. Glutamatergic and serotonergic mechanisms are important in the reflex pathways underlying bladder-sphincter coordination in rats. Spinal serotonergic mechanisms facilitate tonic and bursting EUS activity. The circuitry for generating EUS bursting seems to be located in the spinal cord between T8-9 and L3-4.

Chapter 1 Introduction 1
1.1 Anatomy of the lower urinary tract 1
1.2 Physiological properties of bladder and urethra 1
1.3 Applications of electrical stimulation in the lower urinary tract 5
1.4 Review of drug effects 8
1.5 The Aims of this study 10

Chapter 2 Methodology 14
2.1 Methods for the pudendal-pudendal nerve and pudendal-EUS reflex 14
2.2 Methods for the pelvic-EUS reflex 16
2.3 Methods for the EUS activity and pelvic-EUS reflex in SCI rats 22
2.3.1 Acute spinal transaction 22
2.3.2 Chronic SCI 24
2.4 Combination of the pelvic nerve and pudendal nerve stimulation 25
2.5 Pharmacological experiments 26
2.6 Data analysis 27

Chapter 3 Results 30
3.1 Pudendal-pudendal and pudendal-EUS reflexes 30
3.1.1 Pudendal-pudendal and pudendal-EUS reflexes 30
3.1.2 Role of glutamatergic mechanisms in reflex pathways 33
3.2 The EUS activity and pelvic-EUS reflex in intact-SC rats 45
3.2.1 EUS activity 45
3.2.2 Pelvic-EUS reflex 45
3.2.3 Role of glutamatergic mechanisms in reflex pathways 48
3.2.4 Effects of serotonergic drugs on EUS-EMG activity 57
3.3 Pelvic-pudendal reflex 60
3.4 Time-frequency analysis on the pelvic-EUS and pelvic-pudendal
reflexes in intact-SC rats 68
3.5 EUS activity and the pelvic-EUS reflex in SCI rats 72
3.5.1 Acute spinal cord transaction 72
3.5.2 Chronic spinal cord injury 73
3.6 Interaction between the pelvic and pudendal stimulation 91

Chapter 4 Discussions 94
4.1 Pudendal-pudendal and pudendal-EUS reflexes in intact-SC rats 94
4.2 Pelvic-EUS reflex and EUS activity in intact-SC rats 99
4.3 Pelvic-EUS reflex and EUS activity in SCI rats 107
4.4 Interaction between pelvic and pudendal stimulation 113
4.5 Future applications 114

Chapter 5 Conclusions 117

Appendix 119

References 125

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