臺灣博碩士論文加值系統

嗎啡是強而有效的止痛劑，在臨床上使用已久，但長期使用卻會產生耐藥性。有兩類機轉用來解釋嗎啡耐藥性；一為系統之間之機制(within system)，指與嗎啡受體訊息傳遞途徑有關。目前的研究顯示包括受體數目的減少和受體-G蛋白之失聯，與乙型休止素 (β-arrestin) 均參與類鴉片受體去敏感性及內化有關。而系統之間之機制 (between system) 則是包括減少麩胺酸轉運蛋白，增加細胞外液中的神經傳導素麩胺酸導致活化麩胺酸傳導系統及神經性發炎，而降低嗎啡止痛效果。腫瘤壞死因子-α是個很重要的炎性前驅物質，可活化脊髓神經膠質細胞，引發神經發炎反應。很多研究顯示嗎啡耐受性與痛覺過敏，在脊髓神經膠質細胞活化反應增強和麩胺酸神經毒性方面非常相似。而腫瘤壞死因子-α不僅可調控麩胺酸轉運蛋白，並且可增加細胞膜上AMPA受器，改變麩胺酸在突觸間的傳導。我們希望能以抗發炎和減緩麩氨酸在突觸間的傳導的觀點，提供另一種治療嗎啡耐藥性的選擇。在本論文的研究中，我們使用雄性Wistar大白鼠為實驗動物，利用椎管內給予嗎啡 (15 μg/h) 持續5天產生嗎啡耐藥性。在第五天，剪斷微滲透幫浦的連接椎管後，選擇給予恩博 (etanercept 5 μg, 25 μg and 50 μg/10 μl) 或是生理食鹽水 (10 μl)，三小時後再以嗎啡15μg椎管內注射來測試嗎啡之止痛效果。在產生嗎啡耐藥性的大鼠，我們發現給予50 μg恩博 (etanercept) 治療、嗎啡仍可明顯產生止痛效果。在嗎啡耐藥性大鼠的脊髓背角，即時定量聚合酶反應結果顯示腫瘤壞死因子-α之mRNA的表現增加2.5倍、而細胞激素IL-1β與IL-6分別增加13及 111倍。這些發炎性細胞激素的表現均可被50 μg恩博 (etanercept) 所阻斷。免疫組織染色分析同樣發現50 μg恩博 (etanercept) 可壓制小神經膠質細胞的神經發炎反應和細胞激素 (TNF-α, IL-1β和IL-6) 的表現。在嗎啡耐藥性大鼠，西方墨點實驗指出、給予50 μg etanercept不只可以防止在嗎啡耐藥鼠麩胺酸轉運蛋白 (GLAST, GLT-1及EAAC1) 的含量均降低，且可抑制誘發細胞膜上AMPA- 及NMDA-receptor subunits的表現。總之，使用恩博(etanercept; 腫瘤壞死因子α-抑制劑)阻斷TNF-α的傳導，可減緩嗎啡耐藥性的產生。其機轉來自回復神經膠質細胞膜上麩胺酸轉運蛋白含量、抑制細胞膜上AMPA- 及NMDA-receptor subunits增加及壓抑小神經膠質細胞的活化和細胞激素的表現。這些結果顯示恩博 (etanercept) 在臨床疼痛處置上，可做為嗎啡耐藥性的輔助療法，延續嗎啡的止痛效果，特別是神經性疼痛需要長期嗎啡治療的病人。

Opioids are potent and effective analgesics; they are widely used in clinical pain management. Long-term exposure to morphine leads to analgesic tolerance. There are two possible mechanisms for drug tolerance; within-system and between-system adaptation. Recent investigations on the mechanisms of within-opioid system adaptation include downregulation of G-protein coupled receptors, G protein uncoupling, and β-arrestin binding and internalization of opioid receptors. Studies of between-system adaptation have focused on glutamatergic synaptic transmission via downregulation of glutamate transporters (GTs), increased glutamate level and activation of NMDA receptor function, and glia activation with increasing of proinflammatory cytokine expression; which reduced antinociceptive effect of morphine. Tumor necrosis factor-α (TNF-α) has been demonstrated to correlate with neuronal plasticity via activating spinal glia cells and enhancing glutamatergic transmission. The present study examined the mechanism of etanercept, a TNF-α inhibitor on morphine tolerance in male Wistar rats. Intrathecal morphine infusion (15 μg/h) for 5 days was used for tolerance induction. On day 5, either etanercept (5 μg, 25 μg and 50 μg/10 μl) or saline (10 μl) was injected after discontinued morphine infusion, and three hours later morphine (10 μg/10 μl, i.t) was given for tail-flick latency measurement. We found that pretreatment with etanercept (50 μg) caused a significant antinociceptive effect of morphine in morphine-tolerant rats. The real-time PCR data showed that the expression of TNF-α mRNA was increased by 2.5 fold, IL-1β mRNA increased by 13 fold and IL-6 mRNA by 111 fold in the dorsal horn of morphine-tolerant rat spinal cords. The increase in TNF-α, IL-1β and IL-6 mRNA expression was blocked by 50 μg etanercept pretreatment. The immunohistochemistry analysis revealed that 50 μg etanercept suppressed the proinflammatory cytokines expression and neuroinflammation in the microglia. In addition, Western blotting indicated that etanercept downregulated membrane glutamate transporters (GTs), EAAC1, GLT1 and GLAST in morphine tolerant rats. Etanercept also inhibited the upregulation of surface AMPA- and NMDA-receptor subunits, including GluR1/GluR2 and NR1/NR2A. In summary, blockade of TNF-α signaling attenuated morphine tolerance. This effect may be mediated by restoration of glial membrane GTs expression, inhibition of surface AMPA- and NMDA-receptor upregulation, and suppression of microglial activation and proinflammatory cytokine expression. The results suggest that etanercept could also be an adjuvant therapy for morphine tolerance, which extends the effectiveness of opioids in clinical pain management.

Contents
Chinese abstract -------------------------------------------------------------------- 1
English abstract -------------------------------------------------------------------- 3
Abbreviations -------------------------------------------------------------------- 5
Text contents
1.0 Background -------------------------------------------------------------------- 8
1.1 Morphine tolerance ----------------------------------------------------------- 8
1.11 Within system of morphine tolerance ------------------------------------------ 9
I. Modulation of adenylyl cyclase and cAMP-dependent PKA activation
II. Uncoupling of G protein
III. β-arrestin and opioid receptor internalization
IV. μ-opioid receptor oligomerization
1.12 Between system of morphine tolerance ------------------------------------------ 11
I. Neuroinflammation
II. Glutamatergic system
III. Cholecystokinin
IV. Apoptosis
1.2 TNF-α and Etancecpt ----------------------------------------------------------- 17
2.0 Materials and Methods ----------------------------------------------------------- 20
2.1 Animal preparation and intrathecal drug delivery --------------------------------- 20
2.2 Construction of the intrathecal catheter --------------------------------- 20
2.3 Nociception test ----------------------------------------------------------- 21
2.4 Spinal cord preparation -------------------------------------------------- 22
2.5 Quantitative real-time PCR -------------------------------------------------- 23
2.6 Immunocytochemistry and image analysis ----------------------------------------- 24
2.7 Preparation of spinal cord plasma membrane, cytosolic, and nuclear fractions for
Western blotting analysis -------------------------------------------------- 25
2.8 Western blotting analysis -------------------------------------------------- 26
2.9 Data and statistical analysis -------------------------------------------------- 27
3.0 Intrathecal etanercept partially restores morphine’s antinociception in
morphine-tolerant rats via attenuation of neuroinflammation and glutamatergic
transmission -------------------------------------------------------------------- 29
3.1 Introduction -------------------------------------------------------------------- 29
3.2 Materials and Methods ----------------------------------------------------------- 29
3.3 Results -------------------------------------------------------------------- 30
I. Neuroinflammation ----------------------------------------------------------- 30
II. Glutamatergic transmission -------------------------------------------------- 36
3.4 Discussion ------------------------------------------------------------------- 45
I. Neuroinflammation ---------------------------------------------------- ------ 45
II. Glutamatergic transmission ------------------------------------------------- 50
4.0 Conclusion and future work ------------------------------------------------- 59
5.0 References ------------------------------------------------------------------- 62
Appendix

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