目前，臨床止痛藥物和鴉片類麻醉藥品仍無法有效減輕慢性疼痛症狀，而相關機制也還有待釐清。本研究中，我們尋找對於慢性疼痛具有療效的海洋天然物，並探討可能的細胞學作用機轉。相較於加巴噴丁(gabapentin)，椎管(intrathecal)給予珊瑚化合物穗花珊瑚醇，能更有效減弱慢性束縛損傷(chronic constriction injury, CCI)所誘發之神經病變性的痛覺過敏，並抑制脊髓的神經發炎性反應，包括微膠細胞(microglia)和星狀細胞(astrocyte)的活化，以及腫瘤壞死因子-α (tumor necrosis factor-α, TNF-α)的增量表現。另外，我們也發現周邊注射具有抗發炎活性的珊瑚化合物sinularin，能明顯地抑制鹿角菜膠(carrageenan)所導致神經源性疼痛行為與脊髓的神經發炎性反應，同時也引起第一型乙型轉化生長因子(transforming growth factor-β1, TGF-β1)的增量表現。此外，我們成功建立一新型的斑馬魚發炎模式，可加速抗發炎藥物的開發。最後透過大鼠模式，我們證實脊髓內的一個抑制腫瘤基因的抗神經發炎作用，以及其對於神經病變性疼痛的形成和維持具有重要的影響。綜和以上研究結果，我們發現兩個具有鎮痛療效的化合物，以及釐清一個抑制腫瘤基因在慢性疼痛治療上的角色。

Up to the present, clinical analgesics and opiates have not been able to alleviate symptoms of chronic pain effectively and the cellular mechanisms of this disorder are still under investigation. In the present study, we first evaluated the anti-nociceptive effects and cellular mechanisms of two marine-derived anti-inflammatory compounds in two standard chronic pain models. Compared with gabapentin, one of the coral-derived compounds, lemnalol, effectively attenuated nociceptive sensitization and inhibited spinal neuroinflammation (comprising astrocyte and microglia activation, and tumor necrosis factor-α upregulation) in chronic constriction injury (CCI)-induced neuropathy. The other compound, sinularin, significantly inhibited nociception and spinal neuroinflammation, and upregulated spinal transforming growth factor-β1 in carrageenan-induced neurogenic pain. Second, we successfully established a novel inflammatory zebrafish model for accelerating the discovery of anti-inflammatory drugs. Third, we demonstrated that a spinal tumor suppressor gene plays an important role in anti-neuroinflammation and in the development/maintenance of neuropathic pain. Based on our findings, we identified two potential therapeutic agents and a role for a tumor suppressor gene in treating chronic pain.

Table of Contents..............................................................................................................................i
List of Figures..................................................................................................................................ii
List of Tables...................................................................................................................................iv
List of abbreviations..........................................................................................................................v
中文摘要.........................................................................................................................................vi
Abstract.........................................................................................................................................vii
General Introduction.........................................................................................................................1
General Methods and Materials.........................................................................................................6
Part I. The therapeutic effects of lemnalol on CCI-induced neuropathic pain behavior and spinal neuroinflammation...........................................................................................................................20
Introduction....................................................................................................................................21
Results..........................................................................................................................................22
Discussion.....................................................................................................................................33
Part II. The beneficial effects of sinularin on carrageenan-induced inflammatory pain behavior and spinal neuroinflammation...........................................................................................................................37
Introduction....................................................................................................................................38
Results..........................................................................................................................................40
Discussion.....................................................................................................................................52
Part III. A beneficial role for a tumor suppressor gene in neuropathic pain.............................................56
Introduction....................................................................................................................................57
Results..........................................................................................................................................59
Discussion.....................................................................................................................................75
Part IV. Establishment of carrageenan-injected adult zebrafish as an novel in vivo inflammatory edema model............................................................................................................................................80
Introduction....................................................................................................................................81
Results..........................................................................................................................................83
Discussion.....................................................................................................................................94
Summary.......................................................................................................................................99
References...................................................................................................................................102
Autobiography...............................................................................................................................118

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