在先前的研究中，來自海洋的化合物flexibilide已經發現能顯著抑制角叉菜膠(carrageenan)誘導的痛覺行為和脊髓神經炎症，並上調角叉菜膠誘導的發炎組織內第一型乙型轉化生長因子的產生。因此，在我們的第一個研究，主要是利用一個已經確立的慢性束縛損傷所誘導的神經病變性疼痛的大鼠模型中，探討flexibilide的鎮痛特性並闡明其止痛作用和第一型乙型轉化生長因子間的關係。首先，我們發現椎管內給予flexibilide能顯著改善因慢性束縛損傷所誘發之熱痛覺過敏，同時能預防慢性束縛損傷大鼠熱痛覺過敏及負重差異的發展。第二，椎管內給予flexibilide顯著抑制同側背角內慢性束縛損傷誘導的膠質細胞活化及誘導型一氧化氮合酶(iNOS)的上調。第三，flexibilide能減低慢性束縛損傷所誘發之脊椎內第一型乙型轉化生長因子的下調，同時椎管內給予第一型乙型轉化生長因子選擇性接收器抑制劑SB431542，能阻斷flexibilide在神經性大鼠的鎮痛作用。在我們第二項研究中，我們希望評估第一型乙型轉化生長因子的止痛效果以及闡釋第一型乙型轉化生長因子在緩解神經病理性疼痛的細胞機轉。我們證明了椎管內給予第一型乙型轉化生長因子顯著減弱神經病變性疼痛老鼠因慢性束縛損傷所誘發之熱痛覺過敏，顯著抑制慢性束縛損傷誘導的小膠質細胞和星形膠質細胞的激活，以及腫瘤壞死因子-α的上調。此外，椎管內給予第一型乙型轉化生長因子顯著減弱慢性束縛損傷誘導的同側谷氨酸轉運體的下調。同時，椎管內給予第一型乙型轉化生長因子顯著降低慢性束縛損傷大鼠脊髓透析液內天門冬氨酸(aspartate)和谷氨酸(glutamate)的濃度。綜上所述，我們得出結論，flexibilide止痛作用的機轉可能和減低因慢性束縛損傷所誘發之脊椎內第一型乙型轉化生長因子的下調有關。然而，第一型乙型轉化生長因子在神經病變的鎮痛作用機制可能包括減低脊髓神經炎症，衰減或上調谷氨酸轉運體的下調，並且減少脊椎內興奮性氨基酸。

In previous studies, the marine-derived compound, flexibilide, has been found to significantly inhibit carrageenan-induced nociceptive behaviors and spinal neuroinflammation, and upregulated production of transforming growth factor-β1 (TGF-β1) in carrageenan-induced inflamed paw tissue. Therefore, in our first study, we sought to investigate the antinociceptive properties of flexibilide in a well-established chronic constriction injury (CCI) model of neuropathic pain in rats, and elucidate the relationship between its anti-nociceptive effects and TGF-β1. First, we found that intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia and was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Second, i.t. administration of flexibilide significantly inhibited the CCI-induced activation of glial cells and upregulation of inducible nitric oxide synthase (iNOS) in the ipsilateral dorsal horn (DH) of the spinal cord. Third, flexibilide attenuated CCI-induced downregulation of spinal TGF-β1 expression and i.t. administration of SB431542, a selective inhibitor of TGF-β receptor 1 blocked the analgesic effects of flexibilide in neuropathic rats. In our secondary study, we sought to evaluate the anti-nociceptive effects of TGF-β1 and to elucidate the cellular mechanisms of TGF-β1 in alleviating neuropathic pain. We demonstrated that i.t. administration of TGF-β1 significantly attenuated CCI-induced thermal hyperalgesia, and inhibited CCI-induced microglial and astrocytic activation, and upregulation of tumor necrosis factor-α in neuropathic rats. Moreover, i.t. administration of TGF-β1 significantly attenuated the CCI-induced downregulation of glutamate transporters on the ipsilateral side and decreased the concentrations of aspartate and glutamate in the spinal dialysates of CCI rats. In summary, we conclude that the mechanisms of flexibilide-induced antinociception may be associated with attenuation of CCI-induced downregulation of spinal TGF-β1 expression. Moreover, the antinociceptive effects of TGF-β1 in neuropathy may include attenuation of spinal neuroinflammation, attenuation or upregulation of glutamate transporter downregulation, and reduction in spinal excitatory amino acids (EAAs).

論文審定書...........................................................................................................................i
誌謝.....................................................................................................................................ii
中文摘要.............................................................................................................................iii
Abstract..............................................................................................................................iv
Table of Contents................................................................................................................v
List of Figures....................................................................................................................vii
List of Tables.......................................................................................................................x
List of abbreviations ...........................................................................................................xi
General Introduction...........................................................................................................1
General Methods and Materials.......................................................................................27
Part I. Flexibilide obtained from cultured soft coral has anti-neuroinflammatory and analgesic effects through the upregulation of spinal transforming growth factor-β1 in neuropathic rats................................................................................................................43
Introduction.......................................................................................................................44
Results..............................................................................................................................47
Discussion........................................................................................................................51
Part II. TGF-β1 attenuates spinal neuroinflammation and the excitatory amino acid system in rats with neuropathic pain................................................................................68
Introduction......................................................................................................................69
Results.............................................................................................................................72
Discussion........................................................................................................................77
Summary..........................................................................................................................98
References.....................................................................................................................103
Appendix.........................................................................................................................123
Autobiography…………………….........................................…….………………………..127
Published papers………........................................…….......………………………...……133

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