2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642828摘要：嗎啡是一種經常用來止痛和造成成癮的藥物，它的作用機轉是透過鴉片受體進行疼痛控制的作用。根據以往的文獻，嗎啡用來當麻醉藥時或多或少都有抑制生物體免疫力的情形包括特異性的免疫系統及非特異性的免疫系統。而因為免疫的降低在臨床上則可能提高手術之後的感染率及手術後腫瘤擴散的機會。近年來，嗎啡類的藥物用來治療癌症疼痛及一些神經痛的病患已成為止痛的常規用藥。然而令人憂心的是，藥物濫用已經是目前全世界各地所遭遇的重要醫療問題。更有甚者，藥物濫用者在性行為上通常是屬於比較高的危險群。我們研究團隊在先前的研究計畫中已經證實嗎啡在免疫能力健全的 naïve 老鼠中具促進腫瘤生長的能力，而且抑制T 淋巴細胞的增生能力和消耗活體內腫瘤疫苗的保護能力。再以內皮細胞為研究模式下，我們也探討嗎啡造成內皮細胞凋亡的分子作用機轉，包括細胞內自由基生成與細胞膜電位的改變，Bcl-2 家族蛋白表現量的改變都會受到嗎啡的刺激而改變。然而先前的結果中這些現象並不能完全說明嗎啡刺激腫瘤發生的原因。樹突細胞的抗原呈現能力在腫瘤免疫學上相當重要，腫瘤現象發生時往往伴隨著抗原呈現能力的低下，使腫瘤細胞不容易被毒殺T 細胞所辨認而引起免疫逃避的反應。嗎啡是否會影響樹突細胞抗原呈現的能力進一步的促使腫瘤發生則不得而知。因此我們設計了這個三年的計畫並嘗試了解：第一，在以骨髓細胞衍生樹突細胞的研究模式下，嗎啡影響這些樹突細胞的抗原吞噬及呈現能力調節的免疫反應為何?第二，以長期接受嗎啡的動物模式，研究嗎啡影響生物體內之樹突細胞抗原吞噬、呈現能力、免疫反應及抗腫瘤活性是否會受到影響?第三，以人類週邊血液為材料，研究嗎啡影響週邊血液單核球衍生之樹突細胞在自身抗原呈現能及吞噬能力是否也會受到抑制?這個計畫的研究結果將能提供完整的瞭解嗎啡與免疫系統的關連與分子機制，進一步的推測這些現象與腫瘤發生間之關係。對於爾後進行之藥癮患者較容易罹患癌症，以及是否需要先戒毒後，並能評估腫瘤疫苗對於藥癮病患的癌症治療及預防才比較有效果。<br> Abstract: Morphine is a widely-used drug for analgesics and drug abuse. With high affinity tothe μ-opioid receptor, it effects on opioid receptors in the post operation control have all beenwell-characterized. Previous studies have also demonstrated that the widely used as ananesthetic agent as well as adjuvant for the treatment of cancer pain and neuropathic pain, willbring harmful effects on specific immune system. Furhermore, the suppressed immunefunction may lead to postoperative infection and postoperative dissemination of carcinoma. Inrecent years, morphine has been widely used for pain management and addiction in paincontrol. Moreover, drug abuse has become the most important medical problem all over theworld. And the majority of morphine addicts are also associated with frequent sexualcontamination.Our research team has confirmed that morphine could promote tumor growth in naïveimmuno-compromised mice in our previous project, and morphine could suppress theproliferative ability of T lymphocytes even erased the tumor protection effects enhanced bytumor vaccines in vivo. We further confirmed that morphine could induce cell apoptoticmachinery in endothelial cells model, including free radical generation, membrane potentialchange and the alternation of Bcl-2 family protein expression. However, these apoptoticphenomena could not explain the complete reasons that morphine induced tumor progression.The antigen processing and presenting activity enhanced by antigen presenting cells is themain cause in tumor development, especially in dendritic cells. The tumorgenesis is alwaysassociated with the low antigen presentation activity, and it results the poor recognization bycytotoxic T cells even causes the immuno-escape responses. Whether morphine interuptdendritic cells-mediated immunity or not is remained unknown.So we proposed this three-year proposal to evaluate: First, what is the influence ofmorphine on antigen processing and presenting activity by using ex-vivo bonemarrow-derived dendritic cells model? Second, what is the influence of long-term use ofmorphine animals on antigen processing and presenting activity even in the tumor promotingeffects in dendritic cells-mediated immunological responses? Third, what is the influence ofmorphine on antigen processing and presenting activity by using ex-vivo monoctye-deriveddendritic cells from human peripherial blood? From the results of this project, we willunderstand the complete molecular mechanism and the correlation between morphine andimmunity. And we can further propose the relationship of the deficiency of immunity andtumorgenesis. We may also evaluate the risk of cancer incidence in drug abuser, and theefficiency of tumor prevention and treatment by tumor vaccine in drug abuser with quitnarcotics in the future.