臺灣博碩士論文加值系統

由於神經的受傷，慢性發炎，帶狀皰疹後疼痛，腦中風或糖尿病等原因引起的慢性神經性疼痛，其真正詳細的機轉尚未完全明瞭。在臨床上，治療慢性疼痛的方法或藥物亦有待突破。其間，免疫及發炎反應的強弱對慢性神經性疼痛引起的神經重塑過程中，很可能會有決定性的影響。過去總認為發炎反應會增強疼痛程度。但最近有文獻報告，發炎反應引起的數種免疫細胞會分泌多種抑制作用之物質，亦可能導致減輕疼痛。因此，我們的第一個實驗是利用數種先天性免疫功能不全的小鼠，觀察周邊神經受傷後造成的慢性疼痛反應之差異，發炎反應的強弱，發炎物質，抗發炎物質和數種鴉片類止痛蛋白之改變，加以分析免疫及發炎反應對慢性神經性疼痛的影響，可能的機制和結果。
同樣的，發炎反應引起的數種免疫細胞，特別是多型核白血細胞在特殊之情況下可分泌具有止痛效果之物質。因此，目前認為免疫細胞之數量和功能的改變，會產生一定的止痛效果。顆粒球群落刺激因子是一種刺激介素。文獻顯示給予顆粒球群落刺激因子，可刺激骨髓細胞的移行，進而降低腦部缺血之嚴重度和改善神經的可塑性。因此，我們的第二個實驗是探討外源性顆粒球群落刺激因子對小鼠周邊神經受傷後造成的慢性疼痛反應之影響。我們觀察疼痛反應之差異，發炎反應的強弱和數種鴉片類止痛蛋白之改變，加以分析外源性顆粒球群落刺激因子對免疫及發炎反應以及慢性神經性疼痛的影響。我們的結果顯示神經受傷後的發炎反應可能具有雙重作用。受傷初期所引發的發炎反應和胞泌素會使疼痛更強烈。但晚期發炎反應，胞泌素和鴉片類蛋白可能會有抑制疼痛之效果。期望依據本研究所發現的慢性神經性病變時引發之免疫及發炎反應為基礎，於不同階段的神經性疼痛時期，調控不同的發炎症反應或分泌物質，或許可做為日後研發新的疼痛治療方式或藥物的方向。

Chronic neuropathic pain, resulting from nerve injury due to trauma or disease, such as chronic inflammation, postherpetic neuralgia, diabetic neuropathy, is one of the most difficult challenges in pain management. Multiple mechanisms, including changes in the peripheral nervous system, spinal cord, brainstem or brain, may contribute to the neuropathic pain. Traditionally, inflammatory and neuropathic pain syndromes have been considered different entities. In fact, inflammatory and immune mechanisms would be associated with the development of hyperalgesia but several variables are worth noting in approaching the question of immune mechanisms to neuropathic pain. For instance, in contrast with the concept of inflammation induce pain; several studies have demonstrated that immune cells also produce mediators that can effectively counteract pain. In order to clarify this issue, we utilized wild-type C57BL/6C, Non-obese diabetic (NOD) and Non-obese diabetic-severe combined immune deficiency (NOD-SCID) mice, which all have a different level of an immunocompromised state, to examine the effect of inflammation on the development of neuropathic pain. In our first project, we analyzed the profile of immune cell infiltrates as well as the mRNA and proteins expression levels of various cytokines and opioid peptides in sciatic nerves of mice receiving a partial sciatic nerve ligation (PSNL).
Granulocyte-colony stimulating factor (G-CSF), mainly stimulates the development of committed hematopoietic progenitor cells to neutrophils and modulates neutrophil actions and distribution. Previous studies demonstrated that G-CSF treatment may accelerate the improvement of organ functions and prevent tissue injury in different animal models. Based on these results, our second project was designed to test the hypothesis that exogenous administration of recombinant mouse granulocyte-colony stimulating factor (rmG-CSF) to enhance the recruitment of inflammatory cells, particularly opioid-containing PMN, to painful inflamed sites could attenuate pain in a chronic neuropathic pain model in mice. Our results demonstrate that inflammation may have a dual role in the modulation of the behavioral hypersensitivity in the murine PSNL model. Inflammation will facilitates the development of behavioral hypersensitivity in the early stage of nerve injury, and with the accumulation of opioid containing leukocytes and anti-inflammatory cytokines, attenuates behavioral hypersensitivity in the late stage of injury. Hopefully our current experiments on relating the immune response to chronic neuropathy will eventually lead to innovative possibilities for therapeutic intervention in neuropathic pain, based on targeting the inflammatory response in different stages.

指導教授推薦書................................................
口試委員會審定書...............................................
長庚大學博碩士論文著作授權書..................................iii
誌謝......................................................iv
中文摘要...................................................vi
英文摘要................................................ viii
縮寫表......................................................x

CHAPTER I INTRODUCTION.................................1-18
1.1 BACKGROUND AND RELATED STUDIES........................2
1.2 HYPOTHESIS AND SPECIFIC AIMS..........................8
1.3 RESEARCH PLANS.......................................13

CHAPTER II MATERIALS AND METHODS......................19-29
2.1 ANIMALS AND PREPARATION .............................20
2.2 SURGICAL PROCEDURES..................................22
2.3 NOCICEPTIVE TESTS....................................22
2.4 IMMUNOHISTOCHEMISTRY.................................23
2.5 CELL PREPARATION AND FLOW CYTOMETR...................25
2.6 MEASUREMENT OF CYTOKINES LEVELS IN THE SCIATIC NERVES.….........................................................26
2.7 TOTAL RNA ISOLATION AND QUANTITATIVE REAL-TIME PCR…..26
2.8 USE OF OPIOID RECEPTOR ANTAGONISTS TO CONFIRM THE DISTRIBUTION OF PERIPHERAL OPIOIDS........................27
2.9 STATISTICAL ANALYSIS.................................28

CHAPTER III RESULTS (I)...............................30-49
3.1 REDUCED PAIN HYPERSENSITIVITY IN BOTH NOD AND NOD-SCID MICE WAS OBSERVED PREDOMINANTLY IN THE ACUTE PHASE........31
3.2 LESS INFLAMMATION AND CELLS INFILTRATION WAS OBSERVED IN THE DAMAGED NERVES OF NOD AND NOD-SCID MICE...............34
3.3 LESS PRO-INFLAMMATORY CYTOKINE EXPRESSION WAS OBSERVED IN THE DAMAGED NERVES OF NOD AND NOD-SCID MICE............39
3.4 LESS ANTI-INFLAMMATORY CYTOKINE EXPRESSION WAS OBSERVED IN THE DAMAGED NERVES OF NOD AND NOD-SCID MICE............42
3.5 LESS PERIPHERAL OPIOID PEPTIDE EXPRESSION WAS OBSERVED IN THE DAMAGED NERVES OF NOD AND NOD-SCID MICE............44
3.6 OPIOID RECEPTOR ANTAGONIST EXACERBATED THERMAL HYPERALGESIA IN C57BL/6 MICE BUT NOT IN NOD-SCID MICE AT THE LATER PHASE...............................................48

CHAPTER IV RESULTS (II)...............................50-69
4.1 SUBCUTANEOUS INJECTION OF RMG-CSF RESULTED IN SIGNIFICANTLY ALTERED BLOOD CELLULARITIES.................51
4.2 SUBCUTANEOUS INJECTION OF RMG-CSF EXACERBATED THERMAL HYPERALGESIA AND TACTILE ALLODYNIA INDUCED BY NERVE INJURY....................................................53
4.3 CELL INFILTRATION IN DAMAGED NERVE FOLLOWING PSNL WAS MORE SEVERE IN RMG-CSF THAN VEHICLE TREATED MICE..........57
4.4 SUBCUTANEOUS INJECTION OF RMG-CSF INCREASED PRO- INFLAMMATORY CYTOKINE PRODUCTION IN THE INJURED NERVE FOLLOWING PSNL............................................61
4.5 SUBCUTANEOUS INJECTION OF RMG-CSF SUPPRESSED ANTI- INFLAMMATORY CYTOKINE PRODUCTION IN THE INJURED NERVE FOLLOWING PSNL............................................64
4.6 PERIPHERAL OPIOID PEPTIDE EXPRESSION WAS INCREASED IN RMG-CSF TREATED MICE......................................67

CHAPTER V DISCUSSION..................................70-85
5.1 INFLAMMATION WOULD HAVE A DUAL ROLE IN THE MODULATION OF THE BEHAVIORAL HYPERSENSITIVITY........................72
5.2 THE NEUROPATHIC ALLODYNIA AND HYPERALGESIA WERE SIGNIFICANTLY REDUCED IN IMMUNODEFICIENT MICE.............72
5.3 THE CONTRIBUTION OF INFLAMMATION TO NEUROPATHIC PAIN DEVELOPMENT WAS PREDOMINANTLY OBSERVED IN THE EARLY PHASE AFTER PSNL................................................74
5.4 THE ENDOGENOUS OPIOID PEPTIDE MEDIATED ANALGESIA WAS PREDOMINANTLY OBSERVED AT THE LATE STAGE AFTER PSNL.......75
5.5 THE RMG-CSF EXACERBATED THE BEHAVIORAL HYPERSENSITIVITY THERMAL HYPERALGESIA AND TACTILE ALLODYNIA AFTER PSNL.....78
5.6 THE G-CSF PROMOTES NEUROINFLAMMATION ............... 81
5.7 G-CSF INCREASED PRO-INFLAMMATORY AND REDUCED ANTI- INFLAMMATORY CYTOKINE RELEASE IN A MURINE PSNL............81
5.8 TREATMENT WITH G-CSF DID NOT ADVANCE THERMAL HYPERALGESIA AND TACTILE ALLODYNIA INDUCED BY PERIPHERAL NERVE INJURY..............................................83
5.9 G-CSF MAY BE TARGETS FOR THERAPEUTIC INTERVENTION IN CHRONIC NEUROPATHIC PAIN..................................84

CHAPTER VI CONCLUSION.................................86-90

CHAPTER VII FUTURE WORKS..............................91-94

REFERENCES............................................95-104

APPENDIX.................................................105

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