博碩士論文 992404007 詳細資訊




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姓名 蘇禹軒(Yeu-Shiuan Su)  查詢紙本館藏   畢業系所 生命科學系
論文名稱
(Peripheral 5-HT3 participates in mediating mirror-image pain by a cross-talk with ASIC3)
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摘要(中) 當組織受傷或發炎的時候,許多內源性的介質包括:前列腺素(PGE2)、血清素(5-HT)、氫離子、組織胺(Histamine)、三磷酸腺苷(ATP),會從這些部位的組織或免疫細胞釋出,誘導發炎和傷害感受的產生。5-HT是一種發炎的介質,參與調控發炎性疼痛。在週邊和中樞痛覺神經元上存在許多5-HT受體的亞型,因此研究5-HT在疼痛中的作用也相對複雜。在之前的研究中,我們發現5-HT2B/2C受體的拮抗劑可以抑制由5-HT所誘導的機械性痛覺敏感。然而,造成這種痛覺敏感所影響的神經元類型以及訊號路徑,仍然還不清楚。本篇論文的第一個部分,我證明了5-HT2B受體透過調控Gq /11β-蛋白質激酶C(PKCε)的途徑參與5-HT在小鼠中所誘導的機械性痛覺敏感。注射TRPV1的拮抗劑抑制了5-HT所造成的機械性痛覺敏感現象;而TRPV1基因剔除的小鼠在注射5-HT後也得到相同的結果。因此,5-HT2B受體透過調控TRPV1的功能,參與在血清素所引發的機械性痛覺敏感現象。
論文的第二個部分,我研究的重點是鏡像疼痛(MIP),鏡像疼痛常常在許多臨床的疾病上伴隨發生,例如複雜疼痛症候群(CRPS)、類風濕性關節炎(RA)以及慢性偏頭痛,而這類型的疼痛主要的特徵在於病人除了實際受傷或發炎的身體區域會感到疼痛,在身體對側的區域往往也會感到疼痛。已經有研究發現,嚴重的週邊組織發炎,會活化週邊或中樞神經膠質細胞,進而產生MIP。然而是哪些受體調控這些神經膠質細胞的活化,目前仍不清楚。實驗中發現,個別注射5-HT或酸性緩衝溶液到小鼠的腳掌只會產生單側疼痛,但共同注射5-HT和酸性緩衝溶液,則造成雙側的痛覺敏感現象。阻斷血清素受體3(5-HT3)和酸敏感離子通道3(ASIC3),可以降低週邊衛星膠細胞的活化,抑制MIP。值得注意的是,腳掌注射5-HT3活化劑產生的MIP,以及5-HT3受體調控的MIP,可以被5-HT3受體抑制劑或ASIC3阻斷劑所降低。使用ASIC3活化劑也發現相同的結果。此外,實驗也觀察到5-HT3受體與ASIC3在背根神經節有共同表現;5-HT3受體活化後會促進細胞內鈣離子濃度的增加,且可被ASIC3的阻斷劑所抑制,反之亦然。因此5-HT3受體與ASIC3透過彼此間的交互作用活化衛星膠細胞,進而引發鏡像疼痛。
摘要(英) The endogenous mediators, such as prostaglandin E2 (PGE2), bradykinin (BK), serotonin [5-hydroxytryptamine (5-HT)], proton, histamine, and ATP, are released from the damaged site of the tissue and immune cells to induce inflammation and nociception. 5-HT, an inflammatory mediator, contributes to inflammatory pain. The presence of multiple 5-HT subtype receptors on peripheral and central nociceptors complicates the role of 5-HT in pain. Previously, we found that 5-HT2B/2C antagonist blocks 5-HT-induced mechanical hyperalgesia. However, the types of neurons or circuits underlying this effect remained unsolved. In the first part of this thesis, I demonstrate that the Gq/11β-protein kinase Cε (PKCε) pathway mediated by 5-HT2B is involved in 5-HT-induced mechanical hyperalgesia in mice. Administration of a transient receptor potential vanilloid 1 (TRPV1) antagonist inhibited the 5-HT-induced mechanical hyperalgesia. Similar results were found in TRPV1-deficient mice. Thus, 5-HT2B mediates 5-HT-induced mechanical hyperalgesia by regulating TRPV1 function.

In the second part of the theis, I focus on mirror-image pain (MIP), which occurs along with complex regional pain syndrome, rheumatoid arthritis and chronic migraine, is characterized by increased pain sensitivity of healthy body regions other than the actual injured or inflamed sites. A high level of peripheral inflammation may activate central or peripheral glia, triggering mirror-image pain. However, which receptors mediate inflammatory signals to contribute glial activation remains unclear. Intraplantarly injecting mice with 5-HT or acidic buffer (proton) caused only unilateral hyperalgesia, but co-injection of 5-HT/acid induced bilateral hyperalgesia (MIP). Blocking 5-HT3 or acid-sensing ion channel 3 (ASIC3) abolished satellite glial activation, inhibiting MIP. Interestingly, intraplantar administration of a 5-HT3 agonist induced MIP, and 5-HT3–mediated MIP can be reversed by a 5-HT3 antagonist or an ASIC3 blocker. Similar results were found using ASIC3 agonist. Furthermore, 5-HT3 was observed to co-localize with ASIC3 in DRG neurons; 5-HT3 activation induced an increase in intracellular calcium that was inhibited by an ASIC3 blocker and vice versa. A cross-talk between 5-HT3 and ASIC3 mediates satellite glial activation, thereby triggering mirror-image pain.
關鍵字(中) ★ 鏡像疼痛
★ 發炎性疼痛
★ 血清素受體3
★ 酸敏感離子通道
關鍵字(英) ★ mirror-image pain
★ inflammatory pain
★ 5-HT3 receptor
★ ASIC3
★ cross-talk
論文目次 Table of Contents

中文摘要 I
Abstract III
Table of Contents V
List of Figures VIII

Chapter 1 General Introduction 1
1-1 What is pain? 2
1-2 Inflammatory pain 2
1-3 Inflammatory mediators of pain 3
1-4 Tissue acidosis and acid sensing receptors 4
1-4-1 Proton-gated ion channels 5
1-4-2 Proton-sensing GPCRs 8
1-5 Serotonin (5-Hydroxytryptamine, 5-HT) and serotonin receptors 9
1-6 Bradykinin 11
1-7 Prostaglandin E2 (PGE2) 11
1-8 Transition from acute to chronic pain 13
Chapter 2 Materials and Methods 15
2-1 Materials 16
2-1-1 Animals 16
2-1-2 Agents 16
2-2 Methods 18
2-2-1 Animal experiments and tissue collection 18
2-2-2 Animal tissue and RNA preparation. 19
2-2-3 Reverse transcription-PCR and quantitative PCR 19
2-2-4 Intrathecal drug administration 20
2-2-5 Behavioural test 21
2-2-6 Cell cultures and intracellular calcium imaging 21
2-2-7 Immunostaining, Immunoblotting and in situ hybridization 22
2-2-8 Statistical analysis 24
Chapter 3 Serotonin Receptor 2B Mediates Mechanical Hyperalgesia by Regulating Transient Receptor Potential Vanilloid 1 26
Chaper 3 Serotonin Receptor 2B Mediates Mechanical Hyperalgesia by Regulating
Transient Receptor Potential Vanilloid 1 26
3-1 Introductions 27
3-2 Results 28
3-2-1 5-HT-induced mechanical hyperalgesia is regulated by the 5-HT2B- PKCε pathway. 28
3-2-2 TRPV1 is involved in 5-HT-induced mechanical hyperalgesia. 30
3-3 Discussions 31
3-3-1 5-HT2B mediates 5-HT-induced mechanical hyperalgesia through Gq-PKCε pathway 31
3-3-2 Participation of TRPV1 in 5-HT signaling transduction: contribution to induction of mechanical hyperalgesia 32
Chapter 4 Peripheral 5-HT3 mediates mirror-image pain by a cross-talk with acid-sensing ion channel 3 39
4-1 Introductions 40
4-2 Results 43
4-2-1 5-HT signals induce bilateral hyperalgesia in co-injection of 5-HT with acid or PGE2 43
4-2-2 5-HT3A is involved in 5-HT/acid-induced mirror-image pain through activation of satellite glial cells 43
4-2-3 5-HT3A activation mediates development of contralateral hyperalgesia 45
4-2-4 5-HT2B mediates an inhibitory signal to prevent development of contralateral hyperalgesia 45
4-2-5 ASIC3 is also involved in 5-HT/acid-induced mirror-image pain by regulating glial activation 46
4-2-6 ASIC3 activation mediates the development of contralateral hyperalgesia 47
4-2-7 5-HT3-mediated contralateral hyperalgesia is cross-regulated by ASIC3 48
4-3 Discussions 50
4-3-1 5-HT3-mediated contralateral hyperalgesia is inhibited by 5-HT2B 50
4-3-2 The cross-talk between 5-HT3 and ASIC3 regulates 5-HT/acid-induced contralateral hyperalgesia 51
4-3-3 The cross-talk between 5-HT3 and ASIC3 regulates SGCs activation 52
4-3-4 5-HT3 plays a major role in mediating mirror-image pain 53
4-3-5 Conclusion 55
Chapter 5 References 72
Appendix 87

List of Figures
Figure 3- 1 5-HT2B mediates 5-HT-induced mechanical hyperalgesia 34
Figure 3- 2 5-HT2B mediates 5-HT-induced mechanical hyperalgesia through protein kinase Cε. 36
Figure 3- 3 5-HT-induced mechanical hyperalgesia is inhibited by peripheral injection of TRPV1 antagonist or in mice lacking TRPV1 37
Figure 4-1 Co-injection of 5-HT with acid or PGE2 induces bilateral hyperalgesia………………………………………………………………………….56
Figure 4-2 5-HT/PGE2-induced mechanical hyperalgesia of contralateral side is inhibited by injection of 5-HT3A antagonist. 57
Figure 4-3 5-HT/acid-induced mechanical hyperalgesia of contralateral side is inhibited by injection of 5-HT3A antagonist. 58
Figure 4-4 Activation of satellite glial cells is induced by co-injection of 5-HT/acid causes and inhibited by injection of 5-HT3 antagonist. 59
Figure 4-5 Administration of 5-HT3A agonist alone induces bilateral mechanical hyperalgesia. 61
Figure 4-6 5-HT3 agonist-induced contralateral hyperalgesia is inhibited by injection of 5-HT2B agonist or PKC activator. 43
Figure 4-7 5-HT/acid-induced contralateral hyperalgesia is inhibited in mice lacking ASIC3, but not in mice lacking TRPV1 or TDAG8. 64
Figure 4-8 5-HT/GMQ-induced mechanical hyperalgesia of contralateral side is inhibited by injection of 5-HT3 or ASIC3 antagonist. 66
Figure 4-9 5-HT3 agonist-induced contralateral hyperalgesia is cross-regulated by ASIC3. 68
Figure 4-10 Possible mechanisms of the cross-talk between 5-HT3 and ASIC3 in regulating 5-HT/acid-induced mirror-image pain. 71
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指導教授 孫維欣(Wei-Hsin Sun) 審核日期 2017-12-11
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