血清素受體2B調控鈣離子變化影響機械性痛覺敏感

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林詩媛(Shih-yuan Lin) 查詢紙本館藏

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論文名稱

血清素受體2B調控鈣離子變化影響機械性痛覺敏感
(5-HT2B regulated calcium response mediating mechanical hyperalgesia)

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摘要(中)

血清素（Serotonin, 5-Hydroxytryptamine, 5-HT）是一種重要的發炎調節因子，會參與疼痛以及產生痛覺敏感現象。藉由周邊組織的肥大細胞或是血小板釋放血清素，可以產生兩種調節下游機制的反應：第一，可以直接作用在血清素離子通道（5-HT3）上，使通道開起改變細胞的離子通透性，並且會使可以痛覺神經興奮；第二，血清素與細胞膜上的血清素G蛋白偶合受體（5-HT1, 2, 4, 5, 6, 7）結合，活化下游G蛋白，進而產生一連串訊號傳遞機制。先前研究發現血清素受體2B主要表現在中小直徑（10-34 μm）的小鼠背根神經節細胞，且血清素2B/2C抑制劑可以抑制由血清素引發的機械性痛覺敏感。然而血清素受體2B在此所扮演的角色以及作用機制依舊不清楚。因此我利用注射血清素或血清素受體2B/2C的抑制劑於小鼠的後腳掌內，並培養背根神經節細胞，之後以血清素刺激觀察細胞內鈣離子含量的變化情形。研究發現血清素刺激引發三種細胞內鈣離子含量變化：短暫快速上升、延遲以及混合型。注射血清素後，細胞對血清素刺激的敏感性提升2.6倍（5.1% vs. 13.3%），IB4 (-)細胞內鈣離子含量增加2.4倍，IB4 (+)細胞則無顯著差異。在注射血清素受體2B/2C抑制劑後，細胞對血清素的敏感性下降至1.3%，短暫快速上升的鈣離子曲線亦被完全抑制，此外在IB4 (-)的細胞中，血清素可增強辣椒素引發的細胞內鈣離子含量變化，並且可經由血清素受體2B/2C抑制劑所抑制。值得注意的是注射血清素無法增強血清素引發的細胞內鈉離子變化，但是細胞內鈉離子含量變化可以受血清素受體2B/2C抑制劑所抑制，綜合以上結果顯示血清素受體2B確實參與機械性痛覺敏感現象。

摘要(英)

Serotonin (5-Hydroxytryptamine, 5-HT) is one of the important inflammatory mediators in pain and hyperalgesia. 5-HT released from mast cells or platelets in peripheral tissues, can directly act on 5-HT-gated ion channel (5-HT3) to change sodium and calcium permeability and excitability of nociceptors. 5-HT can also induce chemical interaction through the activation of 5-HT G-protein coupled receptors (5-HT1, 2, 4, 5, 6, 7). Previous studies have found that 5-HT2B is highly localized in small-to-medium diameter (10-34 μm) dorsal root ganglion (DRG) neurons but not 5-HT2C. The antagonist of 5-HT2B/2C inhibits 5-HT-induced mechanical hyperalgesia. However, it remains unclear whether 5-HT2B-mediated 5-HT signaling is involved in 5-HT-induced mechanical hyperalgesia and detailed mechanisms. To address this question, I have injected 5-HT and 5-HT2B/2C antagonist into mouse hind paw and DRG were taken from injected mice to culture. Cultured neurons were stimulated by 5-HT, followed by calcium imaging. Three patterns of 5-HT-induced intracellular calcium increase were found: transient, sustained and mixed. After 5-HT-injection, the number of 5-HT-responding neurons had 2.6-fold increase (5.1% vs. 13.3%) and the 5-HT-induced calcium increase was 2.4-fold increased on ipsilateral IB4-negative neurons but not on IB4-positive neurons. 5-HT2B/2C antagonist injection reduced the number of 5-HT-responding neurons (1.3%) and inhibited the transient [Ca2+]i rise in patterns 1 and 2. I also found that capsaicin-induced calcium influx was increased on IB4-negative neurons after 5-HT-injection and the increased calcium influx was inhibited by 5-HT2B/2C antagonist. Interestingly, 5-HT-induced sodium current was not enhanced by 5-HT injection but reduced by injection of 5-HT2B/2C antagonist. These results suggest that 5-HT2B-mediated calcium response is involved in 5-HT-induced mechanical hyperalgesia.

關鍵字(中)

★ 背根神經節
★ 機械性痛覺敏感
★ 血清素受體2B

關鍵字(英)

★ DRG
★ 5-HT2B
★ mechanical hyperalgesia

論文目次

中文摘要 i
英文摘要 ii
致謝辭 iii
目錄 iv
圖目錄 vii
表目錄 viii
第一章　緒論 1
1-1　痛覺（pain） 1
1-2　痛覺傳遞過程（nociception） 2
1-3　發炎性疼痛（inflammatory pain） 3
1-4　血清素引發的發炎性疼痛與痛覺敏感現象相關的血清素受體 4
1-5　痛覺敏感相關的離子通道 6
1-5-1　辣椒素受體1（transient receptor potential vanilloid channel 1, TRPV1） 6
1-5-2　酸敏感離子通道 (acid-sensing ion channels, ASICs) 8
1-5-3　電壓調控鈉離子通道（voltage-gated sodium channel, Nav） 9
1-6　研究動機與目的 9
第二章　材料與方法 11
2-1　實驗材料 11
2-1-1　菌株 11
2-1-2　細胞株 11
2-1-3　實驗用動物 11
2-1-4　藥品 11
2-2　實驗方法 12
2-2-1　轉型作用（transformation） 12
2-2-2　細菌培養 12
2-2-3　質體製備 13
2-2-4　細胞培養 14
2-2-5　轉染作用（transfection） 15
2-2-6　鈣離子分析（single cell calcium imaging） 16
2-2-7　鈉離子分析 17
2-2-8　RNA萃取 17
2-2-9　cDNA合成 19
2-2-10　聚合酶鏈反應（polymerase chain reaction, PCR） 19
第三章　結果 21
3-1　血清素受體1A、2A、2B、2C、3A會受到血清素誘導使細胞內鈣離子含量增加 21
3-2　小鼠背根神經節細胞受血清素刺激誘導，促使細胞內鈣離子含量增加 23
3-3　血清素受體2B/2C抑制劑可抑制血清素引起短暫快速上升的鈣離子增加 24
3-4　血清素增強血清素受體2B的功能，並經由活化PLCβ路徑促使細胞內鈣離子增加 25
3-5　血清素刺激細胞後經由PKCε調節胞內鈣離子增加 26
3-6　血清素刺激引發的胞內鈣離子變化可經由細胞膜上離子通道開啟或經由胞內質網釋放大量鈣離子至細胞質 27
3-7　血清素受體2在無鈣離子的平衡溶液中，仍可受血清素誘導使細胞內鈣離子含量增加 27
3-8　IB4 (+)細胞可經由血清素受體3A調控血清素引發的胞內鈣離子含量增加，而IB4 (-)的細胞則不會 28
3-9　血清素會增強由辣椒素引起的IB4 (-)神經細胞內鈣離子增加，此現象可被血清素受體2B/2C抑制劑所抑制 29
3-10　辣椒素刺激細胞後經由PKCε調節胞內鈣離子增加 31
3-11　血清素無法增強胞內鈉離子變化，而血清素受體2B/2C抑制劑可抑制胞內鈉離子的增加 32
3-12　血清素受體2B調控鈣離子變化影響機械性痛覺敏感 33
第四章　討論 34
4-1　血清素受體2B參與調節由血清素引發的機械性痛覺敏感 34
4-2　血清素刺激引發不同型式的胞內鈣離子變化 35
4-3　血清素受體2B增強IB4 (-)細胞辣椒素受體1的功能，此現象可經由5-HT2B/2C抑制劑所抑制 39
4-4　血清素無法增強胞內鈉離子變化，而血清素受體2B/2C抑制劑可抑制胞內鈉離子的增加 41
第五章　參考文獻 43
附錄一 107
附錄二 109
附錄三 113

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指導教授

孫維欣(Wei-hsin Sun)

審核日期

2011-11-23

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