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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题名:	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
作者:	林詩媛;Shih-yuan Lin
贡献者:	生命科學研究所
关键词:	背根神經節;機械性痛覺敏感;血清素受體2B;DRG;5-HT2B;mechanical hyperalgesia
日期:	2011-11-23
上传时间:	2012-01-05 14:28:50 (UTC+8)
摘要:	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。 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.
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