在週邊發炎反應中，常可發現在受傷組織有因血流速率減低、代謝速率增快、組織滲透壓改變等原因，造成高濃度氫離子累積，而導致局部組織酸化的情形。這些高濃度氫離子會去活化痛覺神經細胞 (small-diameter neurons) 上之正離子通道，如辣椒素受體 (VR1) 或酸敏感受體3 (ASIC3) ，進而造成發炎反應中之痛敏感現象。然而，氫離子除了活化這些相關之離子通道外，同時亦可活化其他G蛋白偶合受體。本篇論文主要即在探討這些受酸活化之G蛋白偶合受體是否亦參與發炎反應中之痛覺相關現象。我們發現，已被證明為受酸性活化之Ｔ-細胞死亡相關受體8 (TDAG8 receptor)有表現在痛覺相關之神經細胞。在週邊發炎反應一天後，Ｔ-細胞死亡相關受體基因8在神經細胞有表現量明顯增加之情形。其中一類痛覺相關之神經細胞其在表面有醣蛋白 (IB4) 結合，已被證明與發炎反應後痛覺敏感之現象有相關性。而這類神經細胞有明顯增加Ｔ-細胞死亡相關受體8之表現量。另外，另一纇在自然情況下非傳遞痛覺之神經細胞 (large-diameter neurons)在發炎反應後亦增加Ｔ-細胞死亡相關受體8之表現量。因此，我們推測Ｔ-細胞死亡相關受體8增加在發炎反應可能與發炎後之痛敏感 (hyperalgesia) 以及觸感痛 (allodynia) 現象有關。另外，高濃度氫離子能刺激大量表現Ｔ-細胞死亡相關受體8之細胞累積環單磷酸腺甘 (cAMP)。因此Ｔ-細胞死亡相關受體8可能在發炎反應中經由環單磷酸腺甘相關路徑，而調控神經細胞內之反應。 High concentrations of hydrogen ions are usually found in local area surrounding the insulted tissues during several inflammatory responses. The tissue acidosis phenomenon is thought to be associated with inflammatory pain because the proton molecule can activate nociceptors (pain-related neurons) directly through proton-sensing ion channels. Several proton-sensing receptors expressed in dorsal root ganglia neurons. Some of them, such as vallinoid receptor1 and acid-sensing ion channel 3 are thought to be involved in inflammatory hyperalgesia. However, it is still unclear that whether there are any other proton-sensing receptors involved in inflammation. Here we have demonstrated that a proton-sensing G-protein-coupled receptor, mouse T-cell Death Associated gene 8 (mTDAG8), was predominantly expressed in small-diameter neurons, which give rise to the majority of nociceptors. The transcripts of mTDAG8 were increased 24 hours after complete Freund’s Ajuvant (CFA)-induced inflammation, suggesting that the TDAG8 receptors might associate with inflammatory pain. Consistently, data of in situ showed that the total TDAG8-expressing neurons increased approximately 15% in DRG neurons after CFA-inflammation. Most of the increased TDAG8-expressing neurons are large-diameter neurons (9-10%), and the increased small-diameter neurons expressing TDAG8 are restricted in IB4-positive neurons (5-7%). Since the large-diameter neurons can be activated by non-noxious stimulations during inflammation, and the responses of IB4-positive neurons are enhanced after treating with inflammatory mediators, the increased number of neurons expressing TDAD8 receptors may associate with allodynia and hyperalgesia in inflammation. In addition, the mTDAG8-transfected HEK 293 cells accumulated the cAMP in responding to pH 6.0 buffers. Thus the TDAG8 may mediate certain responses through cAMP-pathway in neurons after inflammation.
