週邊神經損傷引起的神經性疼痛常伴隨著慢性發炎情形，這對人類的生活品質造成重大的影響。神經與免疫系統通常以整合及協調的形式協同工作以調節疼痛感。當周圍組織受傷，有害刺激會促進傷害感受神經進而造成衛星膠細胞及免疫細胞聚集。衛星膠細胞與免疫細胞的活化亦使傷害感受神經敏感化。儘管這些非神經細胞在調節疼痛機制上佔有角色，但其詳細機制仍不清楚。 T細胞凋亡相關基因8 (TDAG8)，卵巢癌G蛋白耦合受體1家族成員之一，主要被酸所活化。TDAG8表現在免疫系統及背根神經節中的小直徑神經元上。目前已知TDAG8參與在慢性發炎疼痛機制上，為了闡明TDAG8在神經性疼痛的機制，我使用TDAG8剃除及沉默的方法來探討TDAG8在神經慢性壓迫性損傷模式所誘導的神經病變性疼痛的作用。我發現神經慢性壓迫性損傷模式所誘導的神經病變性疼痛分成兩個階段：早期階段中，坐骨神經損傷後，TDAG8的活化促使納離子通道1.8 (Nav1.8)活化並引發疼痛。而TDAG8的活化亦促使IB4陰性神經元釋放物質，進而造成M1巨噬細胞的聚集並刺激Nav1.8活化。後期階段中，除了M1巨噬細胞的聚集引發疼痛外，背根神經節中受損的神經元活化周圍的衛星膠細胞進而誘發Nav1.7活化引發疼痛。因此我認為TDAG8藉由調節物質P並經由不同路徑參與在慢性壓迫性損傷所引發不同階段的神經病變性疼痛。 ;Neuropathic pain induced by peripheral nerve injury often accompanies with chronic inflammation, which has a profound effect in life quality of human being. Nervous and immune systems often work together in an integrated and coordinated form to regulate pain sensation. When peripheral tissue injury, noxious stimulus evokes nociceptors that increase satellite glial cells (SGCs) and recruit immune cells. SGCs and immune cells also sensitize nociceptors further enhance pain sensitivity. Although these non-neuronal cells play a role in regulating nociceptive transduction and plasticity, the detailed mechanisms is still unclear. T-cell death associated gene 8 (TDAG8), one member of ovarian cancer G-protein coupled receptor 1 (OGR1) family activated by protons is expressed in immune cells and small-diameter neurons in the dorsal root ganglion (DRG). TDAG8 is involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in inflammatory pain. To elucidate the mechanisms of TDAG8 in neuropathic pain, I used TDAG8 knockout or knockdown methods to explore the role of TDAG8 in chronic constriction injury (CCI)-induced neuropathic pain. I have found that CCI-induced neuropathic pain was mechanistically divided into two phases: At the early phase, sciatic nerve injury causes TDAG8 activation that evokes voltage-gated sodium channel 1.8 (Nav1.8) to induce pain sensation in DRG. Activation of TDAG8 also triggers isolectin B4 negative neurons to release substance P to recruit the M1 macrophages to regulate pain sensitivity. At the late phase, M1 macrophages recruitment induces pain. Pain sensation induced through SGCs-Nav1.7 pathways is reduced by release of SP from IB4 negative neurons in TDAG8-/- mice. Therefore, I consider that TDAG8 participates in different phases of CCI-induced neuropathic pain by regulating distinct pathways of substance P.
