尋找有效治療慢性發炎性疼痛是目前臨床研究上重要的課題。組織受損釋放大量發炎介質引起的發炎反應常常會伴隨著持續性以及慢性疼痛的發生。發炎介質會透過蛋白質激酶A以及蛋白質激酶Cɛ活化痛覺相關神經元 (nociceptor)，引發痛覺過敏感行為。在前人研究中指出，在預發炎的模式中 (priming model) 蛋白質激酶Cɛ可能扮演關鍵的角色在轉換急性疼痛至慢性發炎性疼痛中。但另外利用發炎介質引發持續性的疼痛研究中發現蛋白質激酶A同時與蛋白質激酶Cɛ共同參與在急性以及慢性疼痛中，因此蛋白質激酶A以及蛋白質激酶Cɛ在實際上的發炎反應從開始急性痛到慢性發炎性疼痛的過程中是如何參與以及透過何種機制調控是目前尚未明瞭的課題，因此我藉由長期 (完全弗氏佐劑)、短期 (海藻醣)、神經內源性 (辣椒素) 發炎模式，在發炎反應的不同時間下注射蛋白質激酶A以及蛋白質激酶Cε抑制劑來探討蛋白質激酶A以及Cε參與那些階段下，以及他們透過何種路徑調控急性疼痛以及慢性疼痛之間的轉換。在長期以及短期模式中，抑制蛋白質激酶A只可以降低前期 (1-3小時) 發炎性疼痛，但抑制蛋白質激酶Cɛ可以降低後期 (4小時至16天)，因此推測這樣的蛋白質激酶主導由短期疼痛轉換至長期疼痛的機制主要介於發炎後3-4小時間。在辣椒素引發的短期神經內源性發炎反應中，機械性痛覺過敏只可以受抑制蛋白質激酶Cɛ所減緩，然而熱痛覺過敏感可同時受蛋白質激酶A以及蛋白質激酶Cɛ抑制劑所降低。在神經內源性發炎反應中並無顯著的激酶主導轉換，利用定量聚合酶鏈鎖反應分析發炎後酸敏感G蛋白偶和受體基因變化，發現發炎初期抑制蛋白質激酶A活性會促使G2A基因表現增加，發炎後一天TDAG8基因表現增加的現象可以受蛋白質激酶Cɛ抑制劑作用而降低。The treatment of chronic inflammatory pain continues to be a major management challenge in clinical practice. Inflammation induced by tissue injury release inflammatory mediator often accompanies persistent and chronic pain. Inflammatory mediators activate protein kinase A (PKA) or protein kinase Cε (PKCε) to sensitize pain-related nerve fibers (nociceptors), inducing behavioral hypersensitivity. Some studies have demonstrated that PKCε plays a critical role in the transition from acute to chronic pain using “hyperalgesic priming” model. However it remains unclear whether PKA is involved in such transition, when the transition occurs and what is the molecular mechanism. To address these questions, I have used three (sub-chronic, chronic, neurogenic) inflammatory pain models to explore the roles of PKA and PKCε in the transition from acute to chronic pain. In both subchronic (carrgeenan) and chronic (CFA) models, inhibiting PKA activity reduced mechanical hyperalgesia in the early state (1-3 hours), but PKCε regulated mechanical hyperalgesia in the late state (4-24 hours). The kinase-dependent swithching time was at 3-4 hours, suggesting that the transition from acute pain to chronic pain is around 3-4 hours after inflammation. In a neurogenic model, inhibition of PKCε slightly reduced capsaicin-induced mechanical hyperalgesia but not PKA. Both PKA and PKC? can regulate capsaicin-induced thermal hyperalgesia. Blocking PKC reduced CFA -enhanced TDAG8 gene expression. Pretreatment of PKA inhibitor enhance G2A gene expression at initiation after CFA induced inflammation.
