| 摘要: | 臨床發現子宮內膜異位症 (Endometriosis, EM) 患者經常伴隨著慢性骨盆腔疼痛 (Chronic pelvic pain, CPP) 的症狀產生，然而其病因尚待證實。文獻證實EM會導致雌二醇 (E2) 合成異常，且E2會影響混合血統白血病蛋白1 (Mixed lineage leukemia 1, MLL1) 。已知在神經病變性疼痛上MLL1/WD重複蛋白5 (WD-Repeat Protein 5, WDR5) /谷氨酸代謝型受體亞型5 (Metabotropic glutamatergic receptor subtype 5, mGluR5) 的表現量會顯著提升，且依賴該路徑來調解疼痛。因此，本篇研究目的為探討EM是否透過脊髓MLL1/WDR5/mGluR5依賴性訊息路徑來參與骨盆-尿道反射 (Pelvic-urethra reflex, PUR)的跨臟器敏化作用。此外，已有文獻證實在EM動物模型的脊髓中，能夠偵測到細胞外信號調解激?1/2 (Extracellular signal-regulated kinase 1/2, ERK1/2) 的磷酸化及核因子κB (Nuclear factor kappa B, NF-κB) 的訊息傳遞路徑被活化。因此，我們利用自體移植的方式模擬 EM，於術後 6周後，分別比較未手術 (NAV) 組及子宮內膜異位 (EM) 組動物的 (1) PUR 活性和 (2) 脊髓中的 p-ERK、p-p65、MLL1、WDR5和 mGluR5 的表現量。結果顯示，與 NAV組相比，EM 組實驗動物顯著性地增加 PUR 活性，證實EM促進內臟敏化反應，並且加劇跨臟器敏化作用。而以西方點墨法分析，相較於NAV組，EM組脊髓樣本中p-ERK、p-p65和mGluR5的表現量皆有顯著性增加。然而，MLL1與WDR5在EM組的表現量則仍有待確認。綜上所述，結果證實急性子宮刺激增加PUR活性，造成跨臟器敏化作用，並在結果顯示出EM促進內臟敏化反應，同時也證實 EM增加mGluR5訊息路徑活化促使 CPP 併發症的發生。
Though the etiology waits for proof, patients with endometriosis (EM) demonstrate a higher risk of chronic pelvic pain (CPP). As EM results in aberrant estradiol (E2) synthesis, which impacts expression of mixed lineage leukemia 1 (MLL1). It is known that the expression levels of MLL1, WD-repeat protein 5 (WDR5), and metabotropic glutamatergic receptor subtype 5 (mGluR5) are significantly increased in neuropathic pain and they involved in pain modulation. Therefore, we wonder if EM sensitize pelvic-urethra reflex (PUR) via the spinal MLL1/WDR5/mGluR5-dependent signaling pathway. Furthermore, previous studies have demonstrated phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2) and activation of nuclear factor kappa B (NF-κB) signaling pathway in the spinal cord of animal models with EM. Thus, the (1) PUR activity and (2) abundance of p-ERK, p-p65, MLL1, WDR5 and mGluR5 in the spinal cord were compared among na?ve (NAV) and auto-grafted EM (EM) animals at 6 weeks after the operation. The results showed a significant increase the PUR activity in the EM group compared to the NAV group, confirming that EM can cause visceral hypersensitivity and exacerbate cross-organ sensitization. Western blot results revealed a significant upregulation of p-ERK, p-p65, and mGluR5 expression in the spinal cord of the EM group compared to the NAV group. However, the expressions of MLL1 and WDR5 needs further experiment to be clarified. In conclusion, we confirmed that acute uterine irritation increases PUR activity, leading to cross-organ sensitization. Our results also demonstrate that EM promotes visceral hypersensitivity and suggest that the EM causes CPP via activation of mGluR5 signaling pathway. |
