慢性廣泛肌肉疼痛(CWP)，如纖維肌痛症，常伴隨著睡眠障礙、憂鬱及焦慮症
狀，且目前的藥物治療效果有限。本研究目的在評估打酸誘發的疼痛模型是否會類
似於CWP 綜合患者伴隨睡眠障礙、似焦慮憂鬱共病症，而且在此動物模型評估
pregabalin、duloxetine 及diazepam 對機械性痛覺過敏、似焦慮和似憂鬱行為之影響，進而探討pregabalin 治療效果中杏仁核所扮演的角色。本研究使用重複注射酸性溶液到大鼠的單側腓腸肌中引發CWP 症狀，使用von Frey filament 測量腳掌疼痛退縮閾值（paw withdrawal threshold, PWT），肌肉疼痛壓力閾值 (motor pressure threshold, MPT) 使用Randall–Selittou 儀器測量大鼠之機械性痛覺過敏；本研究使用腦電圖客觀評估CWP 大鼠模型的睡眠障礙的發生，並且記錄與分析5 週的24小時清醒睡眠型態；本研究使用架高十字迷宮及開放空間評估似焦慮行為，透過強迫游泳測試，蔗糖消耗和蔗糖偏好測試來測量似憂鬱行為；pregabalin、duloxetine 及 diazepam 採每天口服兩次方式持續進行2 週，以進行疼痛評估與似焦慮憂鬱行為評估。接受酸注射的大鼠顯示廣泛痛覺過敏現象，以及睡眠障礙和似焦慮憂鬱共病症。
pregabalin 組有緩解疼痛、焦慮及不愉悅的症狀；diazepam 組對疼痛無緩解作用但能降低焦慮及不愉悅感的症狀；duloxetine 組有改善疼痛、不愉悅感及絕望的症狀。pregabalin 注射在雙側的杏仁核中央核區（central nucleus, CeA）可減緩重複酸注射引起的痛覺過敏現象，且雙側CeA 給予GV-58 會顯著抑制pregablin 的止痛效果。本研究提供酸誘發肌肉疼痛模型與人類CWP 症狀之完整的表面效度和預測效度分析，而且也發現杏仁核在pregabalin 止痛效果所扮演之不可或缺角色，這些資料相信有助於慢性肌肉疼痛之未來治療發展與產生機制的探討。

Chronic widespread pain (CWP) syndrome is often comorbid with depression, anxiety,and sleep disorder. Because current medication for CWP is unsatisfactory, this study aims to valid a better animal model with CWP syndrome and investigate the role of the amygdala on analgesic effect of pregabalin. The CWP model was elicited by repeatedly injecting an acidic solution into the unilateral gastrocnemius muscle of rats and measured the paw withdrawal
threshold (PWT) and motor pressure threshold (MPT) to assess mechanical hyperalgesia. First, the current study recorded and analyzed 24-h wake-sleep activity for 5 weeks before and after acid-induced hyperalgesia. Obvious sleep disturbance, including increased light sleep and decreased deep sleep as well as occurrence of alpha-delta electroencephalographic pattern in deep sleep, exhibited in the acid-induced CWP model. Second, anxiety-like behavior was evaluated using the open field and elevated plus maze tests, and depression-like behavior was measured using the forced swimming test, sucrose consumption test, and sucrose preference test. The present study provided evidence on
comorbidity of anxiety- and depression-like behaviors in the acid-induced CWP model. Third, predictive validity of pregabalin, duloxetine, and diazepam was investigated in terms of mechanical hyperalgesia and anxio-depressive comorbidity. In the acid-induced CWP model, pregabalin significantly increased PWTs and ameliorated anxiety-like behaviors; Duloxetine significantly increased PWTs and ameliorated depression-like behavior, but didn’t affect anxiety-like behavior; Diazepam remedied anxiety-like and anhedonic behaviors, but didn’t affect mechanical hyperalgesia. Finally, the role of the amygdala was investigated on analgesic effect of pregabalin in the acid-induced CWP model. Pregabalin through gavage or intra-central nucleus of amygdala (CeA) injection significantly alleviated the mechanical and muscle hyperalgesia. Intra-CeA injection of GV-58, a potential calcium III channel agonist, significantly abolished pregablin-induced analgesia. Taken together, the present study provides numerous evidences to validate the acid-induced CWP model as
human with CWP syndromes. The amygdala plays a crucial role in pregabalin-induced analgesia. Our results strengthen importance of the acid-induced CWP model and advance our understandings for pregabalin analgesia.

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