目的: 複雜性局部疼痛症候群是一種發生機轉和病程不明的疼痛難題。可能的病生理至少包含發炎、周邊或中樞性神經敏感化、組織缺血後再灌流損傷，及交感神經失調等。小鼠慢性缺血疼痛模型會表現急性期組織再灌流充血，以及慢性期持續的機械性痛覺異常。這二時段的疼痛行為，恰可分別模擬人類複雜性局部疼痛症候群第一型之急性及慢性的臨床表現。該模型亦可見老鼠疼痛行為會伴隨肌肉及脊髓組織內介白素-1β及核因子-κB表現升高。前胸腺素α與核因子-κB、免疫及發炎調節有關，而且能在缺氧的狀況下提供神經保護效果。本實驗希望探討前胸腺素α於複雜性局部疼痛症候群的可能作用。

研究設計: 小鼠慢性缺血疼痛模型利用三小時的組織缺血及接踵而來的再灌流損傷，引發機械性痛覺異常。透過腳底觸覺敏感度測量（von Frey纖維絲測試）來評估小鼠於組織缺血前，至再灌流後十四天內的機械性痛覺異常。我們另於組織缺血前、缺血後剛開始再灌流、再灌流後二小時及七天等四個時間點，分別取老鼠同側的腳掌皮膚和脊髓組織，以免疫組織染色定量前胸腺素α陽性表現的細胞比例。

結果: 我們的小鼠慢性缺血疼痛模型符合文獻上典型的二階段機械性痛覺異常，分別於再灌流後二小時、及三至七天間達到疼痛最大值。在同側腳掌皮膚組織裡，前胸腺素α的表現量於缺血後剛開始再灌流（72.8±7.6%）及再灌流後二小時（72.7±2.2%）這二個時間點，與未執行缺血傷害的對照組（44.4%±0%）相比有顯著升高（p=0.012及0.012），並於再灌流後七天時回到對照組水平(36.5±6.2%, p=0.458)。而於同側脊髓背角組織內，前胸腺素α的表現量待到再灌流後七天，與對照組相比才出現顯著提高(48.9±3.3% vs 22.8±4.4%, p=0.005)。

結論: 於缺血後剛開始再灌流及再灌流後二小時的同側腳掌皮膚組織內，及再灌流後七天的同側脊髓背角組織裡可見前胸腺素α的表現量顯著增加，恰與小鼠慢性缺血疼痛模型的二階段疼痛行為及時序相呼應。此結果顯示前胸腺素α有調節複雜性局部疼痛症候群的角色。

PURPOSE: Complex regional pain syndrome (CRPS) is a disabling painful disorder with various courses and unclear mechanism. Its pathophysiology includes inflammatory process, peripheral and central sensitization, ischemia-reperfusion injury, sympathetically mediated condition, etc. Chronic post-ischemic pain (CPIP) model in mice expresses early hyperemia with reperfusion injury, followed by long lasting mechanical allodynia. These two painful stages resembles the warm and cold phases of CRPS type I in human. The increased interleukin-1β and nuclear factor-κB in the local tissue and innervating spinal cord are related to the painful behaviors seen in CPIP model. Prothymosin α is a mediator of immunoactivity and inflammation, and is reported to have neuroprotective effect on ischemia. This study aims to explore the potential role of prothymosin α in CRPS.

EXPERIMENTAL DESIGN: The mechanical allodynia in CPIP model was induced by 3-hour ischemia-reperfusion (I/R) injury. The von Frey hairs test was to evaluate the hind paw withdraw threshold, which was negatively correlated with the mechanical allodynia behaviors, from before I/R injury to 14 days post I/R injury. We harvested the skin of ipsilateral hind paw and the spinal cord tissue before and at the timing of 0 hour, 2 hours and 7 days after I/R injury. We used immunohistochemistry analysis for the quantification of the percentage of prothymosin α-positive cell.

RESULTS: The mice in our CPIP model showed typical two stages of mechanical allodynia, with the lowest withdraw threshold and worst pain at 2 hours and 3~7 days after I/R injury. The percentage of prothymosin α-positive cell in the ipsilateral epidermis significantly increased at 0 hour (72.8±7.6%) and 2 hours (72.7±2.2%) post I/R injury as compared to non-CPIP control group (44.4±0%) (p=0.012 and 0.012, respectively), and returned to baseline level at 7 days post I/R injury (36.5±6.2%, p=0.458). In contrast, the significant elevation of prothymosin α level in ipsilateral spinal cord dorsal horn was only noted at 7 days post I/R injury when compared with control group (48.9±3.3% vs 22.8±4.4%, p=0.005).

CONCLUSIONS: The increment of prothymosin α in the ipsilateral epidermis at 0 hour and 2 hours post I/R injury, and in the ipsilateral spinal cord dorsal horn at 7 days post I/R injury might be correlated with the characteristics of two-stage pain pattern in CPIP model. Prothymosin α might have a potential role to modulate the CRPS.

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