慢性肌肉疼痛動物模式中之憂鬱相關行為和基因調控

長期以來，纖維肌痛症在全世界造成了嚴重的保健問題。大約百分之十的人口受到此病症影響，而病人當中又以女性佔大多數。纖維肌痛症病患除了慢性疼痛外，也經常伴隨有睡眠和情緒失調的問題。KA Sluka的研究團隊發展出藉由重複在鼠朏腸肌注射酸性生理實驗水引發長期痛覺敏感化的動物模式，以進一步研究纖維肌痛症和其他慢性疼痛疾病的機制。目前已知在第三型酸敏性離子通道剔除(Asic3-/-)的小鼠中，無法經由酸誘導產生慢性疼痛過敏現象；然而，尚未有報告研究此動物模式中是否也會引發相關的情緒失調，以及在痛覺傳導中由Asic3所調節的神經活性變化分子機制。本研究初步發現，在酸誘導慢性痛覺敏感化一週後，Asic3野生型母鼠在焦慮相關行為表現尚有增加的趨勢，此現象在公鼠或是Asic3剔除母鼠中皆不存在。在重複注射酸之後，小鼠脊髓內的ERK活性有顯著的增加。進一步的研究發現，重複的酸刺激會誘發Asic3野生型小鼠脊髓中 Cav3.2和mglur1，mgulr5 mRNA長期表現量的增加；和Asic3剔除小鼠脊髓中NR2A表現量增加。我們進一步檢視在重複酸刺激後所活化的腦部神經迴路是否平行調節憂鬱行為和痛覺傳導，然而免疫組織化學的結果顯示，腦部與痛覺訊息下行傳遞或是憂鬱行為相關的核區的ERK活性都沒有顯著的增加。總結以上實驗我們發現由酸所引發、Asic3調控的長期肌肉疼痛過敏化動物模式中會選擇性的在雌性小鼠中引起憂鬱相關行為的增加；而Asic3也調節了中樞敏感化時Cav3.2，mgluR1，mgluR5和NR2A mRNA的表現量。而腦部活動是否參與此動物模式中酸引發的長期痛覺敏感和憂鬱行為，尚須更多實驗加以驗證。

關鍵字

肌肉；疼痛過敏化；第三型酸敏性離子通道；憂鬱；脊髓

並列摘要

Chronic wide-spread pain of skeletal muscle (CWP) has long been a major health problem around the world. 10-15% of the general population reports affected while approximately 90% of the patients are female. In addition to chronic, widespread musculoskeletal allodynia/hyperalgesia, sleep and emotion disorders are also commonly found in patients with CWP syndrome. To study CWP and related chronic muscle pain, Sluka et al. had developed an animal model where repeated injections of acidic saline into one gastrocnemius muscle produced a long-lasting bilateral hyperalgesia without tissue damage. Strikingly, the phenotype is abolished in mice lacking Acid sensing ion channel 3 (Asic3). However, whether this model has associated emotional disorder and the underlying neuronal mechanisms of pain transduction, especially the role of ASIC3, has not been tested. In the present study, we found female Asic3 wild type (Asic3+/+) but not knockout (Asic3-/-) mice showed increased depression-like behavior 7 days after induction of hyperalgesia while male mice appeared to be normal. Decease of locomoton activity was found in male Asic3-/- mice and Asic3+/+ mice receiving intramuscular acid injection. ERK activity was increased in spinal cord dorsal horn after the second acidic saline injection in both Asic3+/+ and Asic3-/- mice. Also, there was prolonged up-regulation of Cav3.2, mgluR1, mgulR5 transcripts in lumbar spinal cord after second acid injection in Asic3+/+ mice. In contrast, the mRNA level of spinal NR2A was increased in Asic3-/- mice. We further examined whether the chronic muscle hyperalgesia involved brain facilitation pathways that affect both pain transduction and emotional disorder. However, the results of immunohistochemistry revealed no significant change in ERK activity in brain regions related to descending pain pathway or depression behavior. In sum, the present study revealed that 1) ASIC3-mediated chronic muscle pain would selectively trigger depression-like behaviors in female mice; 2) ASIC3-dependent central sensitization is involved in the up-regulation of Cav3.2, mgluR1, mgluR5, and NR2A in spinal cord. More works need to be carried out to determine the involvement of super spinal region in the acid-induced hyperalgesia/depression. Key words: muscle, hyperalgesia, ASIC3, depression, pERK, spinal cord

並列關鍵字

muscle ； hyperalgesia ； ASIC3 ； depression ； pERK ； spinal cord

參考文獻

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國際替代計量

慢性肌肉疼痛動物模式中之憂鬱相關行為和基因調控

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