並列摘要

前言：矛盾性類鴉片誘發疼痛是一種少見的疼痛過度或疼痛敏感，可在人類或動物
經長期使用或注射嗎啡後引起。膽囊收縮素(CCK) 是一種內源性抗類鴉片胜肽物質，且
被認為參與以上的現象。在本研究中，我們測試了膽囊收縮素膽囊受體拮抗劑是否可以
減輕嗎啡耐受性大鼠的疼痛過度現象。
材料及方法：雄性SD 大鼠接受嗎啡 4 毫克/ 公斤皮下注射，一天兩次連續五天，
至第五天早上，經注射的大鼠會出現止痛耐受性。在嗎啡注射前30 分鐘，大鼠先分成
三組，分別皮下注射兩種劑量的乙型膽囊收縮素受體拮抗劑LY225,910 (0.1 毫克/ 公
斤或 1.0 毫克/ 公斤) 或食鹽水連續五天。另外兩組為對照組，分別接受單獨食鹽水或
LY225,910 (1.0 毫克/ 公斤) 連續五天的注射。第五天早上嗎啡注射後30 分鐘，大鼠
左腳掌注射福馬林(5O 微升)，觀察福馬林注射誘發之疼痛過度，並以加權疼痛分數計
算及統計。疼痛誘發之Fos 蛋白在脊髓腰椎第四到五節的表現也同時進行分析。
結果：嗎啡耐受鼠左後足注射福馬林後出現明顯的疼痛過度，且與正常鼠有明顯
差異。合併LY225,910 及嗎啡注射，可以減輕嗎啡耐受現象且與劑量相關。統計發現，
LY225,910 高劑量組(1.0 mg/kg) 可明顯地降低福馬林造成的疼痛過度，特別是在福馬
林晚期疼痛表現。福馬林所誘發的脊髓背角Fos 表現在嗎啡耐受鼠也比正常鼠或單獨注
射LY225,910 鼠顯著較高。合併高劑量的LY225,910 可以減少Fos 免疫染色反應，但低
劑量組沒有明顯差別。
結論：我們認為嗎啡合併膽囊收縮素拮抗劑 LY225,910 可以減輕反覆注射嗎啡後引
起的疼痛過度及脊髓神經元Fos 敏感反應，而此抑制現象可能是經由抑制脊髓中樞性敏
感化的效果。

摘要 Summary

Background: Paradoxical opioid-induced pain, an unusual hyperesthesia and allodynia, appears in human and animals after exposure to long-term morphine uses. Cholecystokinin (CCK) is an endogenous anti-opioid peptide and presumed to be involved in this phenomenon. In this study, we tested if CCK-B antagonist could ameliorate nociceptive hyperalgesia in the morphine-tolerant rats.
Materials and Methods: Male Sprague-Dawley rats subjective to morphine 4 mg/kg, s.c. twice daily for 4 days and another injection in the morning of the fifth day, developed morphine analgesic tolerance. LY225,910 (0.1, or 1 mg/kg, s.c.), a CCK-B receptor antagonist, or saline at 1.0 ml was injected 30 min before morphine treatment in separate groups. Two control groups of rats received saline or LY225,910 (1 mg/kg, s.c.) alone twice daily for 5 days. Intraplantar formaline injection at the left hind paw was conducted after the last morphine or saline injection on the 5th day morning. Formalin-induced paw hyperalgesic responses were evaluated and calculated by a weighted pain scoring software. Fos expression by immunohistochemistry at the L4-5 spinal dorsal horn were also analyzed.
Results: The morphine-tolerant rats showed significantly stronger formalin-injection induced hyperalgesia compared to the normal rats, and co-treatment of LY225,910 with morphine attenuated morphine tolerance in a dose-dependent manner. The high-dose co-treatment group (1.0 mg/kg) showed a significant reduction in formalin-induced paw hyperalgesia, especially at the late phase response. Induction of Fos expression after formalin injection was higher in the morphine-treated rats compared to those in the saline or LY225,910 injection rats. Co-administration with LY225,910 at the high dose could decrease the Fos-like immunoreactivity, but the low-dose group did not show difference from the morphine group.
Conclusion: We concluded that CCK-B antagonist LY225,910 could attenuate morphine tolerance-induced behavioral hyperalgesia and spinal Fos reactivity in the rats. The inhibition of Formalin-induced hyperalgesia may be mediated through reduction of spinal mechanism of the CCKergic pathway.