Cholecystokinin-B Receptor Antagonist could Attenuate Repeated Morphine Injection-induced Nociceptive Hyperalgesia in the Rats

膽囊收縮素乙型受體拮抗劑可以減輕大鼠因反覆注射嗎啡誘發之疼痛過度現象

劉玉成(Yu-Cheng Liu) ； 黎尚宜(Shang-Yi Lee) ； 歐陽欣漢(Hsin-Han Ouyang) ； 陳坤堡(Kuen Bao Chen) ； 溫永銳(Yeong-Ray Wen)

《疼痛醫學雜誌》 30卷1期 (2020/03) Pp. 7-18

摘要

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.

關鍵字

Cholecystokinin ； CCK antagonist ； Formalin test ； Morphine tolerance ； Opioid-induced hyperalgesia

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（1.0mg／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。

並列關鍵字

膽囊收縮素 ； 乙型膽囊收縮素（CCK-B）受體拮抗劑 ； 福馬林注射 ； 嗎啡耐受性類鴉片誘發疼痛過度