Cholecystokinin-B Antagonist could Prevent and Reverse Repeated Morphine Injection-induced Antinociceptive Tolerance

Background: Opioids are a class of the most effective analgesics for treating many forms of acute and chronic pain. However, prolonged use of opioid causes analgesic tolerance, withdrawal syndrome, and paradoxical opioid-induced hyperalgesia, which attenuates benefits and hinder the effective use of opioids in human and in animals. Cholecystokinin (CCK) is an anti-opioid endogenous peptide and presumed to be involved in this tolerant-related phenomenon. In this study, we tested if combination with CCK-B receptor antagonist could ameliorate and/or treat the side effects after prolonged morphine treatment. Materials and Methods: SD rats were subjective to morphine 4 mg/kg, s.c. twice daily for 5 days and developed morphine analgesic tolerance. The morphine-treated rats were allocated into four groups to respectively co-injected with LY225,910 (0.1, 0.5, or 1 mg/kg, s.c.), a potent CCK-B antagonist, or saline 1.0 ml 30 min before every morphine injection. Another two control groups are rats injected with either saline or LY225,910 (1 mg/kg, s.c.) alone for comparison. To test if LY225,910 could reverse opioid tolerance, the morphine-tolerant rats, which had been treated as abovementioned, were divided into three groups to receive single injection of saline, or high-dose LY225,910 (1 mg/kg or 5 mg/kg) on the 5th day. Tail-flick tests were measured every morning after each morphine injection, and ＂Maximal Possible Effects (MPE)＂ were calculated for analysis. Results: Co-treatment with LY225,910 and morphine significantly attenuated morphine tolerance in a dose-dependent manner. Besides, the rats which showed antinociceptive tolerance to morphine could partially restore morphine analgesic effect by single injection of high-dose LY225,910 on the 5th day. However, LY225,910 alone did not change nociceptive threshold. Conclusion: We concluded that LY225,910 could evidently prevent the development of morphine-induced antinociceptive tolerance and modestly reverse analgesic reduction after chronic morphine use in the rats. This finding suggests coadministration of CCK-B antagonist in patients with chronic morphine treatment may improve the morphine analgesic quality.

關鍵字

Cholecystokinin ； CCK antagonist ； Morphine tolerance ； Tail-flick test

並列摘要

背景：類鴉片製劑是目前臨床上治療急性或慢性疼痛最有效的止痛藥劑。然而，長期使用類鴉片藥物會產生止痛耐受性、戒斷症候、或矛盾地類鴉片誘發疼痛過度等副作用，減弱或阻礙了臨床上的使用。膽囊收縮素Cholecystokinin（CCK）是一種反鴉片內源性胜肽物質，內認為會參與此耐受性的現象。在本驗證性的研究中，我們重複測試了合併使用乙型膽囊收縮素（CCK-B）受體拮抗劑及嗎啡，是否可以改善甚至治療長期嗎啡使用後產生的這類副作用。材料及方法：SD大鼠接受嗎啡皮下注射，一天兩次，每次4毫克／公斤，連續五天一直到第五天早上，如此會誘發大鼠產生嗎啡止痛耐受性。這些嗎啡鼠分成四組，分別在嗎啡注射前30分鐘，接受生理食鹽水（1毫升）、或三種不同劑量的強力選擇性CCK-B拮抗劑LY225,910（0.1, 0.5, or 1毫克／公斤）的皮下注射。另外兩組對照組大鼠，分別單獨皮下注射生理鹽水或LY225,910（1毫克／公斤）作為比較。另一實驗測試LY225,910是否可以治療或逆轉已形成的類鴉片耐受性：對前述方式已經產生嗎啡止痛耐受的大鼠，分成三組，在第五天最後一次嗎啡注射前30分鐘，分別接受食鹽水、高劑量LY225,910（1毫克／公斤或5毫克／公斤）的單次皮下注射，並比較行為反應。所有大鼠均在每天早上嗎啡注射後，以閃尾試驗測試疼痛閾值改變，最後計算「最大可能效應」（maximal possible effect, MPE）做為統計的分析。結果：合併使用LY225,910和嗎啡可以明顯抑制嗎啡止痛耐受性，且效果與LY225,910的劑量相關。此外，已經產生嗎啡耐受性的大鼠，也可以在第五天利用高劑量的LY225,910逆轉或恢復部分的嗎啡止痛效果。然而，LY225,910本身並不會對疼痛閾值產生改變。結論：我們認為CCK-B拮抗劑可以明顯預防嗎啡反覆注射的止痛耐受性及反轉慢性嗎啡使用後減弱的止痛效果。未來兩者合併，應可以在臨床上幫助慢性疼痛病人長期使用嗎啡的治療品質。

並列關鍵字

膽囊收縮素；乙型膽囊收縮素（CCK-B）受體拮抗劑；嗎啡耐受性；閃尾試驗

國際替代計量

Cholecystokinin-B Antagonist could Prevent and Reverse Repeated Morphine Injection-induced Antinociceptive Tolerance

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