Inhibitory effect of low-dose pentazocine on the development of antinociceptive tolerance to morphine
Inhibitory effect of low-dose pentazocine on the development of antinociceptive tolerance to morphine
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DOI：
10.1007/s00540-008-0697-0
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发表时间：
2009-02-01
影响因子：
2.8
通讯作者：
Yamada, Yoshitsugu
中科院分区：
文献类型：
--
作者：
Chiba, Shunsuke;Hayashida, Masakazu;Yamada, Yoshitsugu
目的.吗啡镇痛耐受的形成是其临床应用中的主要问题之一。因此，探索有效的预防吗啡耐受的措施具有重要的临床意义。我们评估喷他佐辛是否可以防止小鼠吗啡耐受。五组雄性ICR小鼠接受重复皮下（s.c.）注射高剂量的吗啡（10 mg . kg（-1））或生理盐水，伴随s.c.注射低、亚镇痛剂量的喷他佐辛（0.1、0.3或1.0 mg . kg（-1））或生理盐水，每日一次，共14天。在第15天，小鼠在用去甲-binaltorphimine（5 mg . kg（-1）），选择性κ-阿片受体拮抗剂。在每日药物联合注射前和注射后60分钟测量尾部压力阈值。结果。重复皮下注射由于吗啡耐受性的发展，吗啡和盐水的共同注射导致吗啡诱导的抗伤害感受的进行性降低。喷他佐辛（0.1、0.3和1.0 mg . kg（-1））可剂量依赖性地增强吗啡的抗伤害作用，抑制吗啡耐受的形成。去甲binaltorphimine完全抑制吗啡和喷他佐辛联合注射所维持的慢性镇痛作用。当长期共同管理与吗啡，喷他佐辛在低，亚镇痛剂量依赖性地增强吗啡诱导的抗伤害感受在吗啡耐受小鼠，通过其κ-阿片受体介导的耐受预防活动。因为喷他佐辛是唯一的激动剂-拮抗剂镇痛剂，具有适合长期给药的有效口服制剂，本研究的结果保证喷他佐辛的临床试验，以评估其耐受性预防癌症疼痛患者的活动。
Purpose. The development of antinociceptive tolerance to morphine is one of the major problems in its clinical use. Therefore, exploring effective measures to prevent morphine tolerance is of great clinical relevance. We evaluated whether pentazocine could prevent morphine tolerance in mice.Methods. Five groups of male ICR mice received repeated subcutaneous (s.c.) injections of morphine at a high dose (10 mg . kg(-1)) or saline, concomitantly with s.c. injections of pentazocine at low, subanalgesic doses (0.1, 0.3, or 1.0 mg . kg(-1)) or saline, respectively, once daily for 14 days. On day 15, mice received co-injections of morphine and pentazocine 120 min after pretreatment with nor-binaltorphimine (5 mg . kg(-1)), a selective kappa-opioid receptor antagonist. The tail pressure threshold was measured before and 60 min after the daily drug co-injections.Results. Repeated s.c. co-injections of morphine and saline resulted in a progressive decrease in morphine-induced anti-nociception, due to the development of morphine tolerance. Co-injections of pentazocine (0.1, 0.3, and 1.0 mg . kg(-1)) with morphine potentiated the morphine-induced antinociception dose-dependently by preventing the development of morphine tolerance. Nor-binaltorphimine completely inhibited the chronic antinociception maintained by co-injections of morphine and pentazocine.Conclusion. When chronically co-administered with morphine, pentazocine at low, subanalgesic doses dose-dependently potentiated morphine-induced antinociception in morphine-tolerant mice, through its kappa-opioid-receptor-mediated tolerance-preventing activity. Because pentazocine is the only agonist-antagonist analgesic that has an effective oral formulation suitable for chronic administration, the results of the present study warrant clinical trials of pentazocine to assess its tolerance-preventing activity in patients with cancer pain.