Miranda H F, Silva E, Pinardi G
Pharmacology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago.
Can J Physiol Pharmacol. 2004 May;82(5):331-8. doi: 10.1139/y04-027.
The intraperitoneal administration of morphine, diclofenac, ketoprofen, meloxicam, metamizol, paracetamol and piroxicam induced dose-dependent antinociception in mice tested with the acetic acid writhing test. The isobolographic analysis of the simultaneous intraperitoneal administration of fractions of the ED50's of morphine with each nonsteroidal anti-inflammatory drug (NSAID) demonstrated the existence of a supra-additive interaction (synergy). The selective antagonist of micro -opioid receptors naltrexone partially reversed the supra-additive interactions to additive interactions; however, the combinations of morphine/metamizol and morphine/paracetamol were completely antagonized, resulting in subadditive interactions. The selective antagonist of delta-opioid receptors naltrindole failed to significantly attenuate the combinations of morphine with ketoprofen, meloxicam and piroxicam, but decreased the activity of the combinations of morphine with diclofenac, metamizol and paracetamol, transforming the interactions from supra-additive to additive. Nor-binaltorphimine was used to evaluate the involvement of kappa-opioid receptors. Nor-binaltorphimine did not modify the supra-additive interaction of morphine and NSAIDs and the additive interaction of the co-administration of morphine and metamizol. The synergy between morphine and NSAIDs could be related to different pathways of pain transmission, probably related to the different intracellular signal transduction mechanisms of action of opioid and non-opioid agents.
在乙酸扭体试验中，腹腔注射吗啡、双氯芬酸、酮洛芬、美洛昔康、安乃近、对乙酰氨基酚和吡罗昔康可使小鼠产生剂量依赖性的镇痛作用。对吗啡与每种非甾体抗炎药（NSAID）的半数有效剂量（ED50）组分同时进行腹腔注射的等效线图分析表明存在超相加相互作用（协同作用）。μ-阿片受体的选择性拮抗剂纳曲酮可部分将超相加相互作用逆转至相加相互作用；然而，吗啡/安乃近和吗啡/对乙酰氨基酚的组合被完全拮抗，导致次相加相互作用。δ-阿片受体的选择性拮抗剂纳曲吲哚未能显著减弱吗啡与酮洛芬、美洛昔康和吡罗昔康的组合，但降低了吗啡与双氯芬酸、安乃近和对乙酰氨基酚组合的活性，使相互作用从超相加转变为相加。去甲丁丙诺啡用于评估κ-阿片受体的参与情况。去甲丁丙诺啡并未改变吗啡与NSAIDs的超相加相互作用以及吗啡与安乃近联合给药的相加相互作用。吗啡与NSAIDs之间的协同作用可能与不同的疼痛传导途径有关，可能与阿片类和非阿片类药物作用的不同细胞内信号转导机制有关。
