Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida (J.L.W., J.S.F., L.F.R., L.R.M.) and Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (M.I.A., A.C.)
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida (J.L.W., J.S.F., L.F.R., L.R.M.) and Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (M.I.A., A.C.).
J Pharmacol Exp Ther. 2019 Sep;370(3):380-389. doi: 10.1124/jpet.118.255844. Epub 2019 Jun 24.
Better therapeutic options are needed for pain. Baclofen, buspirone, and morphine are characterized as having analgesic properties. However, little is known about potential interactions between analgesic effects of these drugs when combined. Furthermore, it is not known if the magnitude of these potential interactions will be similar for all drug effects. Thus, we tested the effects of these drugs alone and in combination for their capacity to produce thermal antinociception and to decrease food-maintained responding. Four male and four female Sprague-Dawley rats responded for food under a fixed-ratio 10 schedule; afterward they were immediately placed on a 52°C hot plate. Morphine, baclofen, and buspirone were examined alone and in 1:1 combinations, based upon ED values. Morphine and baclofen effects were evaluated with the opioid antagonist naltrexone and the GABA antagonist (3-Aminopropyl)(diethoxymethyl)phosphinic acid (CGP35348), respectively. Morphine, baclofen, and buspirone dose dependently decreased operant responding, with the calculated ED values being 7.09, 3.42, and 0.57 mg/kg, respectively. The respective antinociception ED values were 16.15, 8.75, and 2.20 mg/kg. Analysis of 1:1 combinations showed the effects of morphine plus baclofen to decrease schedule-controlled responding and to produce thermal antinociception were synergistic. Effects of morphine plus buspirone and baclofen plus buspirone to decrease schedule-controlled responding were additive. Effects of the two combinations to produce thermal antinociception were synergistic. Naltrexone and CGP35348 antagonized the effects of morphine and baclofen, respectively. Synergistic antinociceptive effects, in conjunction with additive effects on food-maintained responding, highlight the therapeutic utility of opioid and non-opioid drug combinations.
需要更好的治疗疼痛的选择。巴氯芬、丁螺环酮和吗啡的特点是具有镇痛作用。然而，对于这些药物联合使用时的潜在相互作用知之甚少。此外，尚不清楚这些潜在相互作用的程度是否对所有药物作用都相似。因此，我们测试了这些药物单独使用和联合使用时产生热镇痛和减少食物维持反应的能力。四只雄性和四只雌性 Sprague-Dawley 大鼠在固定比例 10 方案下对食物做出反应；之后，它们立即被放在 52°C 的热板上。根据 ED 值，单独检查了吗啡、巴氯芬和丁螺环酮，并检查了它们的 1:1 组合。使用阿片受体拮抗剂纳洛酮和 GABA 拮抗剂（3-氨基丙基）（二乙氧基甲基）膦酸（CGP35348）分别评估了吗啡和巴氯芬的作用。吗啡、巴氯芬和丁螺环酮剂量依赖性地降低操作性反应，计算出的 ED 值分别为 7.09、3.42 和 0.57mg/kg。各自的镇痛 ED 值分别为 16.15、8.75 和 2.20mg/kg。对 1:1 组合的分析表明，吗啡加巴氯芬降低了控制性反应的作用，并产生了协同的热镇痛作用。吗啡加丁螺环酮和巴氯芬加丁螺环酮降低控制性反应的作用是相加的。这两种组合产生热镇痛的作用是协同的。纳洛酮和 CGP35348 分别拮抗了吗啡和巴氯芬的作用。协同的镇痛作用，加上对食物维持反应的相加作用，突出了阿片类药物和非阿片类药物联合用药的治疗效用。
