LaCourse Hannah, Bennett Lily, Falstad April, Asmus Francesca, Smith Meghan, Davis Ravin, Harrington Kylee, Giuvelis Denise, King Tamara, Stevenson Glenn W
Department of Psychology, University of New England, Biddeford, ME, USA.
Behavior Core, COBRE, University of New England, Biddeford, ME, USA.
Psychopharmacology (Berl). 2025 Apr;242(4):751-762. doi: 10.1007/s00213-025-06743-9. Epub 2025 Jan 20.
In vivo receptor interactions vary as a function of behavioral endpoint, with key differences between reflexive and non-reflexive measures that assess the motivational aspects of pain and pain relief. There have been no assessments of D dopamine agonist / mu opioid receptor (MOR) agonist interactions in non-reflexive behavioral measures of pain. We examined the hypothesis that D/MOR mixtures show enhanced effectiveness in blocking pain depressed behaviors while showing decreased side effects such as sedation and drug reward.
SKF82958 and methadone were used as selective/high efficacy D and mu agonists, respectively. An FR10 operant schedule was utilized in the presence and absence of a lactic acid inflammatory pain-like manipulation, to measure antinociceptive and operant-rate-suppressing effects, respectively. Rewarding properties of the drug combinations were determined using a conditioned place preference procedure.
Methadone alone, but not SKF82958 alone, produced dose-dependent restoration of pain-depressed responding. Both SKF82958 and methadone produced dose-dependent response rate suppression. Three fixed proportion mixtures, based on the relative potencies of the drugs in the rate suppression assay, produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that the 0.17:1 mixture produced supra-additive antinociception and additive sedation. The 0.055:1 mixture produced additive antinociception with sub-additive sedation, and the 0.018:1 mixture had the highest therapeutic index (TI) relative to other mixtures and drugs alone. The antinociceptive doses and component doses for the 0.018:1 mixture did not produce conditioned place preference.
These results suggest that D-selective dopamine agonists may have utility as candidate opioid-sparing analgesics.
体内受体相互作用会因行为终点的不同而变化，在评估疼痛及疼痛缓解的动机方面的反射性和非反射性测量之间存在关键差异。在非反射性疼痛行为测量中，尚未对D多巴胺激动剂/μ阿片受体（MOR）激动剂的相互作用进行评估。我们检验了以下假设：D/MOR混合物在阻断疼痛抑制行为方面显示出增强的效果，同时显示出诸如镇静和药物奖赏等副作用的减少。
分别使用SKF82958和美沙酮作为选择性/高效D和μ激动剂。在存在和不存在乳酸炎性疼痛样操作的情况下，采用FR10操作程序，分别测量抗伤害感受和操作率抑制作用。使用条件性位置偏爱程序确定药物组合的奖赏特性。
单独使用美沙酮可产生剂量依赖性的疼痛抑制反应恢复，但单独使用SKF82958则不能。SKF82958和美沙酮均产生剂量依赖性的反应率抑制。基于药物在率抑制试验中的相对效力，三种固定比例混合物产生剂量依赖性的抗伤害感受和镇静作用。等效应线分析表明，0.17:1的混合物产生超相加性抗伤害感受和相加性镇静作用。0.055:1的混合物产生相加性抗伤害感受和次相加性镇静作用，0.018:1的混合物相对于其他混合物和单独使用的药物具有最高的治疗指数（TI）。0.018:1混合物的抗伤害感受剂量和组分剂量未产生条件性位置偏爱。
这些结果表明，D选择性多巴胺激动剂可能作为候选的阿片类药物节省型镇痛药具有实用价值。
