The long-term treatment of chronic pain by opioids is limited by tolerance and risk of addiction/dependence. Previously, we have shown that combination treatment of morphine with a dopamine D₁ or D₃ receptor modulator restored morphine analgesia in morphine-resistant neuropathic pain and decreased morphine's reward potential in an acute setting. Here, we investigated whether such adjunct therapy with a dopamine D₁ receptor preferring antagonist (SCH 39166) or a dopamine D₃ receptor preferring agonist (pramipexole) could prevent morphine tolerance and reduce withdrawal symptoms. Initially, tolerance to the combination of morphine + pramipexole was assessed in mice. Mice receiving intraperitoneal injections of morphine showed reduced thermal thresholds on Day 7 whereas those receiving morphine + pramipexole maintained analgesia at Day 7. Next, tolerance and withdrawal to both combinations were tested over 14 days in rats. Rats were assigned one of four drug conditions, (1) saline, 2) morphine, 3) morphine + SCH 39166, 4) morphine + pramipexole), for chronic administration via osmotic pumps. Chronic administration of morphine over 14 days resulted in a significant reduction of morphine analgesia. However, analgesia was maintained when morphine was administered with either the dopamine D₁ receptor preferring antagonist or the D₃ receptor preferring agonist. Withdrawal symptoms peaked at 48 h and were decreased in rats receiving either combination compared to morphine alone. The data suggests that adjunct therapy with dopamine D₁ or D₃ receptor preferring modulators prevents morphine tolerance and reduces the duration of morphine withdrawal symptoms, and thus this combination has potential for long-term pain management therapy.

阿片类药物对慢性疼痛的长期治疗受到耐受性和成瘾/依赖性风险的限制。以前，我们已经证明吗啡与多巴胺D ₁或D ₃受体调节剂的联合治疗可恢复吗啡抵抗性神经性疼痛中的吗啡镇痛作用，并在急性环境中降低吗啡的奖励潜力。在这里，我们调查了这种多巴胺D ₁受体偏爱拮抗剂的辅助疗法（SCH 39166）还是多巴胺D ₃受体激动剂（普拉克索）可以预防吗啡耐受并减少戒断症状。最初，在小鼠中评估了对吗啡+普拉克索组合的耐受性。接受腹腔注射吗啡的小鼠在第7天显示降低的热阈值，而接受吗啡+普拉克索的小鼠在第7天保持镇痛作用。接下来，在大鼠中测试了14天对这两种组合的耐受性和戒断率。将大鼠指定为四种药物条件之一，（1）盐水，2）吗啡，3）吗啡+ SCH 39166、4）吗啡+普拉克索），以通过以下方式长期给药渗透泵。长期服用吗啡超过14天导致吗啡镇痛效果显着降低。但是，当吗啡与多巴胺D ₁受体偏爱拮抗剂或D ₃受体偏爱激动剂同时给药时，镇痛作用得以维持。与单独使用吗啡相比，在接受任何一种联合治疗的大鼠中，戒断症状在48小时达到峰值，并有所减轻。数据表明，多巴胺D ₁或D ₃受体偏爱调节剂的辅助治疗可防止吗啡耐受，并减少吗啡戒断症状的持续时间，因此这种组合具有长期疼痛治疗的潜力。