Dopamine D₁ or D₃ receptor modulators prevent morphine tolerance and reduce opioid withdrawal symptoms

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.