Background Evidence has accumulated demonstrating the existence of opioid receptor heteromers and recent data suggest that targeting these heteromers could reduce opioid side effects while retaining therapeutic effects. Indeed, CYM51010 characterised as a MOR (mu opioid receptor)/DOR (delta opioid receptor) heteromers preferring agonist promoted antinociception comparable to morphine but with less tolerance. In the perspective of developing these new classes of pharmacological agents, data on their putative side effects are mandatory. Methods Therefore, in this study, we investigated the effects of CYM51010 in different models related to drug addiction in mice including behavioural sensitization, conditioned place preference and withdrawal. Results We found that, like morphine, CYM51010 promoted acute locomotor activity as well as psychomotor sensitization and rewarding effect. However, it induced less physical dependence than morphine. We also investigated the ability of CYM51010 to modulate some morphine-induced behaviour. Whereas CYM51010 was unable to block morphine-induced physical dependence, it blocked reinstatement of an extinguished morphine induced-conditioned place preference. Conclusions Altogether, our results reveal that targeting MOR-DOR heteromers could represent a promising strategy to block morphine reward.

中文翻译：

---

mu-delta阿片受体异聚体的激活会阻断吗啡的奖赏效应

背景 越来越多的证据证明阿片受体异聚体的存在，最近的数据表明，针对这些异聚体可以减少阿片类药物的副作用，同时保留治疗效果。事实上，CYM51010 的特征是 MOR（μ 阿片受体）/DOR（δ 阿片受体）异聚体，优选激动剂，可促进与吗啡相当的镇痛作用，但耐受性较低。从开发这些新类别药物的角度来看，有关其假定副作用的数据是强制性的。方法因此，在本研究中，我们研究了 CYM51010 在与小鼠药物成瘾相关的不同模型中的影响，包括行为敏化、条件性位置偏爱和戒断。结果我们发现，与吗啡一样，CYM51010 可以促进急性运动活动以及精神运动敏化和奖励效应。然而，它引起的身体依赖性比吗啡要少。我们还研究了 CYM51010 调节某些吗啡诱导行为的能力。虽然 CYM51010 无法阻断吗啡引起的身体依赖性，但它可以阻止吗啡引起的条件性位置偏好的恢复。结论 总而言之，我们的结果表明，靶向 MOR-DOR 异聚体可能代表一种有前途的阻断吗啡奖励的策略。