Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Collaborative Innovation Center for Brain Science, Shanghai, China.
Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai, China.
Br J Pharmacol. 2017 Sep;174(17):2842-2861. doi: 10.1111/bph.13908. Epub 2017 Jul 18.
Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear.
Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Function of heterodimers was evaluated by behavioural studies of locomotor sensitization.
The dopamine D receptor antagonist SCH23390 antagonized the signalling initiated by stimulation of μ opioid receptors with agonists in transfected cells expressing two receptors and in striatal tissues from wild-type but not D receptor knockout (KO) mice, suggesting that SCH23390 modified μ receptor function via receptor heteromers, as the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a characteristic of receptor heteromers. The existence of μ receptor-D receptor heterodimers was further supported by biochemical and biophysical assays. In vivo, when dopamine release was absent (by destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited μ receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D or μ receptor KO mice and thus unable to form μ receptor-D receptor heterodimers, failed to show locomotor sensitization to morphine.
Our results suggest that μ receptor-D receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates.
阿片类药物暴露会导致啮齿动物的运动敏化，这被认为与强迫性觅药行为相对应。许多研究表明，运动敏化可以在多巴胺传递独立的方式下发生；然而，其潜在机制尚不清楚。
共免疫沉淀、BRET 和交叉拮抗测定用于证明受体异二聚体的存在。通过运动敏化的行为研究评估异二聚体的功能。
多巴胺 D 受体拮抗剂 SCH23390 拮抗了在表达两种受体的转染细胞和在野生型而非 D 受体敲除（KO）小鼠纹状体组织中用激动剂刺激 μ 阿片受体引发的信号，表明 SCH23390 通过受体异二聚体改变 μ 受体功能，因为一种受体的拮抗剂抑制由刺激伴侣受体引发的信号的能力是受体异二聚体的特征。μ 受体-D 受体异二聚体的存在进一步得到生化和生物物理测定的支持。在体内，当多巴胺释放缺失（通过破坏腹侧被盖区到纹状体的多巴胺投射）时，SCH23390 仍然显著抑制大鼠中 μ 受体激动剂诱导的行为反应。此外，我们证明 D 或 μ 受体 KO 小鼠因此无法形成 μ 受体-D 受体异二聚体，无法对吗啡表现出运动敏化。
我们的结果表明，μ 受体-D 受体异二聚体可能参与阿片类药物运动敏化的多巴胺独立表达。
