Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction

Morphine is one of the most effective drugs used for pain management, but it is also highly addictive. Morphine elicits acute and long-term adaptive changes at cellular and molecular level in the brain, which play a critical role in the development of tolerance, dependence and addiction. Previous studies indicated that the dopamine D-4 receptor (D4R) activation counteracts morphine-induced adaptive changes of the mu opioid receptor (MOR) signaling in the striosomes of the caudate putamen (CPu), as well as the induction of several Fos family transcription factors. Thus, it has been suggested that D4R could play an important role avoiding some of the addictive effects of morphine. Here, using different drugs administration paradigms, it is determined that the D4R agonist PD168,077 prevents morphine-induced activation of the nigrostriatal dopamine pathway and morphological changes of substantia nigra pars compacta (SNc) dopamine neurons, leading to a restoration of dopamine levels and metabolism in the CPu. Results from receptor autoradiography indicate that D4R activation modulates MOR function in the substantia nigra pars reticulata (SNr) and the striosomes of the CPu, suggesting that these regions are critically involved in the modulation of SNc dopamine neuronal function through a functional D4R/MOR interaction. In addition, D4R activation counteracts the rewarding effects of morphine, as well as the development of hyperlocomotion and physical dependence without any effect on its analgesic properties. These results provide a novel role of D4R agonist as a pharmacological strategy to prevent the adverse effects of morphine in the treatment of pain.