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Morphine is one of the most potent analgesic drugs used to relieve moderate to severe pain. After long-term use of morphine, neuroadaptive changes in the brain promotes tolerance, which result in a reduced sensitivity to most of its effects with attenuation of analgesic efficacy, and dependence, revealed by drug craving and physical or psychological manifestations of drug withdrawal. The mu opioid receptor (MOR) is critical, not only in mediating morphine analgesia, but also in addictive behaviors by the induction of a strong rewarding effect. We have previously shown that dopamine D4 receptor (D4R) stimulation counteracts morphine-induced activation of dopaminergic nigrostriatal pathway and accumulation of Fos family transcription factors in the caudate putamen (CPu). In the present work, we have studied the effect of D4R activation on MOR changes induced by morphine in the rat CPu on a continuous drug treatment paradigm, by analyzing MOR protein level, pharmacological profile, and functional coupling to G proteins. Furthermore, using conditioned place preference and withdrawal syndrome test, we have investigated the role of D4R activation on morphine-related behavioural effects. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment. Interestingly, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. In addition, the administration of the D4R agonist counteracts the rewarding effects of morphine, as well as the development of physical dependence. The present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine and preventing morphine-related behaviour. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Morphine induces dopamine release in the caudate putamen (CPu), which promotes stereotyped behavior and habit learning for drug-seeking and –taking. Nigrostriatal pathway stimulation by morphine is due to a removal of tonic inhibition arising from SNr GABA interneurons on SNc dopaminergic neurons through the mu opioid receptor (MOR). Long-term morphine exposure produces a series of adaptations in SNc dopamine neurons, which affect neuron excitability and dopamine output to CPu. We have previously shown that dopamine D4 receptor (D4R) stimulation counteracts acute and chronic morphine-induced accumulation of several transcription factors in the CPu (Gago et al., 2011 Brain Res.). Since D4R is expressed in the SNr (Rivera et al., Brain Res. 2003), we postulate that a functional D4R-MOR interaction at the midbrain level could exists. We have investigated the role of D4R in the morphine-induced nigroestriatal dopamine metabolism in the rat brain using biochemical and immunohistochemical techniques. We also have studied the influence of D4R on morphine-induced morphological changes in SNc dopamine neurons using both immunohistochemical and image analysis techniques. Finally, we examined a possible underlying mechanism of the D4R-MOR interaction at the SN level using in vitro quantitative receptor autoradiography. We have found that D4R activation restores dopamine metabolism in the nigroestriatal pathway after acute morphine treatment and prevents morphine-induced rise of tyroxine hydroxylase and dopamine transporter. Rats receiving a continuous treatment of morphine (6 days) showed SNc dopamine neurons with smaller size and higher circularity index compared with the controls animals. These morphine-induced morphological adaptatives changes were prevented when a D4R agonist (PD168,077) was administered at the same time with morphine. Autoradiographic studies demonstrated that the D4R agonist reduce the affinity of MOR. The present study provides evidence for the existence of a fully blocking effect of the D4R on the activation of dopaminergic nigroestriatal pathway by morphine. Financiación: P09-CVI- 4702 (Proyecto de Excelencia de la Junta de Andalucía)