Dopamine D4 Receptor Counteracts Morphine-Induced Changes in μ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

International Journal of Molecular Sciences

Diana Suárez-Boomgaard¹  Belén Gago³  Alejandra Valderrama-Carvajal¹  Ruth Roales-Buján¹  Kathleen Van Craenenbroeck⁴  Jolien Duchou⁴  Dasiel O. Borroto-Escuela²  José Medina-Luque¹  Adelaida de la Calle¹  Kjell Fuxe² 

[1] Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain; E-Mails:;Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden; E-Mails:;Department of Neuroscience, Biodonostia Institute, 20014 San Sebastián, Spain; E-Mail:;Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University-Gent, 9000 Ghent, Belgium; E-Mails:

关键词: morphine;    PD168;    077;    μ opioid receptor;    dopamine D₄ receptor;    G proteins;    caudate putamen;    striosomes;    addiction;   

DOI  :  10.3390/ijms15011481

来源: mdpi

【 摘 要 】

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [³⁵S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, 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 B_max values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to G_i/0 protein, 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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland