Dopamine D₄ receptor counteracts morphine-induced changes in µ opioid receptor signaling in the striosomes of the rat caudate putamen.
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 Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/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.
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain. boomgaard@uma.es.
Diana
D
Suárez-Boomgaard
Department of Neuroscience, Biodonostia Institute, 20014 San Sebastián, Spain. belen.gago@biodonostia.org.
Belén
B
Gago
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain. ale_valde@uma.es.
Alejandra
A
Valderrama-Carvajal
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain. rrb@uma.es.
Ruth
R
Roales-Buján
Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University-Gent, 9000 Ghent, Belgium. kathleen.vancraenenbroeck@ugent.be.
Kathleen
K
Van Craenenbroeck
Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University-Gent, 9000 Ghent, Belgium. Jolien.duchou@ugent.be.
Jolien
J
Duchou
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden. Dasiel.Borroto-Escuela@ki.se.
Dasiel O
DO
Borroto-Escuela
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain. medi_luque@hotmail.com.
José
J
Medina-Luque
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain. delacalle@uma.es.
Adelaida
A
de la Calle
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden. Kjell.Fuxe@ki.se.
Kjell
K
Fuxe
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain. arivera@uma.es.
Alicia
A
Rivera
D000222:Adaptation, Physiological; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D018491:Dopamine Agonists; D004745:Enkephalins; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D050638:Receptors, Dopamine D4; D004399:Dynorphins; D009020:Morphine