title: Dopamine D4receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction.
abstract: 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 D4receptor (D4R) activation counteracts morphine-induced adaptive changes of the μ 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.
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Gago
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Suárez-Boomgaard
authors.affiliation: Karolinska Institute, Department of Physiology and Pharmacology, Stockholm, Sweden.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshitake
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Roales-Buján
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Valderrama-Carvajal
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Medina-Luque
authors.affiliation: Karolinska Institute, Department of Physiology and Pharmacology, Stockholm, Sweden.
authors.forename: Zaida
authors.initials: Z
authors.lastname: Díaz-Cabiale
authors.affiliation: Ghent University, Laboratory of GPCR Expression and Signal Transduction (L-GEST), Ghent, Belgium.
authors.forename: Kathleen Van
authors.initials: KV
authors.lastname: Craenenbroeck
authors.affiliation: Karolinska Institute, Department of Neuroscience, Stockholm, Sweden.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Karolinska Institute, Department of Physiology and Pharmacology, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kehr
authors.affiliation: Laboratorio de Medicina Regenerativa, Hospital Regional Universitario Carlos Haya, Fundación IMABIS, Málaga, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Psicología, Málaga, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Santín
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica, Facultad de Ciencias, Málaga, Spain.
authors.forename: Adelaida
authors.initials: A
authors.lastname: de la Calle
authors.affiliation: Karolinska Institute, Department of Neuroscience, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism; D065841:Pars Reticulata / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012201:Reward; D019966:Substance-Related Disorders / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D018491:Dopamine Agonists; C493601:Drd4 protein, rat; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010879:Piperazines; D017450:Receptors, Opioid, mu; D050638:Receptors, Dopamine D4; D009020:Morphine
keywords: caudate putamen; dopamine D4 receptor; morphine