title: μ-δ opioid receptor heteromer-specific signaling in the striatum and hippocampus.
abstract: The μ-δ opioid receptor heteromer activates the pertussis toxin-resistant Gαz GTP-binding protein following stimulation by the δ-agonist deltorphin-II whereas μ- and δ-receptors activate the pertussis toxin-sensitive Gαi3 protein following stimulation by μ- and δ-agonists, respectively. Although the regulation of the μ-δ heteromer is being investigated extensively in vitro, its physiological relevance remains elusive owing to a lack of available molecular tools. We investigated μ-δ heteromer signaling under basal conditions and following prolonged morphine treatment in rodent brain regions highly co-expressing μ- and δ-receptors and Gαz. Deltorphin-II induced Gαz activation in the striatum and hippocampus, demonstrating the presence of μ-δ heteromer signaling in these brain regions. Prolonged morphine treatment, which desensitizes μ- and δ-receptor function, had no effect on μ-δ heteromer signaling in the brain. Our data demonstrate that μ-δ heteromer signaling does not desensitize and is regulated differently from μ- and δ-receptor signaling following prolonged morphine treatment.
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T1R8, Canada; Department of Pharmacology, University of Toronto, Medical Sciences Building RM 4358, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada.
authors: Noufissa
authors: N
authors: Kabli
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T1R8, Canada.
authors: Theresa
authors: T
authors: Fan
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T1R8, Canada; Department of Pharmacology, University of Toronto, Medical Sciences Building RM 4358, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada.
authors: Brian F
authors: BF
authors: O'Dowd
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T1R8, Canada; Department of Medicine, University of Toronto, Medical Sciences Building RM 4358, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada; Department of Pharmacology, University of Toronto, Medical Sciences Building RM 4358, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada. Electronic address: s.george@utoronto.ca.
authors: Susan R
authors: SR
authors: George
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D019281:Dimerization; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine
keywords: Brain; GTPγS; Gα(z); Heterooligomer; δ opioid receptor; μ opioid receptor