μ-δ opioid receptor heteromer-specific signaling in the striatum and hippocampus.

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.