Dopamine receptor D3 agonist (Pramipexole) reduces morphine-induced cardiac fibrosis

Abstract Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2-family with morphine-induced nociception modulation. This study first assessed whether morphine induces cardiac remodeling in healthy mice, then whether DRD3 agonist (DRD3ag, D2-family member) adjunct therapy prevents morphine-induced cardiac remodeling. Mice received morphine (2 mg/kg/day i. p.) for 7 days (D7) and were either euthanized at D7 or kept 7 more days without morphine (i.e. withdrawal period, D8-D14): G1, morphine; G2, morphine/DRD3ag; G3, morphine + withdrawal; G4, morphine/DRD3ag + withdrawal; G5, morphine + withdrawal/DRD3ag. A separate cohort of animals were used as naive tissues. We evaluated functional and molecular parameters of cardiac remodeling. Although we did not observe significant differences in systolic function, morphine induced both interstitial fibrosis and cardiomyocyte hypertrophy. Interestingly, DRD3ag abolished these effects. Compared to naive tissues, collagen 1 increased after withdrawal in G3 and G4 and collagen 3 increased in G1-G4 but at higher levels in G1 and G2. Only G5 did not show collagen differences compared to naive, suggesting DRD3ag treatment during withdrawal may be beneficial and prevent morphine-induced fibrosis. Smad2/3 phosphorylation increased during withdrawal, indicating a likely upstream pathway for the observed morphine-induced fibrosis. Overall, our data suggest that DRD3ag adjunct therapy decreases morphine-induced adverse cardiac remodeling.