Dopamine Receptor D3 Agonist (Pramipexole) Abolishes Morphine‐Induced Cardiac Fibrosis in Mice

Abstract

Prolonged morphine exposure leads to desensitization of the G protein‐coupled mu‐opioid receptor (MOR). Additionally, extended morphine exposure has been shown to associate with cardiac dysfunction. This is problematic for patients undergoing withdrawal from extended morphine pain management, especially those with pre‐existing heart conditions. Recent literature suggests mechanistic interactions between MOR and the dopamine receptor D3 (DRD3). The purpose of this study was to investigate whether a DRD3 agonist (pramipexole, 0.5 mg/kg/day, i.p.; DRD3ag) could reduce morphine‐induced cardiac dysfunction in mice. Thirty mice were randomly divided into 5 groups (G1–G5, Figure 1) and treated with morphine (2 mg/kg/day, i.p.) for 7 days (D7). Two groups were euthanized after morphine tolerance was established at D7 (G1, morphine only; G2, morphine + DRD3ag). The other 3 groups (D14) underwent a subsequent 7‐day period of morphine withdrawal (G3, withdrawal no treatment; G4, morphine + DRD3ag until D7 followed by withdrawal until D14; G5, morphine until D7 followed by withdrawal + DRD3ag until D14). Echocardiography was performed on each animal at D0 to establish a baseline for cardiac function, on D7, and again on D14. Histology and immunoblotting were conducted on the left ventricle (LV) to measure tissue fibrosis, myocyte hypertrophy, and DA receptor expression. Our data show that morphine treatment for 7 days followed by withdrawal induced cardiomyocyte hypertrophy and significantly increased myocardial fibrosis (both at D7 and D14). Picrosirius red staining showed that DRD3ag treatment completely abolished morphine‐induced fibrosis, independent of treatment time. Moreover, significantly decreased cardiomyocyte hypertrophy was noted in all groups receiving DRD3ag in the morphine withdrawal phase. Immunoblotting shows that morphine withdrawal significantly reduced DRD3 expression independent of the presence of DRD3ag. Our results suggest that using a DRD3ag as an adjunctive therapy with morphine could decrease morphine‐induced cardiac fibrosis, and subsequently blunt morphine‐dependent cardiac dysfunction. Further, our data suggest that the DRD3 agonist pramipexole has cardioprotective potential when administered during morphine withdrawal.Support or Funding InformationThe Brody School of Medicine Research Distinction Track, the Department of Physiology, and the Research and Graduate School at East Carolina University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.