Restless Legs Syndrome (RLS) is often and successfully treated with dopamine receptor agonists that target the inhibitory D3 receptor subtype, however there is no clinical evidence of a D3 receptor dysfunction in RLS patients. In contrast, genome-wide association studies in RLS patients have established that a mutation of the MEIS1 gene is associated with an increased risk in developing RLS, but the effect of MEIS1 dysfunction on sensorimotor function remain unknown. Mouse models for a dysfunctional D3 receptor (D3KO) and Meis1 (Meis1KO) were developed independently, and each animal expresses some features associated with RLS in the clinic, but they have not been compared in their responsiveness to treatment options used in the clinic. We here confirm that D3KO and Meis1KO animals show increased locomotor activities, but that only D3KO show an increased sensory excitability to thermal stimuli. Next we compared the effects of dopaminergics and opioids in both animal models, and we assessed D1 and D3 dopamine receptor expression in the spinal cord, the gateway for sensorimotor processing. We found that Meis1KO share most of the tested behavioral properties with their wild type (WT) controls, including the modulation of the thermal pain withdrawal reflex by morphine, L-DOPA and D3 receptor (D3R) agonists and antagonists. However, Meis1KO and D3KO were behaviorally more similar to each other than to WT when tested with D1 receptor (D1R) agonists and antagonists. Subsequent Western blot analyses of D1R and D3R protein expression in the spinal cord revealed a significant increase in D1R but not D3R expression in Meis1KO and D3KO over WT controls. As the D3R is mostly present in the dorsal spinal cord where it has been shown to modulate sensory pathways, while activation of the D1Rs can activate motoneurons in the ventral spinal cord, we speculate that D3KO and Meis1KO represent two complementary animal models for RLS, in which the mechanisms of sensory (D3R-mediated) and motor (D1R-mediated) dysfunctions can be differentially explored.

No abstract

No abstract

No 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.