Abstract
Morphine is a widely used analgesic in humans that is associated with multiple untoward effects, such as addiction and physical dependence. In rodent models, morphine also induces locomotor activity. These effects likely involve functionally selective mechanisms. Indeed, G protein-coupled receptor desensitization and adaptor protein β-arrestin 2 (βarr2) through its interaction with the μ-opioid receptor regulates the analgesic but not the rewarding properties of morphine. However, βarr2 is also required for morphine-induced locomotor activity in mice, but the exact cellular and molecular mechanisms that mediate this arrestin-dependent behavior are not understood. In this study, we show that βarr2 is required for morphine-induced locomotor activity in a dopamine D1 receptor (D1R)-dependent manner and that a βarr2/phospho-ERK (βarr2/pERK) signaling complex may mediate this behavior. Systemic administration of SL327, an MEK inhibitor, inhibits morphine-induced locomotion in wild-type mice in a dose-dependent manner. Acute morphine administration to mice promotes the formation of a βarr2/pERK signaling complex. Morphine-induced locomotor activity and formation of the βarr2/pERK signaling complex is blunted in D1R knockout (D1-KO) mice and is presumably independent of D2 dopamine receptors. However, D1Rs are not required for morphine-induced reward as D1-KO mice show the same conditioned place preference for morphine as do control mice. Taken together, these results suggest a potential role for a D1R-dependent βarr2/pERK signaling complex in selectively mediating the locomotor-stimulating but not the rewarding properties of morphine.
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Acknowledgements
This work was supported in part by the National Institutes of Health, grant numbers RO1-MH-0753 and U-19-MH-082441. We thank Wendy Roberts, Xiuqin Zhang, and Katherine Harley for maintenance of the mouse colony. D2 DA receptor knockout mice were generously provided by Dr Malcolm J Low at the Oregon Health and Science University in Portland, Oregon. D1 DA receptor mice were generously provided originally by Dr John Drago (NIH). GSK3β +/− mice were generously provided by Dr James Woodgett at the Samuel Lunenfeld Research Institute, Toronto, Canada.
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MGC owns stock of Acadia Pharmaceutical. He has consulted and received compensation from Lundbeck, Roche, and Merck. He has also received compensation in the form of honoraria for lecturing at various scientific meetings and academic institutions. None of the above presents any conflicts of interest with the results being described in this paper. Other authors have no disclosures/conflicts of interest.
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Urs, N., Daigle, T. & Caron, M. A Dopamine D1 Receptor-Dependent β-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice. Neuropsychopharmacol 36, 551–558 (2011). https://doi.org/10.1038/npp.2010.186
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DOI: https://doi.org/10.1038/npp.2010.186
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