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* Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599;
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry,
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore;
¶ The National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; and
|| Department of Psychiatry, College of Medicine and Hospital, National Cheng-Kung University, Tainan, Taiwan
Recent studies have shown that morphine modulates the function of glia cells through both opioid receptor dependent and independent mechanisms. However, the mechanism by which morphine regulates neuronal disorders through the alteration of microglia activity remains unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that both l-morphine and its synthetic stereoenantiomer, d-morphine, an ineffective opioid receptor agonist, significantly reduced LPS- or 1-methyl-4-phenylpyridinium-induced dopaminergic neurotoxicity with similar efficacy, indicating a nonopioid receptor-mediated effect. In addition, using reconstituted neuron and glia cultures, subpicomolar concentrations of morphine were found to be neuroprotective only in the presence of microglia, and significantly inhibited the production of inflammatory mediators from LPS-stimulated microglia cells. Mechanistic studies showed that both l- and d- morphine failed to protect dopaminergic neurons in cultures from NADPH oxidase (PHOX) knockout mice and significantly reduced LPS-induced PHOX cytosolic subunit p47phox translocation to the cell membrane by inhibiting ERK phosphorylation. Taken together, our results demonstrate that morphine, even at subpicomolar concentrations, exerts potent anti-inflammatory and neuroprotective effects either through the inhibition of direct microglial activation by LPS or through the inhibition of reactive microgliosis elicited by 1-methyl-4-phenylpyridinium. Furthermore, our study reveals that inhibition of PHOX is a novel site of action for the mu-opioid receptor-independent effect of morphine.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant DE-13079 from the National Institute for Dental and Craniofacial Research and in part by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences.
2 Address correspondence and reprint requests to Dr. Patrick M. Flood, Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599-7455. E-mail address: pat_flood{at}dentistry.unc.edu
3 Abbreviations used in this paper: PD, Parkinson’s disease; MPP+, 1-methyl-4-phenylpyridinium; DA, dopaminergic; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; TH-IR, tyrosine hydroxylase immunoreactive; PHOX, NADPH oxidase; DCFH-DA, dichlorodihydrofluorescein diacetate; SOD, superoxide dismutase; MFI, mean fluorescent intensity.
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