Morphine-Induced Modulation of Endolysosomal Iron Mediates Upregulation of Ferritin Heavy Chain in Cortical Neurons
eNeuro, v 6(4), 0237
01 Jul 2019
: 31300544
HIV-associated neurocognitive disorders (HAND) remain prevalent and are aggravated by mu-opioid use. We have previously shown that morphine and other mu-opioids may contribute to HAND by inhibiting the homeostatic and neuroprotective chemokine receptor CXCR4 in cortical neurons, and this novel mechanism depends on upregulation of the protein ferritin heavy chain (FHC). Here, we examined the cellular events and potential mechanisms involved in morphine-mediated FHC upregulation using rat cortical neurons of either sex in vitro and in vivo. Morphine dose-dependently increased FHC protein levels in primary neurons through mu-opioid receptor (mu OR) and Gai-protein signaling. Cytoplasmic FHC levels were significantly elevated, but nuclear FHC levels and FHC gene expression were unchanged. Morphine-treated rats also displayed increased FHC levels in layer 2/3 neurons of the prefrontal cortex. Importantly, both in vitro and in vivo FHC upregulation was accompanied by loss of mature dendritic spines, which was also dependent on mu OR and Gcti-protein signaling. Moreover, morphine upregulated ferritin light chain (FLC), a component of the ferritin iron storage complex, suggesting that morphine altered neuronal iron metabolism. Indeed, prior to FHC upregulation, morphine increased cytoplasmic labile iron levels as a function of decreased endolysosomal iron. In line with this, chelation of endolysosomal iron (but not extracellular iron) blocked morphine-induced FHC upregulation and dendritic spine reduction, whereas iron overloading mimicked the effect of morphine on FHC and dendritic spines. Overall, these data demonstrate that iron mediates morphine-induced FHC upregulation and consequent dendritic spine deficits and implicate endolysosomal iron efflux to the cytoplasm in these effects.
- Morphine-Induced Modulation of Endolysosomal Iron Mediates Upregulation of Ferritin Heavy Chain in Cortical Neurons
- Bradley Nash - Drexel University, Pharmacology and PhysiologyKevin Tarn - Drexel Univ, Coll Med, Dept Pharmacol & Physiol, 245 North 15th St, Philadelphia, PA 19102 USAElena Irollo - Drexel University, Pharmacology and PhysiologyJared Luchetta - Drexel Univ, Coll Med, Dept Pharmacol & Physiol, 245 North 15th St, Philadelphia, PA 19102 USALindsay Festa - Drexel Univ, Coll Med, Dept Pharmacol & Physiol, 245 North 15th St, Philadelphia, PA 19102 USAPeter Halcrow - University of North DakotaGaurav Datta - Univ North Dakota, Dept Biomed Sci, Sch Med & Hlth Sci, 1301 N Columbia Rd, Grand Forks, ND 58203 USAJonathan D. Geiger - University of North DakotaOlimpia Meucci - Drexel University, Pharmacology and Physiology
- eNeuro, v 6(4), 0237
- Society for Neuroscience
- R37DA015014 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission U54GM115458 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01NS065957 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) DA15014; DA32444; DA040519; MH100972; MH105329; NS065957 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01MH100972 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
- Journal article
- English
- Pharmacology and Physiology
- WOS:000483309700043
- 2-s2.0-85070851753
- 991014877875004721
research.portal.fulldisplay.incitesHighlights.intro
- esploro.research.conf.research.portal.label.prefix.inciteCollaboration
- research.portal.fulldisplay.incitesHighlights.institutionCollaboration
- esploro.research.conf.research.portal.label.prefix.inciteWOSResearchAreas
- Neurosciences