Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy.
Our findings suggest that morphine dysregulates synaptic balance in the hippocampus, a key center for learning and memory, via a novel signaling pathway involving reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy. We demonstrate in this study that exposure of morphine to hippocampal neurons leads to a reduction in excitatory synapse densities with a concomitant enhancement of inhibitory synapse densities via activation of the μ opioid receptor. Furthermore, these effects of morphine are mediated by up-regulation of intracellular ROS from NADPH oxidase, leading, in turn, to sequential induction of ER stress and autophagy. The detrimental effects of morphine on synaptic densities were shown to be reversed by platelet-derived growth factor (PDGF), a pleiotropic growth factor that has been implicated in neuroprotection. These results identify a novel cellular mechanism involved in morphine-mediated synaptic alterations with implications for therapeutic interventions by PDGF.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
Yu
http://orcid.org/0000-0001-7787-8610
Y
Cai
School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610051, China.
Lu
L
Yang
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
Guoku
http://orcid.org/0000-0002-4792-0416
G
Hu
Department of Emergence, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Xufeng
X
Chen
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
Fang
http://orcid.org/0000-0002-5035-7409
F
Niu
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
Li
http://orcid.org/0000-0001-6551-9872
L
Yuan
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
Han
H
Liu
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
Huangui
http://orcid.org/0000-0003-3450-8876
H
Xiong
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 jyothi.arikkath@unmc.edu sbuch@unmc.edu.|Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198.
Jyothi
J
Arikkath
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 jyothi.arikkath@unmc.edu sbuch@unmc.edu.
Shilpa
http://orcid.org/0000-0002-3103-6685
S
Buch
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000077214:Becaplermin; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009020:Morphine / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D018696:Neuroprotective Agents; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D009020:Morphine