Modulations of NeuroD activity contribute to the differential effects of morphine and fentanyl on dendritic spine stability.
The cellular level of neurogenic differentiation 1 (NeuroD) is modulated differentially by mu-opioid receptor agonists; fentanyl increases NeuroD level by reducing the amount of microRNA-190 (miR-190), an inhibitor of NeuroD expression, whereas morphine does not alter NeuroD level. In the current study, NeuroD activity was demonstrated to be also under agonist-dependent regulation. After 3 d of treatment, morphine and fentanyl decreased the activity of the Ca(2+)/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), which phosphorylates and activates NeuroD. Because NeuroD activity is determined by both the CaMKIIalpha activity and the cellular NeuroD level, the overall NeuroD activity was reduced by morphine, but maintained during fentanyl treatment. The differential effects of agonists on NeuroD activity were further confirmed by measuring the mRNA levels of four NeuroD downstream targets: doublecortin, Notch1, neurogenic differentiation 4, and Roundabout 1. Decreased dendritic spine stability and mu-opioid receptor signaling capability were also observed when NeuroD activity was attenuated by miR-190 overexpression or treatment with KN93, a CaMKIIalpha inhibitor. The decrease could be rescued by NeuroD overexpression, which restored NeuroD activity to the basal level. Furthermore, elevating NeuroD activity attenuated the morphine-induced decrease in dendritic spine stability. Therefore, by regulating NeuroD activity, mu-opioid receptor agonists modulate the stability of dendritic spines.
Zheng
Hui
H
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455-0217, USA. zhenhui2055@hotmail.com
Zeng
Yan
Y
Chu
Ji
J
Kam
Angel YuetFang
AY
Loh
Horace H
HH
Law
Ping-Yee
PY
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D000097905:Roundabout Proteins
D051792:Basic Helix-Loop-Helix Proteins; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D005283:Fentanyl; D049452:Green Fluorescent Proteins; D008869:Microtubule-Associated Proteins; D009020:Morphine; D009294:Narcotics; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011971:Receptors, Immunologic; D017450:Receptors, Opioid, mu; D013449:Sulfonamides; D000097905:Roundabout Proteins; C000714848:Dcx protein, rat; C425780:KN 92; C490555:Neurod1 protein, rat; C497763:Notch1 protein, rat; C485765:Oprm1 protein, rat; C485184:enhanced green fluorescent protein