title: Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via mu receptors.
abstract: BACKGROUND
  Chronic morphine treatment inhibits neural progenitor cell (NPC) progression and negatively effects hippocampal neurogenesis. However, the effect of acute opioid treatment on cell development and its influence on NPC differentiation and proliferation in vitro is unknown. We aim to investigate the effect of a single, short term exposure of morphine on the proliferation, differentiation and apoptosis of NPCs and the mechanism involved.
  
  
  METHODS
  Cell cultures from 14-day mouse embryos were exposed to different concentrations of morphine and its antagonist naloxone for 24 hours and proliferation, differentiation and apoptosis were studied. Proliferating cells were labeled with bromodeoxyuridine (BrdU) and cell fate was studied with immunocytochemistry.
  
  
  RESULTS
  Cells treated with morphine demonstrated decreased BrdU expression with increased morphine concentrations. Analysis of double-labeled cells showed a decrease in cells co-stained for BrdU with nestin and an increase in cells co-stained with BrdU and neuron-specific class III β-tubuline (TUJ1) in a dose dependent manner. Furthermore, a significant increase in caspase-3 activity was observed in the nestin- positive cells. Addition of naloxone to morphine-treated NPCs reversed the anti-proliferative and pro-apoptotic effects of morphine.
  
  
  CONCLUSIONS
  Short term morphine exposure induced inhibition of NPC proliferation and increased active caspase-3 expression in a dose dependent manner. Morphine induces neuronal and glial differentiation and decreases the expression of nestin- positive cells. These effects were reversed with the addition of the opioid antagonist naloxone. Our results demonstrate the effects of short term morphine administration on the proliferation and differentiation of NPCs and imply a mu-receptor mechanism in the regulation of NPC survival.
authors: Department of Anesthesia and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Dafna
authors: D
authors: Willner
authors: Department of Pharmacology, Institute of Drug Research, School of Pharmacy, Hebrew University, Jerusalem, Israel.
authors: Ayelet
authors: A
authors: Cohen-Yeshurun
authors: Department of Anesthesia and Critical Care Medicine, Hadassah -Hebrew University Medical Center, Hebrew University School of Medicine, Jerusalem, Israel.
authors: Alexander
authors: A
authors: Avidan
authors: Department of Anesthesia and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Vladislav
authors: V
authors: Ozersky
authors: Department of Pharmacology, Institute of Drug Research, School of Pharmacy, Hebrew University, Jerusalem, Israel.
authors: Esther
authors: E
authors: Shohami
authors: Department of Neurology, Peritz and Chantal Scheinberg Cerebrovascular Research Laboratory, Hadassah-Hebrew University Medical Center, Hebrew University School of Medicine, Jerusalem, Israel.
authors: Ronen R
authors: RR
authors: Leker
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D064231:Nestin; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D064231:Nestin; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D053148:Caspase 3