title: Neurod1 modulates opioid antinociceptive tolerance via two distinct mechanisms.
abstract: BACKGROUND
  The activity of neurogenic differentiation 1 (Neurod1) decreases after morphine administration, which leads to impairments of the stability of dendritic spines in primary hippocampal neurons, adult neurogenesis in mouse hippocampi, and drug-associated contextual memory. The current study examined whether Neurod1 could affect the development of opioid tolerance.
  
  
  METHODS
  Lentivirus encoding Neurod1, microRNA-190 (miR-190), or short hairpin RNA against Neurod1 was injected into mouse hippocampi separately or combined (more than eight mice for each treatment) to modulate NeuroD1 activity. The antinociceptive median effective dose values of morphine and fentanyl were determined with tail-flick assay and used to calculate development of tolerance. Contextual learning and memory were assayed using the Morris water maze.
  
  
  RESULTS
  Decrease in NeuroD1 activity increased the initial antinociceptive median effective dose values of both morphine and fentanyl, which was reversed by restoring NeuroD1 activity. In contrast, decrease in NeuroD1 activity inhibited development of tolerance in a time-dependent manner, paralleling its effects on the acquisition and extinction of contextual memory. In addition, only development of tolerance, but not antinociceptive median effective dose values, was modulated by the expression of miR-190 and Neurod1 driven by Nestin promoter.
  
  
  CONCLUSIONS
  Neurod1 regulates the developments of opioid tolerance via a time-dependent pathway through contextual learning and a short-response pathway through antinociception.
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Songwei
authors.initials: S
authors.lastname: He
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Yuye
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Jianbang
authors.initials: J
authors.lastname: Hao
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Xingru
authors.initials: X
authors.lastname: Zhou
authors.affiliation: College of Pharmacy, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Laboratory, Guangdong Academy of Medical Science & Guangdong General Hospital.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Center of Nanfang Hospital, Guangzhou, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Huang
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. Electronic address: zheng_hui@gibh.ac.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D004361:Drug Tolerance; D005283:Fentanyl / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D055495:Neurogenesis / Q000187:drug effects; D059225:Nociception / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D051792:Basic Helix-Loop-Helix Proteins; D005283:Fentanyl; D009020:Morphine; C501008:Neurod1 protein, mouse
keywords: Analgesia; Neurod1; learning; opioid; tolerance; water maze