Neurod1 modulates opioid antinociceptive tolerance via two distinct mechanisms

Wen Li, Songwei He, Yuye Zhou, Yuan Li, Jianbang Hao, Xingru Zhou, Feng Wang, Yang Zhang, Zhenhua Huang, Zhiyuan Li, Horace H. Loh, Ping Yee Law, Hui Zheng

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Background: The activity of neurogenic differentiation 1 (Neurod1) decreases after morphine administration, which leads toimpairments of the stability of dendritic spines in primary hippocampal neurons, adult neurogenesis in mouse hippocampi, anddrug-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.

Original languageEnglish (US)
Pages (from-to)775-784
Number of pages10
JournalBiological psychiatry
Issue number10
StatePublished - Jan 1 2014



  • Analgesia
  • Learning
  • Neurod1
  • Opioid
  • Tolerance
  • Water maze

Cite this

Li, W., He, S., Zhou, Y., Li, Y., Hao, J., Zhou, X., Wang, F., Zhang, Y., Huang, Z., Li, Z., Loh, H. H., Law, P. Y., & Zheng, H. (2014). Neurod1 modulates opioid antinociceptive tolerance via two distinct mechanisms. Biological psychiatry, 76(10), 775-784.