Wen Li1, Songwei He1, Yuye Zhou1, Yuan Li1, Jianbang Hao1, Xingru Zhou1, Feng Wang2, Yang Zhang3, Zhenhua Huang4, Zhiyuan Li1, Horace H Loh5, Ping-Yee Law5, Hui Zheng6. 1. 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. 2. College of Pharmacy, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University. 3. Department of Laboratory, Guangdong Academy of Medical Science & Guangdong General Hospital. 4. Cancer Center of Nanfang Hospital, Guangzhou, China. 5. Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota. 6. 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.
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.
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.