Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal
Changyou Jiang, … , Lan Ma, Feifei Wang
Changyou Jiang, … , Lan Ma, Feifei Wang
Published January 18, 2024
Citation Information: J Clin Invest. 2024;134(5):e171995. https://doi.org/10.1172/JCI171995.
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Research Article Neuroscience

Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal

Abstract

Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity and dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.

Authors

Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang

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Figure 4

Chronic morphine administration increases the VTA neuronal mitophagy and mitochondrial fragmentation in the VTA dopaminergic Mor-Ens.

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Chronic morphine administration increases the VTA neuronal mitophagy and...
(A) Experimental scheme for fiber photometry to detect mitophagy in Mor-Ens. Representative images show the expression of mt-keima in the VTA neurons. Dashed white lines outline the VTA and fiber optic tract. Scale bar, left: 200 μm; right: 20 μm. (B) Relative mitochondrial autophagy induction (% normalized to baseline) in the VTA neurons after morphine EDA. Paired t test, n = 9. (C) Experimental scheme to analyze mitochondrial morphology in Mor-Ens of mice in saline ctrl and morphine EDA groups. (D) Representative images of dopaminergic Mor-Ens expressing EYFP and mito-tdTomato. ChR2-EYFP was used to label dendrites and mito-tdTomato was used to label mitochondria. The white solid lines indicate primary dendrites and the dashed lines indicate secondary dendrites in each channel. Scale bar: 20 μm. (E and I) Representative images of primary dendrites (E) and secondary dendrites (I) containing labeled mitochondria from saline-ctrl, and withdrawal (WD) mice 1 day and 21 days after morphine EDA. Red, mito-tdTomato; Green, EYFP. Scale bars: 10 μm in E; 5 μm in I. (F–H) Quantification of mitochondrial aspect ratio (F), length (G), and area (H) in primary dendrites of dopaminergic Mor-Ens in saline-ctrl (38 neurons in 6 mice), morphine-EDA WD 1 day (40 neurons in 8 mice), or WD 21 day (40 neurons in 5 mice) groups. (J–L) Quantification of mitochondrial aspect ratio (J), length (K), and area (L) in dopaminergic Mor-Ens in saline-ctrl (36 neurons in 6 mice), morphine-EDA WD 1 day (35 neurons in 8 mice), or WD 21 day (38 neurons in 5 mice) groups. 1-way ANOVA with Bonferroni’s test and Kolmogorov-Smirnov test (F–H and J–L). Data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.