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 12

Mdivi-1 alleviates the development of analgesic tolerance of morphine.

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Mdivi-1 alleviates the development of analgesic tolerance of morphine. (...
(A) The effect of Mdivi-1 on acute analgesia of morphine (10 mg/kg, i.p.) in hotplate assay. The latency of withdrawal to noxious stimulus is shown as the percentage of the maximum possible effect (% MPE). 12–13 mice per group. (B) The effect of Mdivi-1 on analgesic tolerance of chronic morphine (10 mg/kg, once daily) administration for 6 days. Analgesic tolerance was mirrored by the decreased % MPE. 12–15 mice per group, 2-way RM ANOVA with Bonferroni’s test for Morphine (Mor) + vehicle versus Morphine + Mdivi-1 (12.5, 25, 50, 100 mg/kg). (C) The effect of Mdivi-1 on acute analgesia of morphine (10 mg/kg, i.p.) in the tail flick assay. (D) Quantification of the analgesic tolerance of chronic morphine (10 mg/kg, once daily) in mice from Mdivi-1 (50 mg/kg) or vehicle groups. 12 mice/group, 2-way RM ANOVA with Bonferroni’s test in C and D. (E) Respiratory inhibition of morphine assessed by whole-body plethysmography in mice. Respiratory frequency is decreased 15 minutes after morphine injection (10 mg/kg, i.p). 2-way RM ANOVA by Bonferroni’s test, saline versus morphine, 4 mice/group; Morphine + vehicle versus Morphine + Mdivi-1, 8 mice per group. (F) Constipation effects of morphine assessed by accumulated faecal boli in Mdivi-1 or vehicle groups. 10–12 mice per group, 2-way RM ANOVA by Bonferroni’s test for saline + vehicle versus morphine + vehicle or morphine + vehicle versus Morphine + Mdivi-1. Data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.