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Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal
- Source :
- Journal of Clinical Investigation. March 1, 2024, Vol. 134 Issue 5
- Publication Year :
- 2024
-
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.<br />Introduction Prescription opioids, such as morphine, are the most effective clinical analgesics. However, their clinical utility is limited by analgesic tolerance and reinforcing effects (1, 2). Opioids exert potent euphoric [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 5
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.788885258
- Full Text :
- https://doi.org/10.1172/JCI171995