Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:134 |
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| Enthalten in: |
The Journal of clinical investigation - 134(2024), 5 vom: 18. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jiang, Changyou [VerfasserIn] |
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| Links: |
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| Themen: |
76I7G6D29C |
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| Anmerkungen: |
Date Completed 04.03.2024 Date Revised 04.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI171995 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367271567 |
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| 500 | |a Date Revised 04.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Addiction | |
| 650 | 4 | |a Mitochondria | |
| 650 | 4 | |a Neurological disorders | |
| 650 | 4 | |a Neuroscience | |
| 650 | 4 | |a Therapeutics | |
| 650 | 7 | |a Opiate Alkaloids |2 NLM | |
| 650 | 7 | |a Morphine |2 NLM | |
| 650 | 7 | |a 76I7G6D29C |2 NLM | |
| 650 | 7 | |a Analgesics, Opioid |2 NLM | |
| 650 | 7 | |a Dopamine |2 NLM | |
| 650 | 7 | |a VTD58H1Z2X |2 NLM | |
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| 700 | 1 | |a Yang, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Le, Qiumin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Feifei |e verfasserin |4 aut | |
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