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Molecular Mechanism of Neuroprotective Effect of Melatonin on Morphine Addiction and Analgesic Tolerance: an Update

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Abstract

Drug addiction is a global health problem and continues to place an enormous financial burden on society. This addiction is characterized by drug dependence sensitization and craving. Morphine has been widely used for pain relief, but chronic administration of morphine causes analgesic tolerance, hyperalgesia, and addiction, all of which limit its clinical usage. Alterations of multiple molecular pathways have been reported to be involved in the development of drug addiction, including mitochondrial dysfunction, excessive oxidative stress and nitric oxide stress, and increased levels of apoptosis, autophagy, and neuroinflammation. Preclinical and clinical studies have shown that the co-administration of melatonin with morphine leads to a reversal of these affected pathways. In addition, murine models have shown that melatonin improves morphine-induced analgesic tolerance and addictive behaviors, such as behavioral sensitization, reward effect, and physical dependence. In this review, we attempt to summarize the recent findings about the beneficial effect and molecular mechanism of melatonin on mitochondrial dysfunction, uncontrolled autophagy, and neuroinflammation in morphine addiction and morphine analgesic tolerance. We propose that melatonin might be a useful supplement in the treatment opiate abuse.

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Abbreviations

3-MA:

3-Methyladenine

ATG5:

Autophagy related 5

ATG7:

Autophagy related 7

ATP:

Adenosine triphosphate

cAMP:

Cyclic adenosine monophosphate

CPP:

Conditioned place preference

CREB:

CAMP response element-binding protein

ERK:

Extracellular signal-regulated kinase

MD-2:

Myeloid differentiation protein 2

MEG3:

Maternally expressed gene 3

mtDNA:

Mitochondrial DNA

NLRP3:

NOD-like receptor protein 3

NMDA:

N-Methyl-d-aspartate

NR1:

NMDA subtype 1

NO:

Nitric oxide

NOS:

Nitric oxide synthase

Per1:

Period 1

Per2:

Period 2

PINK1:

PTEN induced kinase 1

PKC:

Protein kinase C

RACK1:

Receptor for activated C kinase 1

ROS:

Reactive oxygen species

SNC:

Substantia nigra compacta

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

We are grateful to Ian Logan for language editing on the early version of the manuscript.

Funding

The study was supported by the National Natural Science Foundation of China (31671050 and 31900695), the Strategic Priority Research Program (B) of CAS (XDB02020003 to YGY) and the Bureau of Frontier Sciences and Education of CAS (QYZDJ-SSW-SMC005), the Youth Innovation Promotion Association (to LYS) and “Light of West China” Program (中科院西部之光计划) (to LYS) of CAS, and the Applied Basic Research Foundation of Yunnan Province, Yunnan Department of Science and Technology (202001AT070103).

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  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China

    Ling-Yan Su, Qianjin Liu, Lijin Jiao & Yong-Gang Yao

  2. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China

    Ling-Yan Su, Qianjin Liu, Lijin Jiao & Yong-Gang Yao

  3. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China

    Ling-Yan Su, Qianjin Liu, Lijin Jiao & Yong-Gang Yao

  4. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Yong-Gang Yao

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Yong-Gang Yao, Ling-Yan Su, Qianjin Liu, and Lijin Jiao contributed in the conception and design of the work and drafting of the manuscript. All authors reviewed the content and approved the final version for publication.

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Su, LY., Liu, Q., Jiao, L. et al. Molecular Mechanism of Neuroprotective Effect of Melatonin on Morphine Addiction and Analgesic Tolerance: an Update. Mol Neurobiol 58, 4628–4638 (2021). https://doi.org/10.1007/s12035-021-02448-0

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