Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway

Jinhong Jiang; Lingfei Xu; Long Yang; Su Liu; Zhe Wang

doi:10.1021/acschemneuro.3c00140

Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway

ACS Chem Neurosci. 2023 Jun 21;14(12):2362-2374. doi: 10.1021/acschemneuro.3c00140. Epub 2023 Jun 7.

Authors

Jinhong Jiang¹, Lingfei Xu¹, Long Yang¹, Su Liu¹, Zhe Wang^{1

2}

Affiliations

¹ Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
² School of Food and Biological Engineering, Xuzhou University of Technology, Xuzhou 221018, China.

PMID: 37285113
DOI: 10.1021/acschemneuro.3c00140

Abstract

MOTS-c, a recently discovered mitochondrial-derived peptide, plays an important role in many physiological and pathological functions via adenosine monophosphate-activated protein kinase (AMPK) activation. Numerous studies have demonstrated that AMPK is an emerging target for the modulation of neuropathic pain. Meanwhile, microglia-activation-evoked neuroinflammation is known to contribute to the development and progression of neuropathic pain. MOTS-c is also known to inhibit microglia activation, chemokine and cytokine expression, and innate immune responses. Accordingly, in this study, we evaluated the effects of MOTS-c on neuropathic pain and investigated the putative underlying mechanisms. We found that MOTS-c levels in plasma and spinal dorsal horn were significantly lower in mice with spared nerve injury (SNI)-induced neuropathic pain than in control animals. Accordingly, MOTS-c treatment produced pronounced dose-dependent antinociceptive effects in SNI mice; however, these effects were blocked by dorsomorphin, an AMPK inhibitor, but not naloxone, a nonselective opioid receptor antagonist. Moreover, intrathecal (i.t.) injection of MOTS-c significantly enhanced AMPKα_1/2 phosphorylation in the lumbar spinal cord of SNI mice. MOTS-c also significantly inhibited proinflammatory cytokine production and microglia activation in the spinal cord. The antinociceptive effects of MOTS-c were retained even when microglia activation in the spinal cord was inhibited by minocycline pretreatment, indicating that spinal cord microglia are dispensable for the antiallodynic effects of MOTS-c. In the spinal dorsal horn, MOTS-c treatment inhibited c-Fos expression and oxidative damage mainly in neurons rather than microglia. Finally, in contrast to morphine, i.t. administration of MOTS-c resulted in limited side effects relating to antinociceptive tolerance, gastrointestinal transit inhibition, locomotor function, and motor coordination. Collectively, the present study is the first to provide evidence that MOTS-c may be a promising therapeutic target for neuropathic pain.

Trial registration: ClinicalTrials.gov NCT03998514.

Keywords: AMPK; MOTS-c; antinociception; c-fos; microglia; neuropathic pain.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Analgesics / pharmacology
Animals
Cytokines / metabolism
Hyperalgesia / metabolism
Mice
Microglia*
Neuralgia* / metabolism
Neurons / metabolism
Oxidative Stress
Spinal Cord
Spinal Cord Dorsal Horn / metabolism

Substances

AMP-Activated Protein Kinases
Cytokines
Analgesics

Associated data

ClinicalTrials.gov/NCT03998514