Skip to main content
SpringerLink
Log in

S-ketamine promotes autophagy and alleviates neuropathic pain by inhibiting PI3K/Akt/mTOR signaling pathway

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

Neuropathic pain results from a lesion or disease of somatosensory system that causes pain, numbness, and weakness in human body. S-ketamine has anesthetic and analgesic potency and has been available for the treatment of chronic cancer pain, postoperative, and neuropathic pain. However, the protective mechanism of S-ketamine in neuropathic pain is not fully illustrated.

Objective

To investigate the protective mechanism of S-ketamine in neuropathic pain.

Results

Chronic constriction injury (CCI) caused the upregulation of Paw withdrawal threshold (PWT) and Thermal withdrawal latency (TWL), the induction in the expression of proinflammatory cytokines (IL-6, IL-1β, and TNF-α), and the accumulation of p62. S-ketamine administration significantly relieved the mechanical and thermal hyperalgesia and inflammatory reaction induced by CCI. In addition, S-ketamine increased the expressions of LC3II/LC3I and Beclin1, while decreased p62 expression in a concentration-dependent manner, indicating that S-ketamine promoted autophagy in the rat’s spinal cord after CCI treatment. Furthermore, CCI-caused upregulation in the expressions of p-PI3K, p-Akt and p-mTOR were reversed by S-ketamine administration.

Conclusion

S-ketamine could induce autophagy to alleviate neuropathic pain by inhibition of the PI3K/Akt/mTOR pathway. These findings facilitate understating on the molecular mechanism underlying the protective effects of S-ketamine on neuropathic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Andrade C (2017) Ketamine for depression, 3: does chirality matter? J Clin Psychiatry 78:e674–e677

    Article  PubMed  Google Scholar 

  • Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107

    Article  PubMed  Google Scholar 

  • Berliocchi L et al (2015) Spinal autophagy is differently modulated in distinct mouse models of neuropathic pain. Mol Pain 11:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang Y et al (2017) Ketamine, a Clinically Used Anesthetic, Inhibits Vascular Smooth Muscle Cell Proliferation via PP2A-Activated PI3K/Akt/ERK Inhibition. Int J Mol Sci 18:2545

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  CAS  PubMed  Google Scholar 

  • Colloca L et al (2017) Neuropathic pain. Nat Rev Dis Primers 3:17002

    Article  PubMed  PubMed Central  Google Scholar 

  • Falk E et al (2020) A rapid positive influence of S-ketamine on the anxiety of patients in palliative care: a retrospective pilot study. BMC Palliat Care 19:1

    Article  PubMed  PubMed Central  Google Scholar 

  • Fan JC, Song JJ, Wang Y, Chen Y, Hong DX (2017) Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson’s disease. Asian Pac J Trop Med 10:1007–1010

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb RA, Andres AM, Sin J, Taylor DP (2015) Untangling autophagy measurements: all fluxed up. Circ Res 116:504–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo JS et al (2015) Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury. Neurosci Lett 599:158–163

    Article  CAS  PubMed  Google Scholar 

  • Guo X, Cheng L, Yang S, Che H (2020) Pro-inflammatory immunological effects of adipose tissue and risk of food allergy in obesity: focus on immunological mechanisms. Allergol Immunopathol 48:306–312

    Article  CAS  Google Scholar 

  • Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J (2014) The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 26:2694–2701

    Article  CAS  PubMed  Google Scholar 

  • Kim SY et al (2021) Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells. Arch Biochem Biophys 697:108688

    Article  CAS  PubMed  Google Scholar 

  • Komatsu M et al (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12:213–223

    Article  CAS  PubMed  Google Scholar 

  • Li J et al (2021) Combination of autophagy and NFE2L2/NRF2 activation as a treatment approach for neuropathic pain. Autophagy. https://doi.org/10.1080/15548627.2021.1900498

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu WJ et al (2016) p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell Mol Biol Lett 21:29

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu X, Zhu M, Ju Y, Li A, Sun X (2019a) Autophagy dysfunction in neuropathic pain. Neuropeptides 75:41–48

    Article  CAS  PubMed  Google Scholar 

  • Liu YD, Wang ZB, Han G, Jin L, Zhao P (2019b) Hyperbaric oxygen relieves neuropathic pain through AKT/TSC2/mTOR pathway activity to induce autophagy. J Pain Res 12:443–451

    Article  PubMed  PubMed Central  Google Scholar 

  • Meng XL et al (2020) Increased EZH2 levels in anterior cingulate cortex microglia aggravate neuropathic pain by inhibiting autophagy following brachial plexus avulsion in rats. Neurosci Bull 36:793–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mion G, Villevieille T (2013) Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther 19:370–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741

    Article  CAS  PubMed  Google Scholar 

  • Moscat J, Diaz-Meco MT (2009) p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 137:1001–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen RV, Fomsgaard JS, Nikolajsen L, Dahl JB, Mathiesen O (2019) Intraoperative S-ketamine for the reduction of opioid consumption and pain one year after spine surgery: a randomized clinical trial of opioid-dependent patients. Eur J Pain (lond, Engl) 23:455–460

    Article  CAS  Google Scholar 

  • O’Connor AB, Dworkin RH (2009) Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 122:S22-32

    Article  PubMed  Google Scholar 

  • Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD (2020) Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (vienna, Austria: 1996) 127:589–624

    Article  Google Scholar 

  • Silva RL, Lopes AH, Guimarães RM, Cunha TM (2017) CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization. Neurobiol Dis 105:109–116

    Article  CAS  PubMed  Google Scholar 

  • Sommer C, Leinders M, Üçeyler N (2018) Inflammation in the pathophysiology of neuropathic pain. Pain 159:595–602

    Article  CAS  PubMed  Google Scholar 

  • Tang C, Livingston MJ, Liu Z, Dong Z (2020) Autophagy in kidney homeostasis and disease. Nat Rev Nephrol 16:489–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trimmel H et al (2018) S(+)-ketamine: current trends in emergency and intensive care medicine. Wien Klin Wochenschr 130:356–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Lin C, Lan L, Liu J (2021) Perioperative intravenous S-ketamine for acute postoperative pain in adults: a systematic review and meta-analysis. J Clin Anesth 68:110071

    Article  CAS  PubMed  Google Scholar 

  • Wu J et al (2018) Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway. Oncol Rep 39:1181–1190

    CAS  PubMed  Google Scholar 

  • Xia H, Green DR, Zou W (2021) Autophagy in tumour immunity and therapy. Nat Rev Cancer 21:281–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiang H et al (2020) Targeting autophagy-related protein kinases for potential therapeutic purpose. Acta Pharm Sin B 10:569–581

    Article  CAS  PubMed  Google Scholar 

  • Xu HD, Qin ZH (2019) Beclin 1, Bcl-2 and autophagy. Adv Exp Med Biol 1206:109–126

    Article  CAS  PubMed  Google Scholar 

  • Xu W et al (2021) S-ketamine alleviates carbon tetrachloride-induced hepatic injury and oxidative stress by targeting the Nrf2/HO-1 signaling pathway. Can J Physiol Pharmacol 99:1308–1315

    Article  PubMed  Google Scholar 

  • Zhao S, Shao L, Wang Y, Meng Q, Yu J (2020) Ketamine exhibits anti-gastric cancer activity via induction of apoptosis and attenuation of PI3K/Akt/mTOR. Arch Med Sci 16:1140–1149

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, People’s Hospital of Deyang City, Deyang, 618000, Sichuan Province, China

    Jia Han, Xianjie Zhang, Leqiang Xia & Ou Liao

  2. Department of Anesthesiology, The Affiliated Zhangjiagang Hospital of Soochow University, No. 68 Jiyang Road, Yangshe Town, Zhangjiagang City, Suzhou City, Jiangsu Province, China

    Qiulan Li

Authors
  1. Jia Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xianjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leqiang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ou Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiulan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JH and XZ designed the experiments and LX carried them out. OL analyzed and interpreted the data, QL prepared the manuscript with contributions from all co-authors.

Corresponding author

Correspondence to Qiulan Li.

Ethics declarations

Conflict of interest

Author Jia Han declares that he/she has no conflict of interest; author Xianjie Zhang declares that he/she has no conflict of interest; author Leqiang Xia declares that he/she has no conflict of interest; author Ou Liao declares that he/she has no conflict of interest; author Qiulan Li declares that he/she has no conflict of interest.

Ethical approval

Ethical approval was obtained from the Ethics Committee of People's Hospital of Deyang City.

Statement of informed consent

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 280 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Han, J., Zhang, X., Xia, L. et al. S-ketamine promotes autophagy and alleviates neuropathic pain by inhibiting PI3K/Akt/mTOR signaling pathway. Mol. Cell. Toxicol. 19, 81–88 (2023). https://doi.org/10.1007/s13273-022-00243-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-022-00243-z

Keywords

Search

Navigation