Skip to main content
SpringerLink
Log in

H2S Alleviates Neuropathic Pain in Mice by Nrf2 Signaling Pathway Activation

  • Research
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Neuropathic pain is a chronic pain caused by direct damage to the peripheral or central nervous system, characterized by hyperalgesia, allodynia, and spontaneous pain. Hydrogen sulfide (H2S) therapy has been applied for neuropathic pain treatment, although the underlying mechanisms remain unknown. In this study, we sought to ascertain whether H2S therapy could alleviate neuropathic pain in a model of chronic constriction injury (CCI) and, if so, the potential mechanism. A CCI model was established in mice through a spinal nerve ligation method. Intrathecal injection of NaHS was used to treat CCI model mice. The thermal paw withdrawal latency (TPWL) and mechanical paw withdrawal threshold (MPWT) were used for pain threshold evaluation in mice. A series of experiments including immunofluorescence, enzyme-linked immunosorbent assay, electrophysiological test, mitochondrial DNA (mtDNA) quantification, measurement of ATP content, demethylase activity, and western blot were performed to investigate the specific mechanism of H2S treatment in neuropathic pain. Mice with CCI exposure exhibited a decrease in MPWT and TPWL, an increase in IL-1β and TNF-α expressions, elevated eEPSP amplitude, an upregulation of mtDNA, and a reduction in ATP production, whereas H2S treatment significantly reversed these changes. Furthermore, CCI exposure induced a remarkable increase in vGlut2- and c-fos-positive as well as vGlut2- and Nrf2-positive cells, an increase in Nrf2 located in the nucleus, and an upregulation of H3K4 methylation, and H2S treatment further enhanced these changes. In addition, ML385, a selective Nrf2 inhibitor, reversed the neuroprotective effects of H2S. H2S treatment mitigates CCI-induced neuropathic pain in mice. This protective mechanism is possibly linked to the activation of the Nrf2 signaling pathway in vGlut2-positive cells.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Availability of Data and Material

Available.

References

  • Baranowsky J, Klose P, Musial F et al (2009) Qualitative systemic review of randomized controlled trials on complementary and alternative medicine treatments in fibromyalgia. Rheumatol Int 30(1):1–21

    Article  PubMed  Google Scholar 

  • Batallé G, Cabarga L, Pol O (2019) The inhibitory effects of slow-releasing hydrogen sulfide donors in the mechanical allodynia, grip strength deficits, and depressive-like behaviors associated with chronic osteoarthritis pain. Antioxidants (Basel) 9(1)

  • Betteridge DJ (2000) What is oxidative stress? Metabolism 49(2 Suppl 1):3–8

    Article  CAS  PubMed  Google Scholar 

  • Caglayan B, Kilic E, Dalay A et al (2019) Allyl isothiocyanate attenuates oxidative stress and inflammation by modulating Nrf2/HO-1 and NF-κB pathways in traumatic brain injury in mice. Mol Biol Rep 46(1):241–250

    Article  CAS  PubMed  Google Scholar 

  • Carrasco C, Naziroǧlu M, Rodríguez AB et al (2018) Neuropathic pain: delving into the oxidative origin and the possible implication of transient receptor potential channels. Front Physiol 9:95

    Article  PubMed  PubMed Central  Google Scholar 

  • Cores Á, Abril S, Michalska P et al (2021) Bisavenathramide analogues as Nrf2 inductors and neuroprotectors in in vitro models of oxidative stress and hyperphosphorylation. Antioxidants (Basel) 10(6)

  • Di Cesare ML, Lucarini E, Micheli L et al (2017) Effects of natural and synthetic isothiocyanate-based H(2)S-releasers against chemotherapy-induced neuropathic pain: role of Kv7 potassium channels. Neuropharmacology 121:49–59

    Article  Google Scholar 

  • Francis N, Rao S, Blanchard C et al (2019) Black sorghum phenolic extract regulates expression of genes associated with oxidative stress and inflammation in human endothelial cells. Molecules 24(18)

  • Gilron I, Baron R, Jensen T (2015) Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc 90(4):532–545

    Article  CAS  PubMed  Google Scholar 

  • Guo X, Kang J, Wang Z et al (2022) Nrf2 Signaling in the oxidative stress response after spinal cord injury. Neuroscience 498:311–324

    Article  CAS  PubMed  Google Scholar 

  • Grace PM, Gaudet AD, Staikopoulos V et al (2016) Nitroxidative signaling mechanisms in pathological pain. Trends Neurosci 39(12):862–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hao P, Liang Z, Piao H et al (2014) Conditioned medium of human adipose-derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP-43 expression. Metab Brain Dis 29(1):193–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue K, Tsuda M (2018) Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19(3):138–152

    Article  CAS  PubMed  Google Scholar 

  • Innamorato NG, Rojo AI, García-Yagüe AJ et al (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181(1):680–689

    Article  CAS  PubMed  Google Scholar 

  • Jaggi AS, Singh N (2011) Role of different brain areas in peripheral nerve injury-induced neuropathic pain. Brain Res 1381:187–201

    Article  CAS  PubMed  Google Scholar 

  • Jensen TS, Finnerup NB (2014) Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol 13(9):924–935

    Article  PubMed  Google Scholar 

  • Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354(6312):572–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji RR, Nackley A, Huh Y et al (2018) Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129(2):343–366

    Article  PubMed  Google Scholar 

  • Ji RR, Xu ZZ, Gao YJ (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 13(7):533–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kida K, Marutani E, Nguyen RK et al (2015) Inhaled hydrogen sulfide prevents neuropathic pain after peripheral nerve injury in mice. Nitric Oxide 46:87–92

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Jang BK, Park JH et al (2020) A novel chalcone derivative as Nrf2 activator attenuates learning and memory impairment in a scopolamine-induced mouse model. Eur J Med Chem 185:111777

    Article  CAS  PubMed  Google Scholar 

  • Kovács C, Pecze M, Tihanyi Á et al (2012) The effect of sulphurous water in patients with osteoarthritis of hand. Double-blind, randomized, controlled follow-up study. Clin Rheumatol 31(10):1437–42

  • Li D, Tian H, Li X et al (2020) Zinc promotes functional recovery after spinal cord injury by activating Nrf2/HO-1 defense pathway and inhibiting inflammation of NLRP3 in nerve cells. Life Sci 245:117351

    Article  CAS  PubMed  Google Scholar 

  • Lucarini E, Micheli L, Martelli A et al (2018) Efficacy of isothiocyanate-based compounds on different forms of persistent pain. J Pain Res 11:2905–2913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michalska P, León R (2020) When it comes to an end: oxidative stress crosstalk with protein aggregation and neuroinflammation induce neurodegeneration. Antioxidants (Basel) 9(8)

  • Meacham K, Shepherd A, Mohapatra DP et al (2017) Neuropathic Pain: central vs. peripheral mechanisms. Curr Pain Headache Rep 21(6):28

  • Paul BD, Snyder SH (2018) Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol 149:101–109

    Article  CAS  PubMed  Google Scholar 

  • Popiolek-Barczyk K, Kolosowska N, Piotrowska A et al (2015) Parthenolide relieves pain and promotes M2 microglia/macrophage polarization in rat model of neuropathy. Neural Plast 2015:676473

    Article  PubMed  PubMed Central  Google Scholar 

  • Predmore BL, Lefer DJ, Gojon G (2012) Hydrogen sulfide in biochemistry and medicine. Antioxid Redox Signal 17(1):119–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qabazard B, Masocha W, Khajah M et al (2020) H(2)S donor GYY4137 ameliorates paclitaxel-induced neuropathic pain in mice. Biomed Pharmacother 127:110210

    Article  CAS  PubMed  Google Scholar 

  • Qiang Z, Yu W (2019) Chemokine CCL7 regulates spinal phosphorylation of GluA1-containing AMPA receptor via interleukin-18 in remifentanil-induced hyperalgesia in rats. Neurosci Lett 711:134440

    Article  CAS  PubMed  Google Scholar 

  • Qin ZF, Hou DY, Fang YQ et al (2012) Interferon-alpha enhances excitatory transmission in substantia gelatinosa neurons of rat spinal cord. NeuroImmunoModulation 19(4):235–240

    Article  PubMed  Google Scholar 

  • Rojewska E, Popiolek-Barczyk K, Jurga AM et al (2014) Involvement of pro- and antinociceptive factors in minocycline analgesia in rat neuropathic pain model. J Neuroimmunol 277(1–2):57–66

    Article  CAS  PubMed  Google Scholar 

  • Rojo AI, Innamorato NG, Martín-Moreno AM et al (2010) Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia 58(5):588–598

    Article  PubMed  Google Scholar 

  • Sajadimajd S, Khazaei M (2018) Oxidative stress and cancer: the role of Nrf2. Curr Cancer Drug Targets 18(6):538–557

    Article  CAS  PubMed  Google Scholar 

  • Shim HS, Bae C, Wang J et al (2019) Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain. Mol Pain 15:1744806919840098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snezhkina AV, Kudryavtseva AV, Kardymon OL et al (2019) ROS generation and antioxidant defense systems in normal and malignant cells. Oxid Med Cell Longev 2019:6175804

    Article  PubMed  PubMed Central  Google Scholar 

  • Tozaki-Saitoh H, Masuda J, Kawada R et al (2019) Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. Glia 67(4):729–740

    Article  PubMed  Google Scholar 

  • Verhagen AP, Bierma-Zeinstra SM, Boers M et al (2007) Balneotherapy for osteoarthritis. Cochrane Database Syst Rev (4):Cd006864

  • Wang C, Xu R, Wang X et al (2020) Spinal CCL1/CCR8 regulates phosphorylation of GluA1-containing AMPA receptor in postoperative pain after tibial fracture and orthopedic surgery in mice. Neurosci Res 154:20–26

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Zhao W, Shen X et al (2019) The role of P2Y6 receptors in the maintenance of neuropathic pain and its improvement of oxidative stress in rats. J Cell Biochem 120(10):17123–17130

    Article  CAS  PubMed  Google Scholar 

  • Wang YW, Zhang X, Chen CL et al (2017) Protective effects of Garcinol against neuropathic pain - evidence from in vivo and in vitro studies. Neurosci Lett 647:85–90

    Article  CAS  PubMed  Google Scholar 

  • Xu C, Xu W, Xu H et al (2012) Role of puerarin in the signalling of neuropathic pain mediated by P2X3 receptor of dorsal root ganglion neurons. Brain Res Bull 87(1):37–43

    Article  CAS  PubMed  Google Scholar 

  • Xu F, Li T, Zhang B (2009) An improved method for protecting and fixing the lumbar catheters placed in the spinal subarachnoid space of rats. J Neurosci Methods 183(2):114–118

    Article  PubMed  Google Scholar 

  • Yadav R, Weng HR (2017) EZH2 regulates spinal neuroinflammation in rats with neuropathic pain. Neuroscience 349:106–117

    Article  CAS  PubMed  Google Scholar 

  • Zhang B, Wang G, He J et al (2019) Icariin attenuates neuroinflammation and exerts dopamine neuroprotection via an Nrf2-dependent manner. J Neuroinflammation 16(1):92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Li N, Li Z et al (2022) The involvement of caspases in neuroinflammation and neuronal apoptosis in chronic pain and potential therapeutic targets. Front Pharmacol 13:898574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang YK, Huang ZJ, Liu S et al (2013) WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 123(5):2268–2286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Yu Y, Luo X et al (2021) Myocardial ischemia-reperfusion injury: therapeutics from a mitochondria-centric perspective. Cardiology 146(6):781–792

    Article  CAS  PubMed  Google Scholar 

  • Zhou YQ, Liu DQ, Chen SP et al (2020a) Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain. Acta Pharmacol Sin 41(8):1041–1048

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou YL, Yan YM, Li SY et al (2020b) 6-O-angeloylplenolin exerts neuroprotection against lipopolysaccharide-induced neuroinflammation in vitro and in vivo. Acta Pharmacol Sin 41(1):10–21

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedics, The Graduate School, Tianjin University, Tianjin, China

    Jun Wang

  2. Department of Orthopaedics, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China

    Nan Zhang, Hong-Zheng Liu, Jin-Liang Wang, Yong-Bo Zhang & Dong-Dong Su

  3. Department of Orthopaedics, Tianjin Hospital, Tianjin University, Tianjin, China

    Jun Miao

Authors
  1. Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong-Zheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin-Liang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong-Bo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong-Dong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design of the study: Jun Miao. Editing the manuscript: Jun Miao, Jun Wang, Nan Zhang. Statistical analysis: Jun Miao, Jun Wang. Experiment and data collection: Jun Wang, Nan Zhang, Hong-Zheng Liu, Jin-Liang Wang, Yong-Bo Zhang, Dong-Dong Su, Jun Miao. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jun Miao.

Ethics declarations

Ethical Approval

All experimental protocols were approved by the Institutional Animal Care and Use Committee of Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine.

Consent to Participate

Informed consent was obtained from all study participants.

Consent for Publication

All authors have approved for publication.

Conflict of Interest

The authors declare no competing interests.

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 (DOC 69 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Zhang, N., Liu, HZ. et al. H2S Alleviates Neuropathic Pain in Mice by Nrf2 Signaling Pathway Activation. J Mol Neurosci 73, 456–468 (2023). https://doi.org/10.1007/s12031-023-02134-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-023-02134-x

Keywords

Search

Navigation