Skip to main content

Advertisement

SpringerLink
Log in

Intrathecal Injection of Botulinum Toxin Type A has an Analgesic Effect in Male Rats CCI Model by Inhibiting the Activation of Spinal P2X4R

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Purinergic receptor P2X4 (P2X4R) plays an essential role in neuropathic pain. However, the specific mechanism needs to be clarified. Botulinum toxin type A is a neurotoxin produced by Clostridium botulinum type A. This study found that intrathecal injection of botulinum toxin type A produced an excellent analgesic effect in a rat model of chronic constriction sciatic nerve injury and inhibited the activation of P2X4R, microglia, and astrocytes. The administration of a P2X4R activator can up-regulate the expression of P2X4R and eliminate the analgesic effect of intrathecal injection of botulinum toxin type A. In addition, we found that microglia and astrocytes in the spinal cord of rats injected with botulinum toxin type A were reactivated after administration of the P2X4R activator. Our results suggest that intrathecal injection of botulinum toxin type A has an analgesic effect in a rat model of chronic constriction sciatic nerve injury by inhibiting the activation of P2X4R in the spinal cord.

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

Similar content being viewed by others

Data Availability

Enquiries about data availability should be directed to the authors.

References

  1. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N (2014) Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155:654–662

    Article  PubMed  Google Scholar 

  2. Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lalisse S, Hua J, Lenoir M, Linck N, Rassendren F, Ulmann L (2018) Sensory neuronal P2RX4 receptors controls BDNF signaling in inflammatory pain. Sci Rep 8:964

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K (2009) Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Mol Pain 5:28

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (2008) Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen XM, Xu J, Song JG, Zheng BJ, Wang XR (2015) Electroacupuncture inhibits excessive interferon-γ evoked up-regulation of P2X4 receptor in spinal microglia in a CCI rat model for neuropathic pain. Br J Anaesth 114:150–157

    Article  PubMed  Google Scholar 

  7. Matsumura Y, Yamashita T, Sasaki A, Nakata E, Kohno K, Masuda T, Tozaki-Saitoh H, Imai T, Kuraishi Y, Tsuda M, Inoue K (2016) A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. Sci Rep 6:32461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guo LH, Trautmann K, Schluesener HJ (2005) Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain. J Neuroimmunol 163:120–127

    Article  CAS  PubMed  Google Scholar 

  9. Lee K, Gu S, Jin L, Le TT, Cheng LW, Strotmeier J, Kruel AM, Yao G, Perry K, Rummel A, Jin R (2013) Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog 9:e1003690

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cui M, Khanijou S, Rubino J, Aoki KR (2004) Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 107:125–133

    Article  CAS  PubMed  Google Scholar 

  11. Montecucco C, Molgó J (2005) Botulinal neurotoxins: revival of an old killer. Curr Opin Pharmacol 5:274–279

    Article  CAS  PubMed  Google Scholar 

  12. Zheng H, Huang SL, Chen YY, Tang TC, Qin D, Chen M (2021) Topiramate, acupuncture, and BoNT-A for chronic migraine: a network meta-analysis. Acta Neurol Scand 143:558–568

    Article  CAS  PubMed  Google Scholar 

  13. Park J, Park HJ (2017) Botulinum toxin for the treatment of neuropathic pain. Toxins (Basel) 9:260

    Article  PubMed  Google Scholar 

  14. Park HJ, Lee Y, Lee J, Park C, Moon DE (2006) The effects of botulinum toxin A on mechanical and cold allodynia in a rat model of neuropathic pain. Can J Anaesth 53:470–477

    Article  PubMed  Google Scholar 

  15. Yang H, Wang L, Chu X, Shi X, Li X, Li T (2022) BoNT/A alleviates neuropathic pain in osteoarthritis by down-regulating the expression of P2X4R in spinal microglia. Toxicon 206:55–63

    Article  CAS  PubMed  Google Scholar 

  16. Benoliel R, Tal M, Eliav E (2006) Effects of topiramate on the chronic constriction injury model in the rat. J Pain 7:878–883

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Liu C, Wang L, Liu X, Tan Y, Tao L, Xiao Y, Deng P, Wang H, Deng Q, Lin Y, Jie H, Zhang H, Zhang J, Peng Y, Zhang H, Zhou Z, Sun Q, Cen X, Zhao Y (2021) Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation. Theranostics 11:2966–2986

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li T, Liu H, Cai K, Tian M, Wang Q, Shi J, Gao X, Wang H (2013) Hypersensitive detection and quantitation of BoNT/A by IgY antibody against substrate linear-peptide. PLoS ONE 8:e58908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Price DD (2000) Psychological and neural mechanisms of the affective dimension of pain. Science 288:1769–1772

    Article  CAS  PubMed  Google Scholar 

  21. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thornton PD, Gerke MB, Plenderleith MB (2005) Histochemical localisation of a galactose-containing glycoconjugate expressed by sensory neurones innervating different peripheral tissues in the rat. J Peripher Nerv Syst 10:47–57

    Article  CAS  PubMed  Google Scholar 

  23. Scholz J, Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10:1361–1368

    Article  CAS  PubMed  Google Scholar 

  24. Tanga FY, Nutile-McMenemy N, DeLeo JA (2005) The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 102:5856–5861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Berta T, Qadri YJ, Chen G, Ji RR (2016) Microglial signaling in chronic pain with a special focus on caspase 6, p38 MAP kinase, and sex dependence. J Dent Res 95:1124–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen G, Zhang YQ, Qadri YJ, Serhan CN, Ji RR (2018) Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron 100:1292–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nijs J, Loggia ML, Polli A, Moens M, Huysmans E, Goudman L, Meeus M, Vanderweeën L, Ickmans K, Clauw D (2017) Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients? Expert Opin Ther Targets 21:817–826

    Article  CAS  PubMed  Google Scholar 

  28. Molander C, Grant G (1986) Laminar distribution and somatotopic organization of primary afferent fibers from hindlimb nerves in the dorsal horn. A study by transganglionic transport of horseradish peroxidase in the rat. Neuroscience 19:297–312

    Article  CAS  PubMed  Google Scholar 

  29. Jackson JL, Kuriyama A, Hayashino Y (2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 307:1736–1745

    Article  CAS  PubMed  Google Scholar 

  30. Herd CP, Tomlinson CL, Rick C, Scotton WJ, Edwards J, Ives N, Clarke CE, Sinclair A (2018) Botulinum toxins for the prevention of migraine in adults. Cochrane Database Syst Rev 6:1616

    Google Scholar 

  31. Wheeler A, Smith HS (2013) Botulinum toxins: mechanisms of action, antinociception and clinical applications. Toxicology 306:124–146

    Article  CAS  PubMed  Google Scholar 

  32. Matak I, Lacković Z (2014) Botulinum toxin A, brain and pain. Prog Neurobiol 119–120:39–59

    Article  PubMed  Google Scholar 

  33. He JJ, Wei XM, Wu ML, Song ZB, Jiang L, Zhang WX (2023) Analgesic effect of perineural injection of BoNT/A on neuropathic pain induced by chronic constriction injury of sciatic nerve in rats. Neurochem Res. https://doi.org/10.1038/nrd2605

    Article  PubMed  PubMed Central  Google Scholar 

  34. Burnstock G (2008) Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov 7:575–590

    Article  CAS  PubMed  Google Scholar 

  35. Cheng RD, Ren JJ, Zhang YY, Ye XM (2014) P2X4 receptors expressed on microglial cells in post-ischemic inflammation of brain ischemic injury. Neurochem Int 67:9–13

    Article  CAS  PubMed  Google Scholar 

  36. Zhang WJ, Zhu ZM, Liu ZX (2020) The role of P2X4 receptor in neuropathic pain and its pharmacological properties. Pharmacol Res 158:104875

    Article  CAS  PubMed  Google Scholar 

  37. Ruiz-Rodríguez VM, Cortes-García JD, de Jesús B-E, Rodríguez-Varela E, Vega-Cárdenas M, Gómez-Otero A, García-Hernández MH, Portales-Pérez DP (2019) P2X4 receptor as a modulator in the function of P2X receptor in CD4+ T cells from peripheral blood and adipose tissue. Mol Immunol 112:369–377

    Article  PubMed  Google Scholar 

  38. Xu J, Bernstein AM, Wong A, Lu XH, Khoja S, Yang XW, Davies DL, Micevych P, Sofroniew MV, Khakh BS (2016) P2X4 receptor reporter mice: sparse brain expression and feeding-related presynaptic facilitation in the arcuate nucleus. J Neurosci 36:8902–8920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamakita S, Horii Y, Takemura H, Matsuoka Y, Yamashita A, Yamaguchi Y, Matsuda M, Sawa T, Amaya F (2018) Synergistic activation of ERK1/2 between A-fiber neurons and glial cells in the DRG contributes to pain hypersensitivity after tissue injury. Mol Pain 14:1744806918767508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ghazisaeidi S, Muley MM, Salter MW (2023) Neuropathic pain: mechanisms, sex differences, and potential therapies for a global problem. Annu Rev Pharmacol Toxicol 63:565–583

    Article  PubMed  Google Scholar 

  41. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Salter MW, Mogil JS (2015) Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 18:1081–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Taves S, Berta T, Liu DL, Gan S, Chen G, Kim YH, Van de Ven T, Laufer S, Ji RR (2016) Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord. Brain Behav Immun 55:70–81

    Article  CAS  PubMed  Google Scholar 

  43. Matak I, Bölcskei K, Bach-Rojecky L, Helyes Z (2019) Mechanisms of botulinum toxin type a action on pain. Toxins (Basel) 11:459

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (No. 31960175), Natural Science Foundation of Gansu Province (No. 18JR3RA331), Fund Project of the Cross-cutting projects (No.LK-KY-202300007), Fund Project of the Second Hospital of Lanzhou University (No. CY2017-MS06), and Gansu Province Key R&D Projects (No. 21YF5FA125).

Author information

Author notes

  1. Wen-ming Zhou and Ze-yuan Lei have contributed equally to this work.

Authors and Affiliations

  1. Lanzhou University Second Hospital, 82 Cuiying Men, Lanzhou, 730000, People’s Republic of China

    Wen-ming Zhou, Ze-yuan Lei, Yong-qiang Shi, Chao-yang Gong, Zhang Kai, Nan Wei & Hai-hong Zhang

  2. Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000, People’s Republic of China

    Wen-ming Zhou, Ze-yuan Lei, Yong-qiang Shi, Chao-yang Gong, Zhang Kai & Nan Wei

  3. Lanzhou Biotechnique Development Co., LTD, Lanzhou, 730000, People’s Republic of China

    Lin-na Wang & Cheng-jun Zhang

Authors
  1. Wen-ming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ze-yuan Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-qiang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao-yang Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhang Kai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nan Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin-na Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cheng-jun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hai-hong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have read and approved the manuscript. The corresponding authors, H-HZ and W-MZ, organized, designed and wrote the article. Z-YL, Y-QS, C-YG, KZ, NW, L-NW and C-JZ assisted with manuscript preparation.

Corresponding author

Correspondence to Hai-hong Zhang.

Ethics declarations

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

This study was performed following the Administrative Committee of Experimental Animal Care and Use of Second Hospital of Lanzhou University and was approved by the Second Hospital of Lanzhou University Ethical Committee for Animal Research (D2023-031). The study was in agreement with the Ethical Guidelines of the International Association for the Study of Pain (guidance).

Additional information

Publisher's Note

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

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

Zhou, Wm., Lei, Zy., Shi, Yq. et al. Intrathecal Injection of Botulinum Toxin Type A has an Analgesic Effect in Male Rats CCI Model by Inhibiting the Activation of Spinal P2X4R. Neurochem Res 48, 3099–3112 (2023). https://doi.org/10.1007/s11064-023-03969-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-023-03969-x

Keywords

Search

Navigation