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Transient receptor potential (TRP) channels mRNA transcripts in the lumbar intervertebral discs: biomarkers for inflammation, pain, disability, and clinical outcome

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Abstract

Transient receptor potential (TRP) channels are widely expressed cation channels that play an essential role in mediating Ca2+ homeostasis and are considered potential regulators of inflammatory pain. This study investigates the expression of the TRP channel subtypes TRPV1, TRPV4, TRPC6, TRPM2, TRPM8 in lumbar intervertebral disc (IVD) biopsies from patients with chronic low back pain (LBP). We determined the expression of these TRP channel subtypes in the annulus fibrosus (AF) and the nucleus pulposus (NP) from 46 patients with LBP undergoing 1–2 level lumbar fusion surgery for degenerative disc disease. The mRNA transcripts were analyzed using quantitative real-time polymerase chain reaction (RT-qPCR), and the expression levels were compared against visual analog scale (VAS) and oswestry disability index (ODI) scores (0–100) for pain and disability. A significant positive correlation was demonstrated between VAS score and the mRNA expression of TRPV1, TRPC6, TRPM2, TRPM8 in the AF. We also found a significant positive correlation between ODI scores and expression of TRPV1 and TRPM8. Further, there is a significant positive correlation between TNF-α and TRPV1, TRPM2 and TRPM8 expression in the AF, and IL-6 to TRPV1 in the NP. Interestingly, when investigating treatment response via a 12-month postoperative follow-up ODI, we found a significant correlation between only TRPV1 expression at baseline and the follow-up ODI scores, which indicates this marker could predict the effectiveness of surgery. These results strongly suggest an association between pain, inflammatory mediators, and TRP channel expression in lumbar disc biopsies of patients with chronic LBP.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Maher C, Underwood M, Buchbinder R (2017) Non-specific low back pain. Lancet 389(10070):736–747

    Article  Google Scholar 

  2. Leboeuf-Yde C et al (2009) Pain in the lumbar, thoracic or cervical regions: do age and gender matter? a population-based study of 34,902 Danish twins 20–71 years of age. BMC Musculoskelet Disord 10(1):39

    Article  Google Scholar 

  3. Sadowska A et al (2019) Differential regulation of TRP channel gene and protein expression by intervertebral disc degeneration and back pain. Sci Rep 9(1):18889

    Article  CAS  Google Scholar 

  4. Raj PP (2008) Intervertebral disc: anatomy-physiology-pathophysiology-treatment. Pain Pract 8(1):18–44

    Article  Google Scholar 

  5. Wuertz K, Haglund L (2013) Inflammatory mediators in intervertebral disk degeneration and discogenic pain. Global Spine J 3(3):175–184

    Article  Google Scholar 

  6. Risbud MV, Shapiro IM (2014) Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10(1):44–56

    Article  CAS  Google Scholar 

  7. Aripaka SS et al (2021) Low back pain scores correlate with the cytokine mRNA level in lumbar disc biopsies: a study of inflammatory markers in patients undergoing lumbar spinal fusion. Eur Spine J 30(10):2967–2974

    Article  Google Scholar 

  8. Fozzato S et al (2021) TRPV4 and TRPM8 as putative targets for chronic low back pain alleviation. Pflügers Arch Eur J Physiol 473(2):151–165

    Article  CAS  Google Scholar 

  9. Gavenis K et al (2009) Expression of ion channels of the TRP family in articular chondrocytes from osteoarthritic patients: changes between native and in vitro propagated chondrocytes. Mol Cell Biochem 321(1):135–143

    Article  CAS  Google Scholar 

  10. Krupkova O, ZvickFauWuertz-Kozak KJK (2017) The role of transient receptor potential channels in joint diseases. Eur Cell Mater 34:180–201

    Article  CAS  Google Scholar 

  11. Patapoutian A, Tate S, Woolf CJ (2009) Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8(1):55–68

    Article  CAS  Google Scholar 

  12. Wu LJ, Sweet DE, Fau-Clapham Tb, Clapham DE (2010) International union of basic and clinical pharmacology. LXXVI. current progress in the mammalian TRP ion channel family. Pharmacol Rev 62(3):381–404

    Article  CAS  Google Scholar 

  13. Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12(3):218

    Article  CAS  Google Scholar 

  14. Ramirez GA et al (2018) Ion Channels and transporters in inflammation: special focus on TRP channels and TRPC6. Cells 7(7):70

    Article  Google Scholar 

  15. Kameda T et al (2019) Expression and activity of TRPA1 and TRPV1 in the intervertebral disc: association with inflammation and matrix remodeling. Int J Mol Sci 20(7):1767

    Article  CAS  Google Scholar 

  16. Fairbank JCT (2014) Letter to the editor: oswestry disability index. J Neurosurg 20(2):239–242

    Google Scholar 

  17. Karcioglu O et al (2018) A systematic review of the pain scales in adults: which to use? Am J Emerg Med 36(4):707–714

    Article  Google Scholar 

  18. Pfirrmann CW et al (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine 26(17):1873–1878

    Article  CAS  Google Scholar 

  19. Ahmed AS et al (2019) NF-κB-associated pain-related neuropeptide expression in patients with degenerative disc disease. Int J Mol Sci 20(3):658

    Article  CAS  Google Scholar 

  20. Ito K, Creemers L (2013) Mechanisms of intervertebral disk degeneration/injury and pain: a review. Global Spine J 3(3):145–152

    Article  Google Scholar 

  21. Zheng J (2013) Molecular mechanism of TRP channels. Compr Physiol 3(1):221–242

    Article  Google Scholar 

  22. Brederson JD, Kym A, Fau-SzallasiSzallasi PrA (2013) Targeting TRP channels for pain relief. Eur J Pharmacol 716(1–3):61–76

    Article  CAS  Google Scholar 

  23. Yu L et al (2008) The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund’s adjuvant. Mol Pain 4:61–61

    Article  Google Scholar 

  24. Dhaka A et al (2009) TRPV1 is activated by both acidic and basic pH. J Neurosci 29(1):153

    Article  CAS  Google Scholar 

  25. Urban JP, Smith JCT, Fau-Fairbank S, Fairbank JC (2004) Nutrition of the intervertebral disc. Spine 29(23):2700–2709

    Article  Google Scholar 

  26. Gouin O et al (2017) TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 8(9):644–661

    Article  CAS  Google Scholar 

  27. Walter BA et al (2016) Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells. Eur Cell Mater 32:123–136

    Article  CAS  Google Scholar 

  28. Sivan SS, Wachtel E, Roughley P (2014) Structure, function, aging and turnover of aggrecan in the intervertebral disc. Biochim Biophys Acta 1840(10):3181–3189

    Article  CAS  Google Scholar 

  29. Marwaha L et al (2016) TRP channels: potential drug target for neuropathic pain. Inflammopharmacology 24(6):305–317

    Article  CAS  Google Scholar 

  30. Weyer AD, Lehto SG (2017) Development of TRPM8 antagonists to treat chronic pain and migraine. Pharmaceuticals 10(2):37

    Article  Google Scholar 

  31. Fonfria E et al (2004) TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br J Pharmacol 143(1):186–192

    Article  CAS  Google Scholar 

  32. De Caro C, Russo R, Avagliano C, Cristiano C, Calignano A, Aramini A, Bianchini G, Allegretti M, Brandolini L (2018) Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat. Br J Pharmacol 175:1691–1706

    Article  Google Scholar 

  33. Levi-Montalcini R, Angeletti PU (1963) Essential role of the nerve growth factor in the survival and maintenance of dissociated sensory and sympathetic embryonic nerve cells in vitro. Dev Biol 7:653–659

    Article  Google Scholar 

  34. Mantyh PW et al (2011) Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 115(1):189–204

    Article  Google Scholar 

  35. Denk F, Bennett DL, McMahon SB (2017) Nerve growth factor and pain mechanisms. Annu Rev Neurosci 40(1):307–325

    Article  CAS  Google Scholar 

  36. Aloe L et al (1992) Nerve growth factor in the synovial fluid of patients with chronic arthritis. Arthritis Rheum 35(3):351–355

    Article  CAS  Google Scholar 

  37. Freemont AJ et al (2002) Nerve growth factor expression and innervation of the painful intervertebral disc. J Pathol 197(3):286–292

    Article  CAS  Google Scholar 

  38. García-Cosamalón J et al (2010) Intervertebral disc, sensory nerves and neurotrophins: who is who in discogenic pain? J Anat 217(1):1–15

    Article  Google Scholar 

  39. Barker PA et al (2020) Nerve growth factor signaling and its contribution to pain. J Pain Res 13:1223–1241

    Article  CAS  Google Scholar 

  40. Zhang X, Huang PA, Fau-McNaughton J, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24(24):4211–4223

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to Sajjad Ahmad Chughtai for helping with registering the clinical data and the Pfirrmann rating of the MRI scans. The authors also thankful for Emily Beamen for proofreading the manuscript. In addition, the authors gratefully acknowledge the financial support from the Gigtforeningen and Elsass Foundation.

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The authors have not received any direct funding.

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Authors and Affiliations

  1. Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark

    Sanjay S. Aripaka, Louise M. Jørgensen & Jens D. Mikkelsen

  2. Center for Rheumatology and Spine Diseases, Copenhagen Spine Research Unit, Rigshospitalet, Glostrup, Copenhagen, Denmark

    Rachid Bech-Azeddine & Louise M. Jørgensen

  3. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Sanjay S. Aripaka, Rachid Bech-Azeddine, Louise M. Jørgensen & Jens D. Mikkelsen

  4. Institute of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Jens D. Mikkelsen

Authors
  1. Sanjay S. Aripaka
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  2. Rachid Bech-Azeddine
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  3. Louise M. Jørgensen
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  4. Jens D. Mikkelsen
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Contributions

JDM, RBA, and LMJ designed the study, and SSA conducted experiments. SSA and JDM performed the data analysis, and both contributed to data interpretation; SSA wrote the first draft manuscript, and all authors approved the final manuscript.

Corresponding author

Correspondence to Jens D. Mikkelsen.

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Conflict of interest

The authors have declared no conflict of interest.

Ethical approval

The study was approved by the Danish ethics committee (H-17026301). All participants provided written informed consent according to the Declaration of Helsinki.

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Aripaka, S.S., Bech-Azeddine, R., Jørgensen, L.M. et al. Transient receptor potential (TRP) channels mRNA transcripts in the lumbar intervertebral discs: biomarkers for inflammation, pain, disability, and clinical outcome. Mol Cell Biochem 478, 121–130 (2023). https://doi.org/10.1007/s11010-022-04501-5

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  • DOI: https://doi.org/10.1007/s11010-022-04501-5

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