Background & Aims

Exercise is recognized as an indispensable tool for the management of chronic pain. In this study we investigate the mechanisms of exercise-induced pain relief by analysis of differential gene expression in chronic pain patients undergoing a long-term exercise program. Further, we explore the evidence of the involvement of immune response modulation by performing mouse experiments with a new immunosuppression-induced chronic hyperalgesia model.

Methods

Thirty-two participants with chronic low back pain underwent a 14-week exercise regimen. Blood was collected on week three (T1) and twelve (T2). Analysis of differential gene expression via RNA-sequencing was performed to examine the long-term effects of exercise. Further analyses were done by separating the cohort into two groups: improved or persistent pain, based on a change in pain scores of at least 2 points (on a 0-10 VAS), or lack thereof, between the T1 and T2 sessions.
In parallel, mice received an injection of complete Freund’s adjuvant (CFA) into their hind paw, followed by seven days of dexamethasone (0.5 mg/kg) treatment (immunosuppression). This model has been shown to lead to persistent hyperalgesia [1]. Thirty days after CFA, mice were subjected to 5 weeks of exercise on a running wheel. Mechanical sensitivity was measured at regular intervals using von Frey filaments. Blood samples are collected at relevant timepoints for analysis of inflammatory markers (ELISA).

Results

We identified 101 significantly differentially expressed genes in the improved pain group, while there were zero in the persistent pain group. Pathway analysis revealed differences between the improved and persistent pain groups for inflammatory and cell activation biological pathways: improvers had their inflammatory response pathway downregulated over time, while persisters did not show any significant differences. All the significantly expressed cell type activation pathways were downregulated over time in both groups, but more pathways were downregulated in improvers. Furthermore, macrophage activation was higher in persisters at both T1 and T2. At T2, neutrophil activation pathways were also significantly higher in persisters compared to improvers.
In mice, three weeks of continuous voluntary exercise fully reversed chronic hyperalgesia induced by the CFA + dexamethasone treatment.

Conclusions

Transcriptomics analyses of a cohort of LPB patients undergoing physical exercise indicated that pain improvement in response to exercise is associated with substantial differences in gene expression. Specifically, we found that pain improvement in response to long-term exercise is associated with downregulation of inflammatory pathways over time.
In mice, voluntary exercise reversed chronic hyperalgesia induced by immunosuppression. Ongoing analysis of blood samples collected at relevant points will give insight into exercise effects on pro- and anti-inflammatory mediators overtime.

References

1.Parisien, M., et al., Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Science Translational Medicine, 2022. 14(644): p. eabj9954.

Presenting Author

Lucas Vasconcelos Lima

Poster Authors

Lucas Lima

PT

McGill University

Lead Author

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Ivan Chumakov

Lead Author

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Marc Parisien

McGill University

Lead Author

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Sahel Jahangiri Esfahani

McGill University

Lead Author

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S.J. Thompson

Lead Author

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Jeffrey Mogil

McGill University

Lead Author

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Mathieu Roy

Dept. of Psychology, McGill University, Montreal, Qc., Can., H3A 1G1

Lead Author

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Luda Diatchenko

McGill University

Lead Author

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Topics

  • Genetics