Study: Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Image Credit: RomarioIen / Shutterstock

Inflammation plays a key role in pain resolution

In a recent study published in the journal Science Translational Medicineresearchers explored the mechanisms underlying the transition from acute to chronic low back pain through transcriptome-wide analysis of peripheral immune cells from acute low back pain patients.

Chronic low back pain is the most commonly reported chronic pain. Existing treatment regimens for low back pain include drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, which have been shown to efficiency. A detailed understanding of the molecular mechanisms underlying the transition from acute to chronic pain would allow the development of more effective analgesic therapeutics.

Study: Acute inflammatory response via neutrophil activation protects against development of chronic pain. Image Credit: RomarioIen/Shutterstock

About the study

In the present study, researchers assessed the association between genome-wide transcriptomics and the development of persistent chronic low back pain in patients with pain persisting beyond three months of an acute episode of low back pain. .

Peripheral immune cells from 98 LBP patients were subjected to whole-transcriptome analysis during the acute episode (t0) and at the follow-up visit three months later (t1). The participants were part of the PainOMICS study.

Pain was assessed among participants using a numerical rating scale (NRS) and the painDETECT questionnaire. Based on NRS scores <4 ou> 4 in the week prior to t1, participants were categorized as those with resolved pain (‘R’ group) and those with persistent pain (‘P’ group).

Then, alterations in cell populations were assessed and genes associated with these alterations were enlisted using the CIBERSORT gene expression input matrix. Additionally, changes in the biological pathways underlying the alterations were determined. Rodent pain models have been used to elucidate the mechanisms involved in the transition from acute pain to chronic pain. The results were compared to those of patients with temporomandibular joint disorders (TMD).

Finally, human participants from the United Kingdom (UK) Biobank were analyzed to assess the association between back pain and the use of anti-inflammatories. The authors hypothesized that drugs that inhibit inflammation could interfere with natural recovery processes and prolong pain. Medications such as corticosteroids, NSAIDs, and antidepressants were evaluated comparatively to test the hypothesis.

Mechanical pain sensitivity was assessed before and at multiple time points after chronic constriction injury (CCI) of the sciatic nerve, inflammatory injury using complete injections of Freund’s adjuvant (CFA) and factor nerve growth (NGF) in the muscles of the lower back.

“By analyzing the genes of people with lower back pain, we observed active changes in genes over time in people whose pain disappeared. Changes in blood cells and their activity seemed to be the most important factor, especially in cells called neutrophils,” says Luda Diatchenko, professor at the Faculty of Medicine, Faculty of Dentistry and holder of the Chair of Excellence in Canada’s research in the genetics of human pain.

Results

At t0, no differential gene expressed by patients in the P and R groups reached genome-wide statistical significance. In stark contrast, at t1, more than 5500 genes were differentially expressed in group R patients whereas no differentially expressed genes were detected in group P patients. group R had abundant active biological processes underlying recovery and that the processes were partially driven by changes in blood cell composition.

Moreover, in blood cell composition or cell type analysis, no changes were detected in patients in group P, while patients in group R demonstrated a significant decrease in the number of neutrophils and mast cells with a concomitant increase in CD8+. T cells and natural killer (NK) cells. Of the changes in blood cell composition, the reduction in neutrophil count was the most notable change, along with a decrease in neutrophil-specific genes. The neutrophil-associated changes were driven by neutrophil activation through degranulation and generation of acute inflammatory responses in group R patients. It should be noted that both groups demonstrated the biological alterations; however, the magnitude of the immune response was much higher in patients in group R. Similarly, higher inflammatory responses were noted in TMD patients in group R compared to group P, with analysis scores rapid gene set enrichment (FSGEA) of +0.32 and -0.32, respectively.

In pain tests, treatment with NSAIDs (diclofenac) or corticosteroids (dexamethasone) prolonged pain despite demonstrating short-term analgesic effects, however, such effects were not observed with other analgesics. Upon neutrophil depletion, delayed resolution of pain was observed in mice. Conversely, injections of neutrophils or neutrophil-released S100A8/A9 proteins prevented the development of long-term dexamethasone-induced pain.

When analyzing the pain trajectories of the UK Biobank cohort, an increased risk (1.76 times higher) of pain persistence was observed in patients who reported having used NSAIDs. The percentage of neutrophils in the acute pain stage was inversely proportional to the likelihood of developing chronic low back pain later in life (odds ratio = 0.98), highlighting the protective effects of neutrophil activation in preventing low back pain. transition from acute pain to chronic pain.

Conclusion

Overall, the study results showed that transient upregulation of inflammatory responses in the acute stage of neutrophil-induced musculoskeletal pain prevented the development of chronic pain.

“Our findings suggest that it may be time to reconsider how we treat acute pain. Fortunately, pain can be killed in other ways that don’t involve interfering with inflammation,” says Massimo Allegri, a physician at the Monza Hospital Policlinico in Italy and at the Ensemble Hospitalier de la Côte in Switzerland.”We have discovered that the resolution of pain is in fact an active biological process”, says Professor Diatchenko These results should be followed by clinical trials directly comparing anti-inflammatories to other pain relievers that relieve pain but do not disrupt inflammation.

Journal reference:

  • The acute inflammatory response via neutrophil activation protects against the development of chronic pain. Marc Parisien1 †, Lucas V. Lima2 †, Concetta Dagostino3 †, Nehme El-Hachem1, Gillian L. Drury1, Audrey V. Grant1, Jonathan Huising4, Vivek Verma1, Carolina B. Meloto1, Jaqueline R. Silva5, Gabrielle GS Dutra2, Teodora Markova2, Hong Dang6, Philippe A. Tessier7, Gary D. Slade8, Andrea G. Nackley9, Nader Ghasemlou5, Jeffrey S. Mogil2*, Massimo Allegri10,11*, Luda Diatchenko1*. Science. Transl. Med. 14, eabj9954 (2022), DOI: 10.1126/scitranslmed.abj9954, https://www.science.org/doi/10.1126/scitranslmed.abj9954

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