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

Inflammation plays a key role in resolving pain

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

Chronic LBP is the most commonly reported chronic pain condition. Existing therapeutic regimens for LBP include drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, which have minimal effectiveness† A detailed understanding of the molecular mechanisms underlying the transition from acute to chronic pain would allow the development of more effective analgesic therapies.

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

About the study

In the present study, researchers evaluated the association between genome-wide transcriptomics and the development of persistent chronic LBP in patients with pain that persisted for more than three months after an acute LBP episode.

The peripheral immune cells of 98 LBP patients were subjected to transcriptome-wide 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 the NRS scores <4 of >4 in the week before t1, participants were categorized as those with resolved pain (‘R’ group) and those with persistent pain (‘P’ group).

Next, the changes in cell populations were assessed and the genes associated with such changes were included using the CIBERSORT gene expression input matrix. In addition, the changes in biological pathways underlying the changes were determined. Rodent pain models were used to elucidate the mechanisms that mediate the transition from acute to chronic pain. The findings were compared with those in patients with temporomandibular joint disorders (TMDs).

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

Mechanical pain sensitivity was evaluated prior to and at various time points after chronic sciatic nerve compression injury (CCI), inflammatory injury using complete Freund’s adjuvant (CFA), and nerve growth factor (NGF) injections into the lower back muscles.

“When analyzing the genes of people suffering from low back pain, we observed active changes in genes over time in people whose pain went away. Changes in the blood cells and their activity seemed to be the most important factor, especially in cells called neutrophils,” said Luda Diatchenko, professor of medicine, dentistry and Canada Excellence Research Chair in Human Pain Genetics.

Results

At t0, no differentially expressed genes expressed by the P and R group patients reached genome-wide statistical significance. In striking contrast, at t1, more than 5,500 genes were differentially expressed in R group patients, while no differentially expressed genes were detected in P group patients. This indicated that R group patients had abundant active biological processes underlying recovery and the processes were driven in part by changes in blood cell composition.

Furthermore, in the blood cell composition or cell type analysis, no changes were detected in patients from the P group, while patients from the R group showed 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 most striking change associated with a decrease in neutrophil-specific genes was the decrease in neutrophil counts. The neutrophil-associated changes were driven by neutrophil activation by degranulation and the generation of acute inflammatory responses in the R group patients. Note that both groups showed the biological changes; however, the magnitude of the immune response was much higher in the R group patients. Similarly, higher inflammatory responses were noted in the TMD patients in the R group compared to the P group, with Fast Gene Set Enrichment Analysis (FSGEA) scores of +0.32 and -0.32 respectively.

In the 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 depletion of neutrophils, a delayed pain reduction was observed in mice. Conversely, injections of neutrophils or neutrophil-release S100A8/A9 proteins prevented the development of long-term pain induced by dexamethasone.

When analyzing the pain trajectories of the UK Biobank cohort, an increased (1.76-fold higher) risk of persistent pain was observed in patients reporting NSAID use. The percentage of neutrophils in the acute pain phase was inversely related to the likelihood of developing chronic back pain later in life (odds ratio = 0.98), underscoring the protective effects of neutrophil activation in preventing the transition from acute to chronic pain .

Conclusion

Overall, the study results showed that a transient upregulation of inflammatory responses in the acute phase of musculoskeletal pain, driven by neutrophils, prevented the development of chronic pain.

“Our findings suggest it may be time to rethink the way we treat acute pain. Fortunately, pain can be killed in other ways without interfering with inflammation,” said Massimo Allegri, a doctor at Monza Hospital’s outpatient clinic in Italy and the Ensemble Hospitalier de la Cote in Switzerland: “We found that solving pain is actually an active biological process,” said Professor Diatchenko. These findings should be followed by clinical trials directly comparing anti-inflammatory drugs with other painkillers that reduce pain. and relieve pain, but don’t interfere with inflammation.”

Reference magazine:

  • 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 Ed. med. 14, eabj9954 (2022), DOI: 10.1126/scitranslmed.abj9954https://www.science.org/doi/10.1126/scitranslmed.abj9954

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