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

Inflammation plays a major role in treating pain

In a recent study published in the journal Translational Medicine SciencesIn this study, researchers explored the mechanisms underlying the transition from acute to chronic low back pain (LBP) by transcriptome-wide analysis of peripheral immune cells from acute LBP patients.

Chronic LBP is the most common chronic pain condition. Current regimens for LBP include drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, which have shown little efficacy. A detailed understanding of the molecular mechanisms that underlie the transition of acute to chronic pain will enable the development of more effective analgesic therapies.

Study: Acute inflammatory response by activating neutrophils protects against the development of chronic pain. Image Credit: RomarioIen / Shutterstock

about studying

In this study, researchers evaluated the relationship between genome-wide transcription and the development of persistent chronic LBP among patients with persistent pain for more than three months from an acute LBP episode.

The peripheral immune cells of 98 LBP patients underwent transcription-level analysis during the acute attack (t0) and during the follow-up visit three months later (t1). Participants were part of the PainOMICs Study.

Pain was assessed among participants using the Numerical Rating Scale (NRS) and the painDETECT questionnaire. Based on the results of the NRS <4 or >4 At the week before t1, participants were categorized as those with resolved pain (the “R” group) and those with persistent pain (the “P” group).

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

Finally, human participants from the UK (UK) Biobank were analyzed to assess the relationship between back pain and the use of anti-inflammatory drugs. The authors hypothesized that drugs that suppress inflammation could interfere with normal healing processes and prolong pain. Medications such as corticosteroids, NSAIDs, and antidepressants were comparatively evaluated to test the hypothesis.

Mechanical pain sensitivity was assessed before and after several time points after chronic constrictive injury (CCI) of the sciatic nerve, inflammatory injury using Freund’s adjuvant injection (CFA), and injection of nerve growth factor (NGF) into the lower back muscles.

When analyzing the genes of people with low back pain, we observed active changes in the genes over time in people whose pain was gone. Changes in blood cell activity and activity seem to be the most important factor, particularly in cells called neutrophils,” says Luda Diachenko, MD, professor in the School of Medicine, College of Dentistry, and Canada Chair for Research Excellence in Human Pain Genetics.

consequences

At t0, no differentially expressed genes expressed by P and R group patients obtained statistical significance at the genome level. In stark contrast, at T1, more than 5,500 genes were differentially expressed among group R patients while no differentially expressed genes were detected among group P patients. This indicates that group R patients have abundant active biological processes essential for recovery and that these The processes were driven in part by changes in the composition of blood cells.

Moreover, in blood cell composition or cell type analysis, no changes were detected among group P patients while group R patients showed a significant decrease in neutrophil and mast cell counts with a concomitant increase in CD8+ T cells and natural killer (NK) cells. Among the changes in blood cell composition, the decrease in neutrophil count was the most pronounced change accompanied by a decrease in neutrophil-specific genes. The neutrophil-related changes were driven by the activation of neutrophils through degranulation and the generation of acute inflammatory responses among group R patients. It is noteworthy that both groups showed biological alterations. However, the magnitude of the immune response was significantly higher among group R patients. Similarly, higher inflammatory responses were observed among TMD patients in group R compared to group P, with Fast Gene Set Enrichment Analysis (FSGEA) scores +0.32 and -0.32, respectively.

In pain examinations, treatment with NSAIDs (diclofenac) or corticosteroids (dexamethasone) prolonged pain although showing short-term analgesic effects. However, these effects were not observed with other analgesics. Upon neutrophil depletion, delayed pain resolution was observed in mice. Conversely, injections of neutrophil-edited or S100A8/A9 protein inhibited the development of dexamethasone-induced long-term pain.

When analyzing the pain pathways of the UK Biobank group, a (1.76-fold) increased risk of persistent pain was observed among patients who reported NSAID use. The percentage of neutrophils in the acute pain phase was inversely proportional to the probability of developing chronic back pain later in life (odds ratio = 0.98), confirming the protective effects of neutrophil activation in preventing the transition from acute to chronic pain.

Conclusion

In general, the results of the study showed that the transient upregulation of inflammatory responses in the acute phase of musculoskeletal pain caused by neutropenia prevents the development of chronic pain.

Our findings suggest that it is time to reconsider the way we treat acute pain. “Fortunately, the pain can be eliminated by other methods that do not involve interfering with inflammation,” says Massimo Allegri, MD, a physician at the Policlinico of Monza Hospital in Italy and Ensemble Hospital de la Côte in Switzerland. “We discovered that the resolution of pain is actually an active biological process,” says Professor Dyachenko. These findings should be followed up by clinical trials that directly compare anti-inflammatory drugs with other pain relievers that relieve aches and pains but do not disrupt inflammation.”

Journal reference:

  • Acute inflammatory response by activating neutrophils 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 G.S. Dutra2, Teodora Markova2, Hong Dang6, Philippe A. Tessier7, Gary D. Slade8, Andrea G. Nackley9, Nader Ghasemlou5, Jeffrey S. Mogil2*, Massimo Allegri10, 11*, Luda Diatchenko1*. Sciences. Translation. Med. 14, eabj9954 (2022), DOI: 10.1126/scitranslmed.abj9954, https://www.science.org/doi/10.1126/scitranslmed.abj9954

2022-05-17 06:44:00

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