Background & Aims

Systemic changes related to inflammation, such as immune cell profiles and the levels of cytokines and chemokines in the blood, have been observed in both patients with various chronic pain conditions (Held M et al., 2019; Jönsson M et al., 2021; Langjahr M et al., 2018; Sandy-Hindmarch O et al., 2022), and in mice following nerve injury (Zhou WBS et al., 2023). However, the lasting effect of systemic inflammation following nerve injury or in chronic pain patients has not been thoroughly investigated. In this study, we aim to understand the systemic changes that are present alongside chronic pain in nerve-injured mice across their entire lifespan.

Methods

The spare nerve injury (SNI) and sham surgeries were performed on 3–4-month-old male and female mice (n=10/group). Mouse pain behavior was monitored every 3 months for 2 years using von Frey and acetone tests. Systemic inflammation following the nerve injury was assessed over the lifespan, with 1) flow cytometry to determine circulating immune cell numbers; 2) Proteome Profiler mouse XL cytokine array to identify changes among 111 selected cytokines and mediators at 1-, 12-, and 20-months post-injury; 3) ELISA to measure serum immunoglobulin levels. To confirm the functional significance of systemic inflammation on pain, serum from 1-month post-SNI male and female mice were transferred intravenously to naïve male and female mice (both same-sex: male-male, female-female, and cross-sex: male-female, female-male). The recipient mice were assessed for mechanical and cold sensitivity following the injection.

Results

SNI induced persistent, stable mechanical and cold allodynia over 2 years in both male and female mice. Flow cytometry revealed age- and sex-dependent changes with a contraction of lymphocytes with age, but only in females. However, the impact of nerve injury on the numbers of circulating immune cells appears minor in both sexes. In male mice, following sham surgery, some inflammatory mediators increased with age, which was strongly enhanced by the nerve injury up to two years. In female mice, some increases on similar molecular targets were also observed in sham and nerve injury groups, although it was much less intense compared to males. IgG2b, IgA, and IgM were found to increase with age in both sexes, but the impact of injury was not significant. Interestingly, serum from nerve injured mice, regardless of sex and whether transferred in a same-sex or cross-sex manner, produced mechanical and cold hypersensitivity in naïve male and female recipient mice.

Conclusions

Systemic inflammation was detected in both male and female mice over age, consisting of both injury-triggered and age-associated components, which displayed in sex-, age-, and injury-specific manner. Although there are differences in the composition of the systemic inflammation between male and female mice, the serum of both sexes is sufficient to induce pain hypersensitivity when transferred to naïve mice.

References

Held M, Karl F, Vlckova E, Rajdova A, Escolano-Lozano F, Stetter C, Bharti R, Förstner KU, et al. (2019), Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion. Pain 160:2316-2327.

Jönsson M, Gerdle B, Ghafouri B, Bäckryd E (2021), The inflammatory profile of cerebrospinal fluid, plasma, and saliva from patients with severe neuropathic pain and healthy controls-a pilot study. BMC Neurosci 22:6.

Langjahr M, Schubert AL, Sommer C, Üçeyler N (2018), Increased pro-inflammatory cytokine gene expression in peripheral blood mononuclear cells of patients with polyneuropathies. J Neurol 265:618-627.

Sandy-Hindmarch O, Bennett DL, Wiberg A, Furniss D, Baskozos G, Schmid AB (2022), Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery. Pain 163:526-537.

Zhou WBS, Shi XQ, Liu Y, Tran SD, Beaudry F, Zhang J (2023), Unbiased proteomic analysis detects painful systemic inflammatory profile in the serum of nerve-injured mice. Pain 164:e77-e90.

Presenting Author

Wen Bo Sam Zhou

Poster Authors

Wen Bo Sam Zhou

BSc

McGill University, Alan Edwards Center for Research on Pain

Lead Author

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Xiang Qun Shi

MSc

Alan Edwards Center for Research on Pain, McGill University

Lead Author

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Alain Zhang

Alan Edwards Center for Research on Pain, McGill University

Lead Author

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Magali Millecamps

PhD

ABC Platform, Alan Edwards Center for Research on Pain, McGill University

Lead Author

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Jeffrey Mogil

McGill University

Lead Author

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Ji Zhang

MD PhD

Alan Edwards Center for Research on Pain, McGill University

Lead Author

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Topics

  • Gender/Sex Differences