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. 2025 May 15:10.1097/j.pain.0000000000003658.
doi: 10.1097/j.pain.0000000000003658. Online ahead of print.

Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception

Gillian J Bedwell  1 , Luyanduthando Mqadi  1 , Peter Kamerman  2 , Mark R Hutchinson  3   4   5 , Romy Parker  1 , Victoria J Madden  1   6
Affiliations

Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception

Gillian J Bedwell et al. Pain. .

Abstract

Adversity in childhood elevates the risk of persistent pain in adulthood. Neuroimmune interactions are a candidate mechanistic link between childhood adversity and persistent pain. We aimed to clarify whether immune reactivity is associated with provoked differences in nociceptive processing in adults with a range of childhood adversity. Pain-free adults (n = 96; 61 female; median [range] age: 23 [18-65] years old) with a history of mild to severe childhood adversity underwent psychophysical assessments before and after in vivo neural provocation (high-frequency electrical stimulation) and, separately, before and after in vivo immune provocation (influenza vaccine administration). Psychophysical assessments included the surface area of secondary hyperalgesia after neural provocation and change in conditioned pain modulation (test stimulus: pressure pain threshold; conditioning stimulus: cold water immersion) after immune provocation. Immune reactivity was operationalised as interleukin-6 and tumour necrosis factor-α expression after in vitro lipopolysaccharide provocation of whole blood. We hypothesised associations between immune reactivity and (1) childhood adversity, (2) induced secondary hyperalgesia, and (3) vaccine-associated change in conditioned pain modulation. We found that provoked expression of proinflammatory cytokines was not statistically associated with childhood adversity, induced secondary hyperalgesia, or vaccine-associated change in conditioned pain modulation. The current findings from a heterogenous sample cast doubt on 2 prominent ideas: that childhood adversity primes the inflammatory system for hyper-responsiveness in adulthood and that nociceptive reactivity is linked to inflammatory reactivity. This calls for the broader inclusion of heterogeneous samples in fundamental research to investigate the psychoneuroimmunological mechanisms underlying vulnerability to persistent pain.

Trial registration: ClinicalTrials.gov NCT06127693.

Keywords: Childhood adversity; Childhood trauma; Conditioned pain modulation; Cytokines; Hyperalgesia; Immunity; Inflammation; Neuroimmunomodulation; Pain.

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Conflict of interest statement

Conflicts of interest

GJB occasionally receives speakers’ fees for talks on pain and rehabilitation from the South African National Department of Health, PainSA, and the South African Society of Physiotherapy.

LM has no conflicts of interest related to this work.

PK has no conflicts of interest related to this work.

MRH is a director of the not-for-profit organisation Australian Pain Research Solution Alliance, Chair of the Safeguarding Australia through Biotechnology Response and Engagement (SABRE) Alliance, a member of the Prime Minister’s National Science and Technology Council, and a Director of the Australia’s Economic Accelerator Advisory Board.

RP receives speakers’ fees for talks on pain and rehabilitation from the not-for-profit organisation Train Pain Academy and the Haleon and Faircape Group, is a director of Train Pain Academy, and serves as a councillor for the International Association for the Study of Pain.

VJM is an associate director of, and occasionally receives speakers’ fees from, the not-for-profit organisation, Train Pain Academy.

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References

    1. Allison C, Korey L , John Z S, A novel computational technique for the quantification of temporal summation in healthy individuals. Musculoskelet Sci Pract, 2021; 54(1): p. 102400. DOI: 10.1016/j.msksp.2021.102400. - DOI - PubMed
    1. Amene EW, Annor FB, Gilbert LK, McOwen J, Augusto A, Manuel P, Nobah M.T.V.N.g., Massetti GM, Prevalence of adverse childhood experiences in sub-saharan africa: A multicountry analysis of the violence against children and youth surveys (vacs). Child Abuse Negl, 2024; 150: p. 106353. DOI: 10.1016/j.chiabu.2023.106353. - DOI - PMC - PubMed
    1. Baumeister D, Akhtar R, Ciufolini S, Pariante CM , Mondelli V, Childhood trauma and adulthood inflammation: A meta-analysis of peripheral c-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry, 2016; 21(5): p. 642–649. DOI: 10.1038/mp.2015.67. - DOI - PMC - PubMed
    1. Bedwell GJ, Louw C, Parker R, van den Broeke E, Vlaeyen JW, Moseley GL , Madden VJ, The influence of a manipulation of threat on experimentally-induced secondary hyperalgesia. PeerJ, 2022; 10: p. e13512. DOI: 10.7717/peerj.13512. - DOI - PMC - PubMed
    1. Bernstein DP, Fink L, Handelsman L , Foote J, Childhood trauma questionnaire. Assessment of family violence: A handbook for researchers and practitioners, 1998.

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