Adversity in childhood is robustly associated with persistent pain in adulthood. Neuro-immune interactions are a candidate mechanistic link between childhood adversity and persistent pain, given that both childhood adversity and persistent pain are associated with neural and immune upregulation in adulthood. As such, we aimed to clarify whether immune reactivity is associated with provoked differences in nociceptive processing in humans. 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 then, separately, 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 assessed as IL-6 and TNF-alpha 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 pro-inflammatory 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 two 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 unpack the psychoneuroimmunological mechanisms underlying vulnerability to persistent pain.

GJB receives speakers' fees for talks on pain and rehabilitation. LM has no conflicts of interest related to this work. PK has no conflicts of interest related to this work. MRH receives speakers' fees for talks on pain and rehabilitation. He is a director of the not-for-profit organisation Australian Pain Research Solution Alliance. He is Chair of the Safeguarding Australia through Biotechnology Response and Engagement (SABRE) Alliance. He is a member of the Prime Minister's National Science and Technology Council. He is also a Director of the Australia's Economic Accelerator Advisory Board. RP receives speakers' fees for talks on pain and rehabilitation. She is a director of the not-for-profit organisation Train Pain Academy. She also serves as a councillor for the International Association for the Study of Pain. VJM receives speakers' fees for talks on pain and rehabilitation. She is also an associate director of the not-for-profit organisation Train Pain Academy.

NCT06127693

GJB was supported by postgraduate scholarships from African Pain Research Initiative (University of Cape Town), PainSA, the National Research Foundation (South Africa), and the Oppenheimer Memorial Trust. LM is supported by a postgraduate scholarship from the University of Cape Town and the National Research Foundation (South Africa). PK has no funding related to this work. MRH is supported by an Australian Research Council Future Fellowship (FT180100565). RP is supported by the National Research Foundation of South Africa as a rated researcher. VJM is supported by the Fogarty International Center of the National Institutes of Health (award K43TW011442).

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The study protocol was approved by the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town (HREC REF: 560/2021).

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