Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Pro-inflammatory signalling is a plausible mechanistic link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically pro-inflammatory cytokines (IL1beta, IL6) is a partial mediator between distress and persistent pain, and that it is associated with the secondary hyperalgesia response to an experimental noxious challenge, in people with suppressed HIV. Study participants were 99 adults (mean (range) age: 43(28-64y/o; 72 females) with either no pain (n=54) or persistent pain (n=45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and also showed an association between distress and the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and the evidence on which our hypotheses were based could reflect masking of an effect by differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. Our sample's combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and represents an opportunity to deepen insight into psychoneuroimmunological interactions related to distress and persistent pain.

VJM, GB, and RP receive payment for lectures on pain and rehabilitation. VJM is an unpaid associate director of the not-for-profit organisation, Train Pain Academy. MRH receives speakers' fees for talks on pain and rehabilitation, 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 is a director of the not-for-profit organisation, Train Pain Academy, and serves as a councillor for the International Association for the Study of Pain. All other authors declare no conflicts of interest related to this work.

NCT04757987

https://bmjopen.bmj.com/content/12/6/e059723

This work was funded by NIH award K43TW011442 to VJM. LM received financial support from a postgraduate scholarship from the University of Cape Town and the National Research Foundation (NRF). GJB was supported by postgraduate scholarships from PainSA, the National Research Foundation (South Africa), and the Oppenheimer Memorial Trust. MRH was supported by an Australian Research Council Future Fellowship (FT180100565). JGP's research work is supported by the EDCTP2 program supported by the European Union (grant number TMA2017SF-1981), National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award number R01AI152183, and NIH Fogarty Career development award - K43TW011178. AS is supported by NIH grants R01HD108253 and R01DK123164. RP is supported by the National Research Foundation of South Africa as a rated researcher. RRE was supported by NIH award K24 NS126570.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Human Research Ethics Committees of the University of Cape Town and City of Cape Town (approvals 764/2019 and 24699) gave ethical approval for this study.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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