Psychosocial stress is a major risk factor for depression, stress leads to peripheral and central immune activation, immune activation is associated with blunted dopamine (DA) neural function, DA function underlies reward interest, and reduced reward interest is a core symptom of depression. These states might be inter-independent in a complex causal pathway. Whilst animal-model evidence exists for some specific steps in the pathway, there is currently no animal model in which it has been demonstrated that social stress leads to each of these immune, neural and behavioural states. Such a model would provide important existential evidence for the complex pathway and would enable the study of causality and mediating mechanisms at specific steps in the pathway. Therefore, in the present mouse study we investigated for effects of 15-day resident-intruder chronic social stress (CSS) on each of these states. Relative to controls, CSS mice exhibited higher spleen levels of granulocytes, inflammatory monocytes and T helper 17 cells; plasma levels of inducible nitric oxide synthase; and liver expression of genes encoding kynurenine pathway enzymes. CSS led in the ventral tegmental area to higher levels of kynurenine and the microglia markers Iba1 and Cd11b and higher binding activity of DA D1 receptor; and in the nucleus accumbens (NAcc) to higher kynurenine, lower DA turnover and lower c-fos expression. Pharmacological challenge with DA reuptake inhibitor identified attenuation of DA stimulatory effects on locomotor activity and NAcc c-fos expression in CSS mice. In behavioural tests of operant responding for sucrose reward validated as sensitive assays for NAcc DA function, CSS mice exhibited less reward-directed behaviour. Therefore, this mouse study demonstrates that a chronic social stressor leads to changes in each of the immune, neural and behavioural states proposed to mediate between stress and disruption of DA-dependent reward processing. The model can now be applied to investigate causality and, if demonstrated, underlying mechanisms in specific steps of this immune-neural-behavioural pathway, and thereby to identify potential therapeutic targets.

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are joint senior author. *The members of the COVIDsortium investigators and COVIDsortium immune correlates network can be found at the end of the Acknowledgements.

Previous research has established links between chronic pain and impaired cognitive ability, as well as between chronic pain and anxiety, in osteoarthritis. Furthermore, there is evidence linking risk of osteoarthritis to lower educational attainment. However, the inter-play of these factors with key social factors (e.g., social deprivation) at the early stages of osteoarthritis are not understood. Here, we used data from waves 4, 5, 6 and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 971) and selected a subsample of respondents who initially did not report a diagnosis of osteoarthritis until wave 6. We used path models to test how social deprivation, education and anxiety, before diagnosis (waves 4 and 5), affect the relationship between cognitive ability, pain and limitations in activities of daily living following diagnosis (waves 6 and 7). We show that high social deprivation before diagnosis predicts greater limitations in activities of daily living after diagnosis, with this effect partly mediated by impaired cognitive ability. We also find that higher educational attainment before diagnosis may protect against limitations in activities of daily living after diagnosis via better cognitive ability and lower anxiety. Therefore, improving cognitive ability and managing anxiety may mitigate the associations of social deprivation and low educational attainment with limitations in activities of daily living.

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Background Neuropathic pain symptoms and signs of increased pain sensitization in osteoarthritis (OA) patients may explain persistent pain after total joint replacement (TJR). Therefore, identifying genetic markers associated with pain sensitization and neuropathic‐like pain phenotypes could be clinically important in identifying targets for early intervention. Methods We performed a genome‐wide gene‐based association study (GWGAS) using pressure pain detection thresholds (PPTs) from distal pain‐free sites (anterior tibia), a measure of distal sensitization, and from proximal pain‐affected sites (lateral joint line), a measure of local sensitization, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene‐based fixed‐effects meta‐analysis of PPTs and a neuropathic‐like pain phenotype using genome‐wide association study (GWAS) data from KPIC and from an independent cohort of 613 post‐TJR participants, respectively. Results The most significant genes associated with distal and local sensitization were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain‐associated genes—KCNA1, MTOR, ADORA1 and SCN3B—associated with PPT at the anterior tibia and an inflammatory pain gene—PTAFR—associated with PPT at the lateral joint line. Meta‐analysis results of anterior tibia and neuropathic‐like pain phenotypes revealed genes associated with bone morphogenesis, neuro‐inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function. Conclusions Overall, our results suggest that different biological processes might be involved in distal and local sensitization, and common genetic mechanisms might be implicated in distal sensitization and neuropathic‐like pain. Future studies are needed to replicate these findings. Significance To the best of our knowledge, this is the first GWAS for pain sensitization and the first gene‐based meta‐analysis of pain sensitization and neuropathic‐like pain. Higher pain sensitization and neuropathic pain symptoms are associated with persistent pain after surgery hence, identifying genetic biomarkers and molecular pathways associated with these traits is clinically relevant.

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Background/Aims Exercise has shown a promising effect in reducing central sensitisation (CS), but it is unknown which exercise type is the most effective. This review aimed to rank and compare the effectiveness of different exercise interventions on CS in people with or without chronic musculoskeletal pain. This will help to identify the optimal exercise intervention to improve pain by reducing CS for subsequent use in clinical trials. Methods We searched MEDLINE, EMBASE, AMED, CINAHL, SPORTDiscus, CENTRAL, PEdro, SCOPUS, as well as references cited in the selected papers, and grey literature from inception to February 2022. We included randomized controlled trials (RCTs) that assessed the effect of exercise interventions on CS indices in humans. RCTs where a specific effect of exercise could not be determined were excluded. Pairwise and network meta-analyses (frequentist and Bayesian) were conducted using random effects models. Effect sizes were calculated using standardized mean difference (SMD). P-score as well as SUCRA score were used to rank the exercise interventions (from best to worst) in both frequentist and Bayesian approaches, respectively. Results The search returned 93,657 records, of which 143 RCTs (5,362 participants [4890 participants had musculoskeletal pain (122 studies), and 427 were pain free (21 studies)]) were eligible. Firstly, we performed the pairwise meta-analysis to examine the effect of all exercise interventions on all CS outcomes. It showed moderate improvement of CS outcomes (SMD - 0.77, 95% confidence interval (95%CI) -0.89 to -0.65, I2 = 87%, p < 0.01). After that, 80 RCTs were included in the network meta-analysis (NMA) using inactive controls as a common comparator. In terms of efficacy at improving indices of CS, all exercise interventions were more effective than control. Combined strengthening and stretching exercise exhibited the highest probability to be the optimal intervention reducing CS (P-score: 0.8896, SUCRA score: 0.8719, SMD= -2.02, 95%CI: -2.83: -1.20), followed by strengthening, stretching and aerobic combination (P-score: 0.8557, SUCRA score: 0.8517, SMD = -1.92, 95%CI: -2.90: -0.95), and stretching with aerobic exercise (P-score: 0.7794, SUCRA score: 0.7198, SMD = -1.70, 95%CI: -2.79: -0.62). However, differences between these three interventions’ effect sizes were small, and 95% CI were overlapping. Other interventions included, mind body exercise, aerobic plus strengthening exercise, strengthening exercise, stretching exercise, aerobic exercise. Conclusion Our meta-analysis suggested that various exercise interventions are effective in improving CS. Multicomponent exercise tends to be the most effective, but some exercise combinations might be better than others. Strengthening and stretching combination shows the greatest likelihood among other combinations of being the optimal exercise type. These findings might have utility informing future treatment recommendations for people with CS features. However, Further research should be considered to explore cost-effectiveness of different interventions. Disclosure A.A. Abd Elkhabir: None. D.F. McWilliams: Grants/research support; grant support from Pfizer and Eli Lilly. S. Smith: None. W. Chaplin: None. M. Salimian: None. V. Georgopoulos: None. A. Kouraki: None. D.A. Walsh: Consultancies; Since 2015 DAW has undertaken consultancy through the University of Nottingham to AbbVie Ltd, Pfizer Ltd, Eli Lilly and Company, Love Productions,, Reckitt Benckiser Health Limited and GSK (each non-personal, pecuniary). Honoraria; He has contributed to educational materials through the University of Nottingham, supported by Medscape Education, New York,, International Association for the Study of Pain, and Osteoarthritis Research Society International (OARSI), each of which received financial support from commercial and non-commercial entities, (each non-personal, pecuniary).. Member of speakers’ bureau; He has received speaker fees from the Irish Society for Rheumatology (personal pecuniary).. Grants/research support; He has been responsible for research funded by Pfizer, Eli Lilly, UCB Pharma (non-personal, pecuniary). Other; He receives salary from the University of Nottingham, who have received funding for that purpose from Sherwood Forest Hospitals NHS Foundation Trust,, Nottingham University Hospitals NHS Trust and UKRI/Versus Arthritis (personal, pecuniary).