At the clinical research level, ESRs assembled a unique and extensive collection of multi-level phenotyped human cohorts, established through cross-sectional, prospective, and longitudinal studies. These cohorts consist of well-characterized, age- and sex-matched patients diagnosed with chronic pain and/or anxiety/depression. The project harnesses the power of meta-analyses, combining data from diverse cohorts to gain insights into multiple aspects of pain and emotional processing. Six clinicians of the consortium and three ESRs are involved in this phase. By analysing data from operant and respondent learning, pain inhibition, pain sensitivity, emotional responsivity, stress tests, stress coping, cognitive control, quantitative sensory testing, genetic variables, and brain and peripheral correlates, ESRs established robust associations and identify potential biomarkers or risk factors. Using different preclinical models, ESRs provided side-by-side comparisons of different chronic pain conditions in both male and female subjects. These results showed that it possible to model nociceptive symptoms such as mechanical allodynia, hyperalgesia, ongoing pain which are the main symptoms of chronic pain but also the anxiety and depressive-like consequences. ESRs had clearly showed sexual dimorphism for the development of emotional dysfunctions following chronic pain. Besides classical pharmacological and lesion approaches, by combining state of the art techniques including optogenetic, pharmacogenetics, c-fos TRAP and fiberphotometry, ESRs identified the several brain regions implicated in the comorbidity of chronic pain and mood disorders such as prefrontal cortex, especially anterior cingulate cortex, amygdala, nucleus accumbens, dorsal hippocampus, locus coeruleus, hypothalamus, periacqueductal gray and thalamus. Clinical studies using different imaging techniques further confirmed the implication of certain brains areas especially the anterior cingulate cortex.
