Comorbidity of cHronic Pain and mood disorders: breaking the vicious cYcle

The increasing number of individuals with comorbidities poses an urgent need to improve the management of patients with multiple co-existing diseases. Among these comorbidities, chronic pain and mood disorders, two long-lasting disabling conditions that significantly reduce the quality of life, could be cited first. Chronic pain and neuropsychiatric disorders represent a major threat to Europe both socially and economically and this threat is set to increase with the ageing population. In the European Union, it is estimated that 27% of the population suffers from a mood disorder and 20% from chronic pain during lifespan and that these are the most important risk factors for suicide. Overwhelming evidence suggests that chronic pain and mood disorders do more than co-occur, they also promote the development of each other and have a negative impact on the successful treatment of each condition. To respond to this health and societal emergency, we established a network of academic institutions and non-academic partners to offer early-career researchers (ESRs) a high-quality international training program focused on the co-morbidity of pain and depression. We thus aimed to reach the overall objective of the HaPpY project which is to create an optimal environment for the training of ESRs to break the vicious cycle linking chronic pain and mood disorders. Accordingly, we developed the research project around 3 specific objectives:
Firstly, we aimed to characterize the reciprocal relationship between chronic pain and mood disorders to improve diagnosis. For this purpose, we focused on the behavioral phenotyping of the comorbidity of chronic pain and mood disorders especially anxiety/depression in preclinical models and in patients. Indeed, for the first time, a side by side comparison of several preclinical models of chronic pain and stress/anxiety/depression is performed in different laboratories which provide the development and standardization of models and reinforce the reliability and reproducibility of studies across labs. One of the main reasons why preclinical targets identified in preclinical studies are not transposed into clinical trials is due to the basic nature of many of the preclinical tests, which simply examine helplessness or avoidance behaviors. We have developed new behavioral paradigms to improve the translatability of data. In parallel, clinical research ensures the development of cognitive-emotional tasks, unique to predict and diagnose the comorbidity of chronic pain and mood disorders by comparing behavioral outcomes, imaging datasets, physiological recordings and blood samples from well-characterized cohorts.
Second, we aimed to better understand the underlying molecular, cellular and neuroanatomical mechanisms contributing to the comorbidity in preclinical models and in patients. The ultimate goal is to identify biomarkers for prediction/diagnosis and reveal new treatment strategies.
Third aim is developing new treatment strategies. We adapted two strategies to optimize the use of already existing pharmacological/non-pharmacological treatments and to validate new preclinical targets, and provide novel insight for using brain stimulation facilitate early-stage translation of novel treatment strategies towards the clinic.
Given evidence of sexual dimorphism of both chronic pain and mood disorders, all Individual Research Projects (IRPs) considers sex differences as a cross-cutting objective.

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.

A multi-centre comparison of several preclinical models of chronic pain provided the development and standardisation of these models and reinforced the reliability and reproducibility of studies across labs. During the first year of their projects ESRs developed new, ethologically relevant behavioural paradigms to increase the translatability of data. Given evidence of sexual dimorphism of both chronic pain and mood disorders, all Individual Research Projects (IRPs) considered sex differences. Since ESRs set up the models in different labs and fully characterized by taking into consideration different confounding such as strains, sex, age etc, it is now possible for them: (i)to compare the data across the labs; (ii) to decipher the underlying mechanisms using these models, this is part of WP2 (ongoing). Even though studies focusing on individual brain regions improve our understanding of pathophysiology of this comorbidity challenge, it is also essential to reach circuitry level of understanding. Indeed, most central nervous system disorders are linked to alterations in brain circuits rather than to changes occurring in single structures. Accordingly, ESRs started to identify certain brain circuits.
Future direction will be now:
• To fully compare preclinical and clinical data.
• To reach causal link between these identified alterations and behavioural as well as molecular outcomes.
• To determine potential sex differences (on going).