CHRONIC STRESS AND PAIN IN MAN AND IN ANIMALS

The concomitance of anxio-depressive disorders in over 60% of patients with pain syndromes presents numerous difficulties for clinicians, often faced with a lack of effective treatments. Animal modelisation is vital to identify the underlying mechanisms connecting these disorders. To examine such a complex question in animals, we first had to reproduce anxio-depressive disorders. We therefore used a protocol of social defeat, which has the advantage of recreating a “natural” situation. In rats, it induces anxio-depressive symptoms five days after the last confrontation. A formalin test (typically used to establish an objective pain score) performed five days after the last confrontation, i.e. when anxio-depressive symptoms were present, showed an increase in pain-related behaviours compared to control animals. As all these observations were prevented by a chronic curative treatment with the anxiolytic agent chlordiazepoxide, the observed hyperalgesia could be related to the pathological anxiety state induced in the animals. This protocol was also associated with a transient painful hypersensitivity, estimated by the measurement of mechanical nociceptive thresholds (Von Frey and Randall Selitto tests), and distinct from the hyperalgesia induced by anxiety. The latter type of hyperalgesia is due to a stress-induced spinal neuroinflammation, involving nociception facilitating descendent systems, and is insensitive to anxiolytic treatment. These findings confirmed that increased pain complaints in patients with anxiety or depression disorders do have a biochemical basis, which can be studied in animals.L’existence de troubles anxio-dépressifs chez plus de 60% des patients présentant des symptômes douloureux pose problème aux cliniciens qui restent souvent démunis devant le manque de traitements efficaces. La modélisation chez l’animal est incontournable pour identifier les mécanismes unissant ces affections. Pour aborder une question aussi complexe chez l’animal, il faut pouvoir mimer les troubles anxiodépressifs. Dans ce but, nous avons utilisé un modèle de défaite sociale qui offre l'avantage de reproduire une situation « naturelle ». Il induit chez le rat, cinq jours après la dernière confrontation, des symptômes de type anxio-dépressifs. Une épreuve utilisant le formol comme agent algogène (qui classiquement permet d’établir un score de douleur objectif), imposée cinq jours après la dernière confrontation, c'est-à-dire quand les symptômes anxio-dépressifs sont présents, montre une augmentation des comportements douloureux, reflet de l’expression de la douleur, par comparaison avec les animaux témoins. Comme toutes ces observations sont prévenues par un traitement chronique administré de manière curative avec un anxiolytique, le chlordiazépoxide, l’hyperalgésie observée peut être reliée à l’état « d’anxiété pathologique » de l’animal. Parallèlement, ce protocole induit une hypersensibilité douloureuse transitoire, estimée par la mesure des seuils nociceptifs mécaniques (tests de Von Frey et de Randall Selitto) et distincte de l’hyperalgésie induite par l’anxiété. Cette dernière résulte d’une neuroinflammation spinale induite par le stress, via la mise en jeu des systèmes descendants facilitateurs de la nociception et est insensible au traitement anxiolytique. Ainsi, l’augmentation de la plainte douloureuse décrite chez les patients anxieux ou dépressifs repose effectivement sur des corrélats biochimiques qu’il est possible d’étudier chez l’animal

Etude des relations entre pathologies anxio-dépressives et douleurs (implication des systèmes substancépergiques et cholécystokininergiques)

Afin d étudier les interactions entre les troubles anxio-dépressifs et la douleur, nous avons élaboré un test comportemental associant, chez le rat, un stress social et un test nociceptif. Parallèlement, nous mesurons, par la technique de microdialyse, la libération spontanée de Substance P (SP) et de Cholecystokinine (CCK), deux peptides impliqués dans la dépression et la douleur. Nous avons observé une hyperalgésie induite par l état anxio-dépressif , insensible à la morphine mais réversée par les anxiolytiques. Cet excès de douleur s accompagne d une diminution de la libération de SP dans la Substance Grise Périaqueducale et d une augmentation de CCK dans le cortex frontal, toutes deux prévenues par un traitement avec la morphine ou les benzodiazépines. L association de la morphine et d un antagoniste des récepteurs du CCK pourrait représenter une nouvelle approche thérapeutique pour réduire l excès de douleur observé chez les patients dépressifs.PARIS-BIUP (751062107) / SudocSudocFranceF

De la vulnérabilité à la physiopathologie dépressive chez le rat

Les troubles dépressifs sont des pathologies psychiatriques complexes et d origines très variées, d où l intérêt d en étudier la physiopathologie à l aide de modèles animaux adéquats. Nous avons mis au point et validé au laboratoire un modèle original de dépression reposant sur l application durant 4 semaines d un protocole de défaite sociale (DS). Nous avons ainsi montré que les antagonistes des récepteurs CCK-2 pouvaient constituer une nouvelle piste thérapeutique dans le traitement de la dépression. Des résultats préliminaires laissent également à penser que ce protocole induirait une activation astrocytaire dans l hypothalamus. La majeure partie de cette thèse a reposé sur la mise au point d un modèle original de vulnérabilité aux états dépressifs et sur l étude de ses corrélats biologiques. Un stress chronique intense, la DS, est appliqué pendant 4 jours. Il induit, 5 jours après son terme, des signes anxio-dépressifs marqués. Un mois plus tard, lorsque ces signes ont disparu, un protocole de stress chroniques légers (SCL), qui par lui-même engendre des effets plus modeste, est appliqué pendant 3 semaines. Cinq jours après sa fin, les animaux sont sacrifiés. Deux populations sont identifiées. L'une, non sensibilisée, présente des signes anxio-dépressifs de faible amplitude, équivalents à ceux observés après le SCL seul. L'autre population, sensibilisée par le premier stress, présente un profil de type dépressif, les animaux sont alors qualifiés de répondeurs. Il est possible d identifier ces animaux avant même l application du SCL. Ils se caractérisent par une diminution du BDNF sérique qui reflète une altération de la morphologie de l hippocampe et de l amygdalePARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Low β2 Main Peak Frequency in the Electroencephalogram Signs Vulnerability To Depression.

Objective:After an intense and repeated stress some rats become vulnerable to depression. This state is characterized by persistent low serum BDNF concentration. Our objective was to determine whether electrophysiological markers can sign vulnerability to depression. Methods:Forty-three Sprague Dawley rats were recorded with supradural electrodes above hippocampus and connected to wireless EEG transmitters. Twenty-nine animals experienced four daily social defeats (SD) followed by one month recovery. After SD, 14 rats had persistent low serum BDNF level and were considered as vulnerable (V) while the 15 others were considered as non-vulnerable (NV). EEG signals were analyzed during active waking before SD (Baseline), just after SD (Post-Stress) and 1 month after SD (Recovery).Results:We found that V animals are characterized by higher high θ and α spectral relative powers and lower β2 main peak frequency before SD. These differences are maintained at Post-Stress and Recovery for α spectral relative powers and β2 main peak frequency. Using ROC analysis, we show that low β2 main peak frequency assessed during Baseline is a good predictor of the future state of vulnerability to depression.Conclusion:Given the straightforwardness of EEG recordings, these results open the way to prospective studies in humans aiming to identify population at-risk for depression

Endogenous multidien rhythm of epilepsy in rats.

Recent trials of chronic EEG in humans showed that epilepsy is a cyclical disorder of the brain with rhythms at multiple time-scales: circadian, multi-day (multidien) or even seasonal. Here, we analyzed chronic EEG data (>30 days) in male epileptic rats and unraveled not only circadian but also, slower, multidien rhythms of interictal epileptiform activity with periodicity of about 2-3 and 5-7 days. Importantly, seizures were not uniformly distributed over time, but rather clustered at preferential phases of these underlying rhythms, delineating critical circadian times and multidien phase of heightened seizure risk. Multidien rhythms were not synchronous across animals or with human intervention suggesting an endogenous generator. In epilepsy, across species, unknown factors modulate seizure timing in cyclical patterns over multiple days

The Relationship between Allostasis and Mental Health Patterns in a Pre-Deployment French Military Cohort

(1) Background: While a number of studies among military personnel focus on specific pathologies such as post-traumatic stress disorder (PTSD), anxiety, and depression, they do not address the cumulative impact on mental health of stressors related to the profession. The present study aims to determine the relationship between allostatic load and mental health status in a cohort of fit-for-duty soldiers prior to their deployment to Afghanistan. The aim is to better-define the consequences of stressor adjustment. (2) Methods: A cohort of 290 soldiers was evaluated in a cross-sectional study with respect to psychopathology (PTSD, anxiety, depression), psychological functioning (stress reactivity, psychological suffering), and allostatic profile (urinary cortisol and 8-iso-PGF2α, blood cortisol and BDNF). A hierarchical cluster analysis was used to identify allostatic patterns. (3) Results: Around 10% of the cohort reported high scores for psychopathology, and biological alterations were identified. For the remainder, four allostatic profiles could be identified by their psychological functioning. (4) Conclusions: Both biological and psychological assessments are needed to characterize subthreshold symptomatology among military personnel. The psychological significance of allostatic load should be considered as a way to improve health outcomes

Long-lasting bradypnea induced by repeated social defeat

International audienceRepeated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for four consecutive days. Respiratory rate was recorded under anesthesia six days (D+10) or 26 days (D+30) after social defeat. At D+10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike non-defeated (ND) animals. At D+30, all signs of anxiety had disappeared. However, half of the rats still displayed bradypnea (DL rats, for low respiratory rate indicated by a lower RSA frequency), while those with higher respiratory rate (DH rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT3 receptors reversed bradypnea in all D rats at D+10 and in DL rats at D+30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between D+10 and D+18, while DL rats remained bradypneic until D+30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until D+10, followed by recovery. However, bradypnea may persist in half of the population up until D+30 despite apparent recovery of the anxiety-like state

Author Correction: Tissue damage from neutrophil-induced oxidative stress in COVID-19

International audienc

Low β2 Main Peak Frequency in the Electroencephalogram Signs Vulnerability to Depression

International audienceObjective: After an intense and repeated stress some rats become vulnerable to depression. This state is characterized by persistent low serum BDNF concentration. Our objective was to determine whether electrophysiological markers can sign vulnerability to depression.Methods: Forty-three Sprague Dawley rats were recorded with supradural electrodes above hippocampus and connected to wireless EEG transmitters. Twenty-nine animals experienced four daily social defeats (SD) followed by 1 month recovery. After SD, 14 rats had persistent low serum BDNF level and were considered as vulnerable (V) while the 15 others were considered as non-vulnerable (NV). EEG signals were analyzed during active waking before SD (Baseline), just after SD (Post-Stress) and 1 month after SD (Recovery).Results: We found that V animals are characterized by higher high θ and α spectral relative powers and lower β2 main peak frequency before SD. These differences are maintained at Post-Stress and Recovery for α spectral relative powers and β2 main peak frequency. Using ROC analysis, we show that low β2 main peak frequency assessed during Baseline is a good predictor of the future state of vulnerability to depression.Conclusion: Given the straightforwardness of EEG recordings, these results open the way to prospective studies in humans aiming to identify population at-risk for depression