Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia

Abstract

Chronic stressful events induce biochemical, physiological and psychological changes, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. Using repeated social defeat as a stressful event model, we show that this preclinical paradigm induces a transient increase in the expression of the genes encoding the pro-inflammatory molecules iNOS and COX-2. We provide the first demonstration that chronic stress affects spinal plasticity through a mechanism involving local neuroinflammation. The functional consequences of such neuroinflammation are associated with a transient decrease in the mechanical nociceptive threshold. Administration of the cholecystokinin(CCK)-2 receptor antagonist, CI-988, directly into the Rostral Ventromedial Medulla reverses the chronic stress-induced decrease in the nociceptive threshold. These data strongly suggest that chronic stress induces a spinal neuroinflammation associated with transient sensory hypersensitivity involving the activation of CCK-dependent nociceptive descending facilitatory pathways. Pharmacological data show that chronic social stress-induced long-lasting state of anxiety is not responsible for maintaining the spinal neuroinflammation and, therefore, for the associated sensory hypersensitivity. Conversely, an evaluation of pain-related behavior in the formalin model indicates that anxiety is directly related to prolonged hyperalgesia prevented by systemic benzodiazepine or CCK-2 receptor antagonist treatments. The present study highlights the adverse effects of chronic stress on spinal neuroinflammation triggering sensory hypersensitivity. Exploration of this phenomenon points out the divergence between pain sensitivity and anxiety-induced hyperalgesia, which is in agreement with clinical observations. Altogether, these data open up new perspectives for clinical research devoted to the evaluation and treatment of pain in anxio-depressive patients.