Glucocorticoid receptor dynamics and neuroinflammation in chronic restraint stress-induced mechanical allodynia in female rats

Abstract

Chronic stress increases pain in humans and rodents. It is associated with microglial activation, inflammatory mediators (like HMGB1, TNFα, and IL-1β) production, and alterations in the hypothalamic-pituitary-adrenal (HPA) axis that increase levels of glucocorticoids. Although glucocorticoids and their receptors are known for their anti-inflammatory properties, recent studies suggest they may also have pro-inflammatory effects. Glucocorticoids stimulate the expression of various proteins like NLRP3, Iba-1, and NF-κB, potentially contributing to neuroinflammatory processes. However, the role of the glucocorticoid receptor (GR) in the neuroinflammatory process and mechanical allodynia induced by chronic stress has not been explored. We used a chronic restraint stress (RS) model to develop mechanical allodynia in female rats and examined the role of GR. The administration of dexamethasone increased mechanical allodynia, but blocking GR with RU-486 reduced stress-induced mechanical allodynia. Additionally, adrenalectomy prevented the development of mechanical allodynia. We observed that the pharmacological response to the GR antagonist changes over time, indicating that GR’s role shifts from antinociceptive to pronociceptive in chronic RS. Furthermore, chronic RS for 21 and 28 days increased total and phosphorylated GR expression at the dorsal spinal cord and dorsal root ganglia. Higher levels of GR were observed in neurons, microglia, and macrophages. Lastly, RS increased NLRP3, caspase-1, and NF-κB protein expression, which are associated with neuroinflammation and may induce pain sensitivity. Our findings suggest that glucocorticoids from the adrenal gland play a critical role in causing sensitivity to touch in female rats. Additionally, GR is essential in establishing chronic stress-induced allodynia in female rats.

Perspective

This paper reports that glucocorticoid receptor (GR) signaling shifts from anti- to pronociceptive in chronic stress, driving mechanical allodynia via neuroinflammation. Dexamethasone enhanced hypersensitivity, while RU-486 and adrenalectomy prevented it. Increased GR and NLRP3 expressions suggest a crucial role for glucocorticoids in stress-induced pain, highlighting GR as a therapeutic target.