Acute and chronic stress differentially regulate pain via distinct ensembles in the paraventricular nucleus of hypothalamus.

Stress impacts pain sensation and its development, but the underlying neural mechanisms are largely unclear. Using restraint stress models and complete Freund's adjuvant-induced pain model in male mice, we demonstrated that acute restraint stress (ARS) induces analgesia in both naïve and pain states. In contrast, chronic restraint stress (CRS) enhances pain hypersensitivity in naïve states, prolongs pain duration, and promotes anxiodepressive symptoms in pain states. Notably, ARS and CRS distinctly activate neuronal ensembles in the paraventricular nucleus of the hypothalamus (PVN). Using the targeted recombination in active populations strategy and chemogenetics, we found that these neuronal ensembles mediate the effects of acute and chronic stress on pain sensation and development. Furthermore, through a two-vector strategy and chemogenetic approach, these neuronal ensembles appear to exert their effects via PVN-locus coeruleus and PVN-lateral septum projections, respectively. Overall, our findings offer novel insights into pain sensation and pain chronification, and may provide effective therapeutic strategies for clinical pain and emotional comorbidities.