Pre-injury subchronic stress confers sex-specific protection against pain-associated symptoms in osteoarthritic mice

Exposure to stress in adulthood alters the manifestation of persistent pain, yet its role in chronic pain vulnerability remains unclear. Here, we report that sub-chronic restraint stress experienced two weeks before unilateral osteoarthritis (OA) induction via intra-articular mono-iodoacetate (MIA) promoted the emergence of a resilient-like phenotype in adult male mice. This was evidenced by decreased MIA-induced mechanical hypersensitivity, improved gait dynamics and lower anxiety-like behaviour. In contrast, stress exposed females exhibited augmented pain-associated symptoms. In males, sub-chronic stress mitigated several MIA-induced molecular changes, including reduced adult hippocampal neurogenesis, increased glucocorticoid receptor levels in the hypothalamic paraventricular nucleus (PVN) and elevated c-Fos expression in deep spinal laminae, periaqueductal gray (PAG) and PVN. RNA sequencing suggested that restraint stress in males primed the spinal cord for an exacerbated GABAergic response post-MIA and pre-empted some pro-nociceptive MIA-induced transcriptional changes. However, the combination of stress and injury disrupted longevity-associated programs and shifted neurons toward a stress-vulnerable state. These findings reveal that prior stress exposure can modulate the long-term pain experience in osteoarthritis, with sexually dimorphic outcomes. Importantly, these results challenge the notion of stress as inherently maladaptive and underscore its potential to foster resilience to chronic pain.