Repeated restraint stress-induced increase in post-surgical somatosensory hypersensitivity and affective responding is mediated by β-adrenergic receptor activation and spinal NLRP3-IL1β signalling in male rats

Pre-surgical stress is a well-recognised risk factor for persistent post-surgical pain, and while the precise underlying neurobiological mechanisms remain unknown, neuro-immune interactions are believed to play a pivotal role. Here, we investigated the effect of repeated restraint stress (RRS) on post-surgical somatosensory hypersensitivity and affective responding in male rats and examined underlying mechanisms. We showed that RRS induced behavioural despair, reduced body weight gain and elevated faecal corticosterone levels in male Sprague-Dawley rats. Following paw incision surgery, animals pre-exposed to RRS exhibited exacerbated mechanical and heat hypersensitivity, pain-related aversion, and anxiety-like behaviour compared to non-stress counterparts. RNAseq analysis revealed alterations in expression of glial markers and inflammasome pathways in the dorsal horn of the spinal cord in the RRS + paw incision group, compared to paw incision alone, data further confirmed by immunohistochemistry and RT-qPCR analysis. Intrathecal administration of Interleukin-1 receptor antagonist (IL-1Ra) or MCC950 (an NLRP3 inhibitor) attenuated the RRS-induced increase in pain-related aversion and mechanical hypersensitivity post-surgery. Chronic administration of the β-adrenergic receptor antagonist propranolol, but not the glucocorticoid receptor antagonist RU486, attenuated the RRS-induced exacerbation of mechanical hypersensitivity, pain-related aversion and anxiety-like behaviour post-surgery. These findings suggest that RRS exacerbates and prolongs post-surgical somatosensory and affective pain responding via β-adrenergic receptor activation and increased spinal microglial NLRP3-IL-1β signalling. These data provide further insight into the mechanisms by which chronic stress and mood disorders exacerbate and prolong post-surgical pain.