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 mediating these effects. We showed that RRS induced behavioural despair in the forced swim test, 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 glial and neuro-immune pathways in the dorsal horn of the spinal cord in the RRS + paw incision group compared to paw incision alone, data further confirmed by increased microglial activity and inflammatory gene expression ( iba1 , itgam , il-1β and nlrp3 ). Intrathecal administration of IL-1Ra or MCC950 (an NLRP3 inhibitor) attenuated the RRS-induced increase in pain-related aversion and mechanical hypersensitivity post-surgery. Chronic administration of RU486, a glucocorticoid receptor antagonist, prevented RRS-induced despair-like behaviour but did not alter the effects of RRS on pain-related aversion or mechanical hypersensitivity post-surgery. In contrast, chronic administration of propranolol, a β-adrenergic receptor antagonist and sympathetic nervous system inhibitor, not only prevented the RRS-induced despair-like behaviour but also attenuated 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-IL1β signalling. These data provide further insight into the mechanisms by which chronic stress and mood disorders exacerbate and prolong post-surgical pain.