Chronic restraint stress and social transfer of stress produce tactile allodynia mediated by the HMGB1/TNF/TNFR1 pathway in female and male rats

Previous studies have shown the relevance of high mobility group box 1 protein (HMGB1) and tumor necrosis factor alpha (TNF alpha) in nerve or tissue injury-induced nociception. However, the role of these proteins in chronic stress and social transfer of stress (STS)-induced dysfunctional pain is not entirely known. The aim of this study was to determine the participation of the spinal HMGB1-TNF alpha signaling pathway and TNF alpha receptor 1 (TNFR1) in rats subjected to chronic restraint stress (CRS) and STS. Non-stressed female and male rats in contact with CRS rats increased sniffing behavior of the anogenital area, behavior related to STS. Rats subjected to CRS and STS reduced 50 % withdrawal threshold and reached the value of tactile allodynia after 21 days of stress. Rats return to the basal withdrawal threshold after 30 days without stress and return to allodynia values in only 5 days of stress sessions (priming). Female and male rats subjected to 28 days of CRS or STS were intrathecal injected with glycyrrhizin (inhibitor of HMGB1), thalidomide (inhibitor of the TNF alpha synthesis), and R7050 (TNFR1 antagonist), in all the cases, an antiallodynic effect was observed. Rats under CRS or STS enhanced HMGB1 and TNFR1 protein expression in DRG and dorsal spinal cord. Data suggest that the spinal HMGB1/TNF alpha/TNFR1 signaling pathway plays a relevant role in the maintenance of CRS and STS-induced nociceptive hypersensitivity in rats. These proteins could be helpful in developing pain treatments for fibromyalgia in humans.