SOMATIC AND VISCERAL NOCICEPTIVE HYPERSENSITIVITY INVOLVES HMGB1 AND RAGE IN MICE EXPOSED TO REPEATED COLD STRESS, A MODEL FOR FIBROMYALGIA

Fibromyalgia (FM) more prone to women is characterized by widespread musculoskeletal pain, fatigue, and mental dysfunctions. Patients with FM often show a variety of complications such as irritable bowel syndrome (IBS), bladder pain syndrome and migraine. The pathogenesis of FM is still largely open to question, and currently available medications for treatment of FM are not sufficiently effective. We have reported that the extracellular release of high mobility group box 1 (HMGB1), a nuclear protein, and subsequent activation of some membrane receptors of HMGB1 including the receptor for advanced glycation end-products (RAGE) are involved in the development of neuropathic pain (Br J Pharmacol 2021;178:798) and colonic (Eur J Pharmacol 2025;999:177660) or bladder (Cells 2020;9:1748) pain. In this study, using the mice subjected to repeated cold stress (RCS), known as a model for FM, we examined whether IBS-like visceral hypersensitivity, in addition to somatic hypersensitivity, would develop after stress exposure, and possible involvement of HMGB1 and RAGE. Female ICR mice exposed to RCS for 3-4 days showed mechanical allodynia in the hindpaw, as assessed by von Frey test, and colonic distension hypersensitivity accompanied by referred hyperalgesia in the lower abdomen. They also had decreased bowel movement. Systemic administration of an HMGB1-neutralizing antibody or azeliragon, a RAGE antagonist, restored the somatic and colonic hypersensitivity and constipation-like symptoms. Thus, the HMGB1/RAGE axis is considered to participate in somatic pain and colonic hypersensitivity or dysfunction caused by RCS in mice, and may serve as therapeutic targets for treatment of FM accompanied by IBS.