Alarmins, including HMGB1, are evolutionary unrelated molecules that mediate divergent intracellular signaling, but once released due to cell death or inflammatory cues promote immune activation.13,48 The pronociceptive role of HMGB1 has been widely reported in the spinal cord, dorsal root ganglion (DRG), and local peripheral tissues in experimental pain models of rheumatoid arthritis (RA),1 neuropathy,9,32,41 osteosarcoma,46 interstitial cystitis,23,27 pancreatitis,17,46 and stroke.12,30 Interestingly, the actions of extracellular HMGB1 are dependent on its redox modifications. The gene discussed is HMGB1; the disease is interstitial cystitis.