The extracellular HMGB1 causes activation of membrane receptors, such as the receptor for advanced glycation end-product (RAGE) and Toll-like receptor 4 (TLR4), and acceleration of the CXCL12/ C-X-C motif chemokine receptor 4 (CXCR4) signaling, expressed in the primary afferents, contributing to the pathogenesis of inflammatory or neuropathic pain accompanying arthritis, pancreatitis, cystitis and surgically or chemically induced sensory nerve injury [41,42,43,44,45,46,47,48,49,50,51] (Figure 2B). This evidence concerns the gene TLR4 and chronic cystitis.