Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract

Opposing neural control during bladder filling and voiding. Circuits associated with filling (red) and voiding (green). During filling, receptor-mediated sensory signals from the bladder (blue arrow) are conveyed via the pelvic nerve, eliciting sphincter contraction and detrusor relaxation to retain urine. During voiding, sphincter relaxation and bladder contraction are achieved by inhibitory circuits that suppress the filling state and active circuits that promote detrusor contraction and thus urination ( 17 ).

Inflammatory pain. Factors within the inflammatory microenvironment can trigger pain responses. These factors may be released by damaged cells at the site of injury or by leukocytes. Such inflammatory mediators can trigger action potentials in sensory neurons or reduce firing thresholds for other environmental or physiologic stimuli.

UPEC induces pain separable from other facets of UTI pathogenesis. FimH acts as a tethered toxin that mediates urothelial apoptosis and consequent bladder-barrier dysfunction. LPS plays dual roles through its interactions with TLR4. In addition to the well-characterized role as a trigger for inflammation, LPS mediates pelvic-pain responses. Reproduced from ( 102 ), with permission.

LPS O-antigen acts as a rheostat to modulate UTI pain. Mice exhibited allodynia that varied with O-antigen. The acute-pain phenotype of UPEC strain NU14 was rendered chronic by deleting waaL or the entire O-antigen gene cluster, but was suppressed by expressing 83972 O-antigen genes. K-12 strain SΦ874 induced chronic pain that was suppressed by expressing Klebsiella O-antigen O2a. Adapted from ( 96 ), with permission.

Chronic-pain pathway and ASB E. coli analgesia. A peripheral three-receptor cascade, consisting of TLR4, TRPV1, and CCR2, mediates development of chronic pain that is associated with central sensitization of the sacral spinal cord receiving bladder sensory input due to altered sensory input (green) or inhibitory control (red). Analgesic activity of ASB E. coli disrupts pain in the periphery and/or spinal cord.