FIGURE 1.

Spinal innervation of the bladder. The afferent nerves innervating the bladder wall extend into the detrusor smooth muscle to detect bladder stretch, and into the bladder urothelium to detect bladder stretch, infection, inflammation, and barrier breakdown. The bladder lumen contains numerous commensal bacteria as well as toxic contents such as urea and high potassium. Bacterial infection of the urothelium induces apoptosis of urothelial cells, the release of cytokines, and the infiltration and activation of the immune response, including mast cell degranulation and the subsequent release of histamine and cytokines that can sensitize bladder afferent neurons. During bladder stretch the urothelium releases an array of neurotransmitters, including ATP, which can activate bladder afferents. Breakdown of the urothelial barrier allows access of toxic urine contents into the underlying bladder interstitium which can activate and sensitize bladder afferents. Bladder afferents project via the pelvic nerve or the splanchnic nerve to the dorsal horn of the thoracolumbar and lumbosacral spinal cord, where they activate second order neurons within the spinal cord synapse in the thalamus or the PAG of the midbrain. Thalamic projections provide input into limbic and cortical structures to provide the emotional affective and conscious component of the voiding reflex pathway. The thalamus relays to the PAG and the PAG feeds into the PMC to signal micturition. TL, Thoracolumbar; LS, lumbosacral; SC, spinal cord; PFC, Prefrontal Cortex; ACc, Anterior cingulate cortex; Hyp, hypothalamus; HGN, hypogastric nerve; PAG, periaqueductal gray; PMC, primary micturition center; DRG, dorsal root ganglion; DH, Dorsal horn; Agd, amygdala; LSN, lumbar splanchnic nerve; SPN, pelvic nerve; IMG, inferior mesenteric ganglion; PP, Pelvic Plexus. Figure modified from Grundy et al. (2018c).