Bladder Sensory Neurons as Regulators of Neuro-Immune-Urothelial Interactions: From Molecular Mechanisms to Targeted Therapy for Neurogenic Bladder and Interstitial Cystitis/Bladder Pain Syndrome

Bladder sensory neurons are essential components of lower urinary tract sensory encoding and micturition reflex control. They detect bladder filling, stretch, inflammatory mediators, and pathogen-associated stimuli, and they communicate with urothelial cells, immune cells, and stromal cells through neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Under physiological conditions, this neuro-immune-urothelial axis contributes to bladder homeostasis. Under pathological conditions, including neural injury, infection, inflammation, or epithelial barrier disruption, TRP channels, purinergic signaling, neurotrophic factors, chemokines, and voltage-gated ion channels can induce peripheral sensitization, increased excitability of dorsal root ganglion (DRG) neurons, spinal plasticity, and central sensitization, thereby contributing to urinary frequency, urgency, bladder pain, and detrusor overactivity in neurogenic bladder and interstitial cystitis/bladder pain syndrome (IC/BPS). This review summarizes the anatomical and functional organization of bladder sensory afferents, sensory neuron-associated molecular signaling, neuro-immune-urothelial interactions, disease-specific mechanisms, and targeted therapeutic strategies. We also discuss the translational potential and limitations of interventions targeting TRPV1/TRPV4/TRPA1, P2X3, CGRP, SP/neurokinin receptors, NGF, ion channels, botulinum toxin, and neuromodulation. These mechanisms provide a framework for understanding neurogenic mechanisms in bladder disorders and for developing targeted interventions.