Neuroplasticity of PACAP Expression and Function in Micturition Reflex Pathways

Abstract

Micturition, the storage and periodic elimination of urine, requires a complex neural control system that coordinates the activities of the smooth muscle of the urinary bladder and urethra and the smooth and striated muscle of the urethral sphincters. The lower urinary tract (LUT) reflex mechanisms, organized at the level of the lumbosacral spinal cord, are modulated predominantly by supraspinal controls. Complex neural organization is necessary for the coordination of the reciprocal functions of the urinary bladder, urethra, and urethral sphincters to result in normal micturition function. Injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce LUT dysfunction. Numerous neuropeptide/receptor systems are expressed in central and peripheral nervous system pathways that regulate the LUT and expression can also be found in both neural and non-neural (e.g., urothelium) components. Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate receptor, PAC1 (Adcyap1r1), have tissue-specific distributions in diverse systems including the LUT. PACAP and associated receptors exhibit neurophenotypic changes with neural injury, inflammation, stress, and disease of the LUT. Changes in the balance of the PACAP/receptor system in central and peripheral bladder reflex pathways may underlie and/or contribute to LUT dysfunction including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, detrusor dyssynergia, and/or pain. The PACAP/receptor system in LUT pathways may thus represent a potential target for therapeutic intervention.