The functions of the lower urinary tract to store and periodically release urine depend on neural circuits located in the brain and lumbosacral spinal cord. Severe injury to the spinal cord rostral to the lumbosacral level eliminates voluntary and supraspinal control of voiding, leading initially to an areflexic bladder and complete urinary retention. This period of reflex suppression is followed by the emergence of automatic (reflex) micturition and bladder hyperactivity mediated by spinal pathways. However, voiding in spinal cord injured patients is usually inefficient due to uncoordinated activity of the bladder and urethral sphincter (bladder-sphincter dyssynergia). The long-term objective of the studies is to identify the neural circuitry that mediates lower urinary tract dysfunction after spinal injury. It is expected that a detailed understanding of the chemical properties of this circuitry, including neurotransmitter mechanisms, will facilitate the development of new therapies for the treatment of neurogenic bladder disorders. Neuroanatomical, electrophysiological and pharmacological experiments will be conducted in chronic spinal cord transected cats because this model has provided important insights into the mechanisms that underlie the recovery of bladder activity after spinal injury. Previous studies in chronic paraplegic animals revealed a marked reorganization of bladder reflex pathways and focused attention on the role of unmyelinated (C-fiber) bladder afferents in triggering spinal voiding reflexes. This has led to the testing of new treatments, such as intravesical administration of C-fiber afferent neurotoxins (capsaicin and RTX), for the management of bladder hyperreflexia and incontinence in patients with neurogenic bladder disorders. Based on animal and human data, it is hypothesized that detrusor hyperreflexia after cord injury occurs as a result of plasticity in spinal interneuronal circuitry as well as in primary afferent neurons. The project will examine the mechanisms underlying this plasticity with the goal of identifying new molecular targets for the pharmacotherapy of neurogenic voiding dysfunction.
Specific aims i nclude: (1) characterization of the synaptic reorganization in spinal interneuronal pathways that mediates the recovery of voiding function in chronic paraplegic cats; (2) evaluation, with electrophysiological techniques, of the properties of A-delta and C-fiber bladder afferent neurons and the changes which underlie the emergence of mechanosensitivity in C-fiber afferent receptors after spinal injury; and (3) examination of the putative role of the urothelium in sensory transduction mechanisms and how changes in the urothelium might contribute to altered afferent sensitivity in paraplegic cats.
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