The neural control of the lower urinary tract is mediated by pathways in the brain and spinal cord which function like simple switching circuits to shift the LUT between its two principal modes of operation: urine storage and release. In infants these switching mechanisms function in purely a reflex manner to produce involuntary voiding; however in adults, voiding is controlled by voluntary mechanisms organized in the brain. Disruption of voluntary controls leads to the reemergence of involuntary (reflex) voiding and incontinence. This project will use anatomical, electrophysiological and pharmacological techniques to examine the spinal pathways that are involved in bladder hyperreflexia and reflex voiding in adult and neonatal female rats. Clinical as well as animal data indicate that bladder hyperreflexia and incontinence can be mediated by spinal mechanisms activated by capsaicin- sensitive, C-fiber bladder afferents. These reflex mechanisms can emerge as a result of alterations of normal excitatory or inhibitory synaptic mechanisms or due to formation of new synaptic connections in the spinal cord. The proposed experiments will evaluate these forms of synaptic plasticity using in vitro and in vivo preparations in which synaptic transmission in bladder reflex pathways can be studied: (1) directly with intracellular and patch clamp recording techniques or (2) indirectly using axonal tracing methods and by measuring the activity of the bladder or firing on bladder nerves. It is hypothesized that involuntary voiding in the adult is due to changes in interneuronal mechanisms in the spinal cord as a result of loss of regulatory input from higher centers in the brain. A reduction in supraspinal regulation may cause the emergence of primitive neonatal reflexes as well as abnormal bladder reflexes. These possibilities will be tested by using a chronic spinal cord injury model which induces bladder hyperreflexia and plasticity in the neural pathways controlling micturition. The effect of spinal cord injury on the maturation of voiding function in the early postnatal period will be compared to the effect of injury on voiding reflexes in adult animals. Several hypotheses will be tested: (1) plasticity in spinal interneuronal projections to sacral preganglionic neurons contributes to developmental and injury-induced changes in bladder reflex pathways, (2) spinal injury reverses the changes in interneuronal pathways that occur during postnatal development, (3) multiple transmitter systems including glutamatergic, GABAergic, peptidergic and nitric oxidergic are involved in the spinal control of bladder function; and the role of these transmitters is different in neurologically intact and spinal cord injured animals, (4) at least two parallel, anatomically and pharmacologically distinct spinal reflex pathways contribute to the bladder hyperreflexia in the spinal injured animal. It is expected that the proposed studies will provide insights into the pathophysiology of neurogenic disorders of the LUT and may eventually lead to new therapeutic approaches for the treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051402-03
Application #
2701212
Study Section
Special Emphasis Panel (SRC (07))
Project Start
1996-05-10
Project End
2000-04-30
Budget Start
1998-05-18
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
de Groat, W C; Fraser, M O; Yoshiyama, M et al. (2001) Neural control of the urethra. Scand J Urol Nephrol Suppl :35-43; discussion 106-25
Yoshiyama, M; De Groat, W C (2001) Role of spinal alpha1-adrenoceptor subtypes in the bladder reflex in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 280:R1414-9
Miura, A; Kawatani, M; de Groat, W C (2001) Effects of pituitary adenylate cyclase activating polypeptide on lumbosacral preganglionic neurons in the neonatal rat spinal cord. Brain Res 895:223-32
Miura, A; Kawatani, M; de Groat, W C (2001) Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons elicited from the lateral funiculus. J Neurophysiol 86:1587-93
Yoshiyama, M; deGroat, W C; Fraser, M O (2000) Influences of external urethral sphincter relaxation induced by alpha-bungarotoxin, a neuromuscular junction blocking agent, on voiding dysfunction in the rat with spinal cord injury. Urology 55:956-60
Sugaya, K; de Groat, W C (2000) Influence of temperature on activity of the isolated whole bladder preparation of neonatal and adult rats. Am J Physiol Regul Integr Comp Physiol 278:R238-46
Yoshiyama, M; Yamamoto, T; de Groat, W C (2000) Role of spinal alpha(1)-adrenergic mechanisms in the control of lower urinary tract in the rat. Brain Res 882:36-44
Miura, A; Kawatani, M; Araki, I et al. (2000) Electrophysiological properties of lumbosacral preganglionic neurons in the neonatal rat spinal cord. Brain Res 872:54-63
Yoshiyama, M; Nezu, F M; Yokoyama, O et al. (1999) Changes in micturition after spinal cord injury in conscious rats. Urology 54:929-33
Yoshiyama, M; Erickson, K A; Erdman, S L et al. (1999) Effects of N-methyl-D-aspartate (dizocilpine) and alpha-amino-3-hydroxy-4-isoxazolepropionate (LY215490) receptor antagonists on the voiding reflex induced by perineal stimulation in the neonatal rat. Neuroscience 90:1415-20

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