Electrophysiologic, pharmacologic and neuroanatomical techniques will be used to investigate the brain stem and spinal cord mechanisms that integrate autonomic and somatic efferent pathways controlling lower urinary tract function in the cat and rat. The LUT is ideal for studying viscerosomatic interactions since it has only two functions (storage and release of urine) which are regulated by simple """"""""on-off"""""""" switching circuits in the central nervous system and which require a close coordination between autonomic and somatic efferent organs. This study will examine the organization of and neurotransmitter mechanisms involved in the micturition switching circuitry in the pons and lumbosacral spinal cord. Several hypotheses will be tested: (1) multiple transmitter systems (enkephalinergic, GABAergic, dopaminergic and cholinergic) contribute to the pontine control of micturition, (2) urine storage and release are regulated by separate populations of neurons in the pons, many of which send axonal projections to the lumbosacral cord where they modulate spinal interneuronal mechanisms that control the efferent outflow to the bladder and urethral sphincter, (3) in normal animals, spinal reflex pathways play an important role in urine storage, but a relatively minor role in urine release, which is controlled by spinobulbospinal pathways. However, following spinal cord damage or local disorders in the urinary tract such as partial urethral obstruction, spinal reflex mechanisms can assume a major role in the initiation of micturition, (4) emergence or facilitation of spinal reflex mechanisms is an important factor in the development of bladder hyperreflexia and uncoordinated bladder-sphincter activity, (5) the micturition reflex pathway exhibits considerable plasticity both in young animals during postnatal development as well as in adult animals in response to neural injury or peripheral pathology. A part of this plasticity is attributable to changes in primary afferent input to the spinal cord, which then leads to changes in the properties of central synapses. The ultimate objective in this investigation is to provide a wiring diagram for the central pathways which coordinate the autonomic and somatic efferent outflow to the LUT. Considerable data is available about the characteristics of incoming and outgoing signals from the spinal cord, but and efferent pathways in the autonomic system or which mediate somatic modulation of autonomic function. The identification of neurotransmitters in these pathways and the elucidation of the mechanisms contributing to the reorganization of visceral reflexes following spinal cord injury or urethral obstruction may lead to new therapeutic approaches for the management of prostatic disease as well as neurogenic disorders of the lower urinary tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK037241-05
Application #
3236050
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-09-23
Project End
1994-11-30
Budget Start
1990-02-01
Budget End
1990-11-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sugaya, Kimio; de Groat, William C (2002) Inhibitory control of the urinary bladder in the neonatal rat in vitro spinal cord-bladder preparation. Brain Res Dev Brain Res 138:87-95
Araki, I; de Groat, W C (1997) Developmental synaptic depression underlying reorganization of visceral reflex pathways in the spinal cord. J Neurosci 17:8402-7
Yoshiyama, M; Roppolo, J R; de Groat, W C (1997) Effects of LY215490, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, on the micturition reflex in the rat. J Pharmacol Exp Ther 280:894-904
Vizzard, M A; Erdman, S L; de Groat, W C (1996) Increased expression of neuronal nitric oxide synthase in bladder afferent pathways following chronic bladder irritation. J Comp Neurol 370:191-202
Kawatani, M; Suzuki, T; de Groat, W C (1996) Corticotropin releasing factor-like immunoreactivity in afferent projections to the sacral spinal cord of the cat. J Auton Nerv Syst 61:218-26
Vizzard, M A; Erdman, S L; de Groat, W C (1995) Increased expression of neuronal nitric oxide synthase (NOS) in visceral neurons after nerve injury. J Neurosci 15:4033-45
Vizzard, M A; Erickson, V L; Card, J P et al. (1995) Transneuronal labeling of neurons in the adult rat brainstem and spinal cord after injection of pseudorabies virus into the urethra. J Comp Neurol 355:629-40
Sculptoreanu, A; Figourov, A; De Groat, W C (1995) Voltage-dependent potentiation of neuronal L-type calcium channels due to state-dependent phosphorylation. Am J Physiol 269:C725-32
Cheng, C L; Ma, C P; de Groat, W C (1995) Effect of capsaicin on micturition and associated reflexes in chronic spinal rats. Brain Res 678:40-8
Yoshiyama, M; Roppolo, J R; de Groat, W C (1995) Effects of GYKI 52466 and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat. Brain Res 691:185-94

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