William C. de Groat

Bio: William C. de Groat is an academic researcher from University of Pittsburgh. The author has contributed to research in topics: Urinary bladder & Reflex. The author has an hindex of 79, co-authored 438 publications receiving 22351 citations. Previous affiliations of William C. de Groat include Paralyzed Veterans of America & Veterans Health Administration.

The neural control of micturition

Abstract: Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.

Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder

Abstract: 1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M-3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M-2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M-3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events. (Less)

Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells.

Abstract: Edited by Louis J. Ignarro, University of California, Los Angeles School of Medicine, Los Angeles, CA, and approved August 27, 2001 (received for review May 16, 2001)

Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine

Abstract: Electrophysiological and horseradish peroxidase (HRP) techniques have provided new insights into the organization of the sacral parasympathetic reflex pathways to the large intestine and urinary bladder. The innervation of the two organs arises from separate groups of sacral preganglionic cells: (1) a dorsal band of cells in laminae V and VI providing an input to the intestine; and (2) a lateral band of cells in lamina VII providing an input to the bladder. These two groups of cells were separated by an interband region containing tract cells and interneurons. Neurons in the interband region received a visceral afferent input and exhibited firing correlated with the activity of intestine and urinary bladder. It seems reasonable therefore to consider the interband region as a third component of the sacral parasympathetic nucleus. Anterograde transport of HRP revealed that visceral afferents from the intestine and bladder projected into the parasympathetic nucleus. Most of the projections were collaterals from afferent axons in Lissauer's tract that passed in lamina I laterally and medially around the dorsal horn. These afferent collaterals were located in close proximity to preganglionic perikarya and dendrites in laminae I, V and VI. The proximity of visceral afferents and efferents in the sacral cord probably reflects the existence of polysynaptic rather than monosynaptic connections since electrophysiological studies revealed that both the defecation and micturition reflexes occurred with very long central delays (45-70 msec). The reflex pathways mediating defecation and micturition in cats with an intact neuraxis were markedly different. Defecation was dependent upon a spinal reflex with unmyelinated (C-fiber) peripheral afferent and efferent limbs. On the other hand, micturition was mediated by a spinobulbospinal pathway with myelinated peripheral afferent (A-fiber) and efferent axons (B-fiber). Transection of the spinal cord at T12-L2 blocked the micturition reflex but only transiently depressed the defecation reflex. In chronic spinal cats the micturition reflex recovered 1-2 weeks after spinalization; however, in these animals bladder-to-bladder micturition reflexes were elicited by C-fiber rather than A-fiber afferents. The C-fiber afferent-evoked reflex was weak or undetectable in animals with an intact neuraxis. Transection of the spinal cord also changed the micturition reflex in neonatal kittens (age 5-28 days). In neonates with an intact neuraxis bladder-to-bladder reflexes occurred via a long latency spinobulbospinal pathway (325-430 msec). The long latency is attributable to the slow conduction velocity in immature unmyelinated peripheral and central axons. In chronic spinal kittens (3-7 days after spinalization) the long latency reflex was abolished and a shorter latency (90-150 msec) bladder reflex was unmasked. The emergence of this spinal pathway may reflect axonal sprouting and the formation of new reflex connections within the sacral parasympathetic nucleus.

Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Abstract: Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

Vanilloid (Capsaicin) Receptors and Mechanisms

Abstract: Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

Nitric oxide signaling in the central nervous system.

Abstract: Nitric oxide (NO) was first recognized as a messenger molecule in the central nervous system (eNS) in 1988 (52), when it was identified as the unstable intercellular factor that had been hypothesized, a year earlier (53), to mediate the increased cyclic GMP (cGMP) levels that occur on activation of glutamate receptors, particularly those of the NMDA (N-methyl-D-aspartate) subtype. The presence of an NO-forming enzyme (NO synthase, or NOS) in the brain was later confirmed (74), and this enzyme was subsequently purified (14) and its cDNA cloned and sequenced (12). The discovery that NO functions as a signaling molecule in the brain opened a new dimension in our concept of neural communication, one overlaying the classical picture of chemical neurotransmission, where information is passed between neuronal elements at discrete loci (synapses), and in one direction, with a diffusive type of signal that disregards the spatial constraints on neu­ rotransmitter activity normally imposed by membranes, transporters, and in­ activating enzymes. In principle, NO could spread out from its site of produc­ tion to influence many different tissue elements (neuronal, glial, and vascular) that are not necessarily in close anatomical juxtaposition. During the past few years, much information on the enzymology and mo­ lecular characteristics of NO synthesis has accrued, as reviewed in other articles in this volume. Furthermore, data from immunocytochemistry, in situ hybridization, and NADPH diaphorase histochemistry have combined to give