The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
We investigated whether primary afferent neurons innervating different regions of the lower urina... more We investigated whether primary afferent neurons innervating different regions of the lower urinary tract have different histochemical and electrophysiological properties. Neurons in rat L6 -S1 DRG were identified by axonal transport of a fluorescent dye. Neurofilamentnegative C-fiber cells comprise ϳ70% of bladder and proximal urethral afferent neurons that send axons through the pelvic nerves, but comprise a smaller proportion (51%) of distal urethral neurons that send axons through the pudendal nerves. Isolectin-B4 (IB4) binding was detected in a higher percentage (49%) of C-fiber neurons innervating the distal urethra than in those innervating the bladder or proximal urethra (18 -22%). Neurofilament-positive A-fiber neurons innervating the distal urethra had a larger average somal size than neurons innervating the bladder or proximal urethra. In patch-clamp recordings, the majority (70%) of bladder and proximal urethral neurons were sensitive to capsaicin and exhibited TTX-resistant, high-threshold action potentials, whereas a smaller proportion (53%) of distal urethral neurons exhibited TTX-resistant spikes. T-type Ca 2ϩ currents were observed in 47% of distal urethral neurons with TTX-sensitive spikes, but not in TTX-sensitive bladder or proximal urethral neurons. In summary, afferent neurons innervating bladder or proximal urethra differ from those innervating distal urethra. The latter, which more closely resemble cutaneous afferent neurons, consist of a smaller number of C-fiber neurons containing a higher percentage of IB4-positive cells and a more diverse population of A-fiber neurons, some of which exhibit T-type Ca 2ϩ channels. These differences may be related to different functions of respective target organs in the lower urinary tract.
Purpose-This review summarizes possible spinal reflexes involved in micturition control as well a... more Purpose-This review summarizes possible spinal reflexes involved in micturition control as well as current treatments for lower urinary tract dysfunction after spinal cord injury (SCI) in an effort to further promote the development of new treatments for people with SCI.
Journal of Pharmacology and Experimental Therapeutics
In the ventral horn of the sacral spinal cord of the cat, opioid terminals are preferentially loc... more In the ventral horn of the sacral spinal cord of the cat, opioid terminals are preferentially localized in Onuf's nucleus, an area containing motor neurons that innervate the striated muscle of the external urethral sphincter. The present study was undertaken to 1) compare the effects of selective opioid agonists on sphincter reflex pathways with the effects of these drugs on hindlimb reflexes and urinary bladder reflexes and 2) determine if the physiological inhibition of sphincter reflexes, which accompany bladder contractions, is mediated by endogenous opioids. The effects of intrathecal (i.t.) and i.v. drug administration on bladder activity, sphincter reflexes and reflexes to the hindlimb musculature were monitored in chloralose-anesthetized cats. Ethylketocyclazocine (0.05-500 micrograms i.t.) produced a dose-dependent, naloxone-sensitive, inhibition of sphincter reflexes to less than 10% of control amplitude while having no consistent effects on hindlimb reflexes or bladder activity. D-Ser2-leu5-enkephalin-thr6 (DSLET; 0.1-2.0 micrograms i.t.) abolished rhythmic bladder activity, while having no effects on sphincter or hindlimb reflexes. Larger doses of DSLET (5.0-10 micrograms i.t.) produced a modest reduction of sphincter reflexes (to 60% of control amplitude), without affecting hindlimb reflexes. Naloxone (50 micrograms i.t.) reversed DSLETs marked inhibition of bladder activity, whereas large doses (greater than 250 micrograms i.t.) only partially antagonized DSLETs weak inhibition of sphincter reflexes. Morphine (5-500 micrograms i.t.) had no consistent effect on any of the measures.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Pharmacology and Experimental Therapeutics
... ions. Various aspects of the blockade by ACh or nicotine of transmission in untreated ganglia... more ... ions. Various aspects of the blockade by ACh or nicotine of transmission in untreated ganglia have been described (eg, Lundberg and Thesleff, 1953; Paton and Perry, 1953; Krivoy and Wills, 1956; Wurzel et al., 1962). The ...
This study used the Frankenhaeuser-Huxley axonal model to analyze the effects of non-symmetric wa... more This study used the Frankenhaeuser-Huxley axonal model to analyze the effects of non-symmetric waveforms on conduction block of myelinated axons induced by high-frequency (10-300 kHz) biphasic electrical stimulation. The results predict a monotonic relationship between block threshold and stimulation frequency for symmetric waveform and a non-monotonic relationship for non-symmetric waveforms. The symmetric waveform causes conduction block by constantly activating both sodium and potassium channels at frequencies of 20-300 kHz, while the non-symmetric waveforms share the same blocking mechanism from 20 kHz up to the peak threshold frequency. At the frequencies above the peak threshold frequency the non-symmetric waveforms block axonal conduction by either hyperpolarizing the membrane (if the positive pulse is longer) or depolarizing the membrane (if the negative pulse is longer). This simulation study further increases our understanding of conduction block in myelinated axons induced by high-frequency biphasic electrical stimulation, and can guide future animal experiments as well as optimize stimulation parameters that might be used for electrically induced nerve block in clinical applications.
Objective: This paper reviews recent studies in animals that examined the effect on lower urinary... more Objective: This paper reviews recent studies in animals that examined the effect on lower urinary tract function of · 1 -adrenoceptor agonists and antagonists. Methods: Bladder reflexes were studied in vivo on anesthetized rats and cats using cystometrographic and electrophysiologic techniques. Neurally-evoked bladder contractions and release of acetylcholine (ACh) were also studied in rat bladder strips in vitro. Results: Administration of the · 1 -adrenoceptor agonist, phenylephrine (PE) to isolated strips of rat bladder enhanced neurally-evoked bladder contractions and increased basal tone. The former effects of PE were blocked by a selective · 1A antagonist and the latter by an · 1B antagonist. Activation of · 1A receptors by PE enhanced ACh release evoked by electrical field stimulation in bladder strips. PE also enhanced transmission in cat bladder ganglia. PE or noradrenaline act on ·-and ß-adrenoceptors on urothelial cells to release nitric oxide. It is concluded that facilitato-ry · 1A -adrenoceptors are located prejunctionally in the bladder, whereas · 1B adrenoceptors are located postjunctionally. In the central nervous system of the rat and cat facilitatory · 1 -adrenergic mechanisms can modulate the sympathetic, parasympathetic and somatic outflow to the urinary tract. In addition inhibitory · 1 adrenoceptor mechanisms have been detected in the rat spinal cord. Activation of these receptors with PE raises the intravesical pressure threshold for inducing micturition and decreases voiding frequency. Conclusions: · 1 -adrenoceptors are located at various sites in the bladder and in the neural pathways controlling lower urinary tract function. At most sites these receptors mediate facilitatory responses that enhance smooth muscle activity or facilitate storage or voiding reflexes. However, · 1 -adrenoceptor inhibitory mechanisms in the rat spinal cord, can also reduce the frequency of voiding reflexes. This effect is possibly mediated by an inhibition in the afferent limb of the micturition reflex pathway.
Two main functions of lower urinary tract, storage and periodic elimination of urine, are regulat... more Two main functions of lower urinary tract, storage and periodic elimination of urine, are regulated by a complex neural control system located in the brain and spinal cord which coordinates the activity of the reservoir (urinary bladder) and the outlet (bladder neck, urethra and urethral sphincter). These organs are regulated by three sets of peripheral nerves: sacral parasympathetic (pelvic nerves), thoracolumber sympathetic nerves (hypogastric nerves) which innervate the bladder trigone and prostate, and sacral somatic nerves (pudendal nerves) which innervate external urethral sphincter (EUS). The relationship between the bladder and EUS is controlled by reflex pathways in the lumbosacral spinal cord that are activated by primary afferent input from the bladder or the urethra. This study was conducted to examine the reflexes that mediate bladder and sphincter coordination. We compared the properties of the pelvic nerve afferent to pudendal nerve reflex (pelvic-to-pudendal nerve re...
Mathematics and Engineering Techniques in Medicine and Biological Scienes, 2004
The lower urinary tract has two main functions: storage and periodic elimination of urine. These ... more The lower urinary tract has two main functions: storage and periodic elimination of urine. These functions are regulated by a complex neural control system located in the brain and spinal cord which coordinates the activity of the two components of the lower urinary tract: (1) the reservoir (urinary bladder) and (2) the outlet (bladder neck, urethra and urethral sphincter).
Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 1997
Isometric torques were generated about the knee joint by microstimulation of the cat lumbar L6 sp... more Isometric torques were generated about the knee joint by microstimulation of the cat lumbar L6 spinal cord. Stimulation via a single microelectrode in the ventral part of the L6 spinal cord produced large knee joint extension torques. The extension torques were influenced by stimulus intensity, frequency and pulsewidth. Certain stimulation parameters (100 μA intensity, 40 Hz frequency and 0.20 ms
The afferent innervation of the urinary bladder consists primarily of small myelinated (Adelta) a... more The afferent innervation of the urinary bladder consists primarily of small myelinated (Adelta) and unmyelinated (C-fiber) axons that respond to chemical and mechanical stimuli. Immunochemical studies indicate that bladder afferent neurons synthesize several putative neurotransmitters, including neuropeptides, glutamic acid, aspartic acid, and nitric oxide. The afferent neurons also express various types of receptors and ion channels, including transient receptor potential channels, purinergic, muscarinic, endothelin, neurotrophic factor, and estrogen receptors. Patch-clamp recordings in dissociated bladder afferent neurons and recordings of bladder afferent nerve activity have revealed that activation of many of these receptors enhances neuronal excitability. Afferent nerves can respond to chemicals present in urine as well as chemicals released in the bladder wall from nerves, smooth muscle, inflammatory cells, and epithelial cells lining the bladder lumen. Pathological conditions...
1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation w... more 1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. [3H]NA and [14C]ACh release was greater during continuous stimulation (CS; 10 Hz, 100 shocks) or in the presence of eserine than during intermittent train stimulation (IS; 10 Hz, 10 shocks every 5 s, 10 times). Atropine (1 microM) or pirenzepine (0.05-0.1 microM) blocked the CS- or eserine-facilitated release. 3. The protein kinase C (PKC) activator phorbol dibutyrate (PDB; 0.05 and 0.5 microM) increased the release of both [3H]NA and [14C]ACh in a concentration-dependent manner. Atropine blocked the PDB-induced facilitation of ACh release but not the facilitation of NA release. 4. The protein kinase A (PKA) activator 8-Br-cAMP did not affect ACh release but enhanced NA release. 5. The PKC inhibitor H-7 (50-100 microM) inhibited the CS- or eserine-facilitated release of both ACh and NA, but did not affect the ...
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
We investigated whether primary afferent neurons innervating different regions of the lower urina... more We investigated whether primary afferent neurons innervating different regions of the lower urinary tract have different histochemical and electrophysiological properties. Neurons in rat L6 -S1 DRG were identified by axonal transport of a fluorescent dye. Neurofilamentnegative C-fiber cells comprise ϳ70% of bladder and proximal urethral afferent neurons that send axons through the pelvic nerves, but comprise a smaller proportion (51%) of distal urethral neurons that send axons through the pudendal nerves. Isolectin-B4 (IB4) binding was detected in a higher percentage (49%) of C-fiber neurons innervating the distal urethra than in those innervating the bladder or proximal urethra (18 -22%). Neurofilament-positive A-fiber neurons innervating the distal urethra had a larger average somal size than neurons innervating the bladder or proximal urethra. In patch-clamp recordings, the majority (70%) of bladder and proximal urethral neurons were sensitive to capsaicin and exhibited TTX-resistant, high-threshold action potentials, whereas a smaller proportion (53%) of distal urethral neurons exhibited TTX-resistant spikes. T-type Ca 2ϩ currents were observed in 47% of distal urethral neurons with TTX-sensitive spikes, but not in TTX-sensitive bladder or proximal urethral neurons. In summary, afferent neurons innervating bladder or proximal urethra differ from those innervating distal urethra. The latter, which more closely resemble cutaneous afferent neurons, consist of a smaller number of C-fiber neurons containing a higher percentage of IB4-positive cells and a more diverse population of A-fiber neurons, some of which exhibit T-type Ca 2ϩ channels. These differences may be related to different functions of respective target organs in the lower urinary tract.
Purpose-This review summarizes possible spinal reflexes involved in micturition control as well a... more Purpose-This review summarizes possible spinal reflexes involved in micturition control as well as current treatments for lower urinary tract dysfunction after spinal cord injury (SCI) in an effort to further promote the development of new treatments for people with SCI.
Journal of Pharmacology and Experimental Therapeutics
In the ventral horn of the sacral spinal cord of the cat, opioid terminals are preferentially loc... more In the ventral horn of the sacral spinal cord of the cat, opioid terminals are preferentially localized in Onuf's nucleus, an area containing motor neurons that innervate the striated muscle of the external urethral sphincter. The present study was undertaken to 1) compare the effects of selective opioid agonists on sphincter reflex pathways with the effects of these drugs on hindlimb reflexes and urinary bladder reflexes and 2) determine if the physiological inhibition of sphincter reflexes, which accompany bladder contractions, is mediated by endogenous opioids. The effects of intrathecal (i.t.) and i.v. drug administration on bladder activity, sphincter reflexes and reflexes to the hindlimb musculature were monitored in chloralose-anesthetized cats. Ethylketocyclazocine (0.05-500 micrograms i.t.) produced a dose-dependent, naloxone-sensitive, inhibition of sphincter reflexes to less than 10% of control amplitude while having no consistent effects on hindlimb reflexes or bladder activity. D-Ser2-leu5-enkephalin-thr6 (DSLET; 0.1-2.0 micrograms i.t.) abolished rhythmic bladder activity, while having no effects on sphincter or hindlimb reflexes. Larger doses of DSLET (5.0-10 micrograms i.t.) produced a modest reduction of sphincter reflexes (to 60% of control amplitude), without affecting hindlimb reflexes. Naloxone (50 micrograms i.t.) reversed DSLETs marked inhibition of bladder activity, whereas large doses (greater than 250 micrograms i.t.) only partially antagonized DSLETs weak inhibition of sphincter reflexes. Morphine (5-500 micrograms i.t.) had no consistent effect on any of the measures.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Pharmacology and Experimental Therapeutics
... ions. Various aspects of the blockade by ACh or nicotine of transmission in untreated ganglia... more ... ions. Various aspects of the blockade by ACh or nicotine of transmission in untreated ganglia have been described (eg, Lundberg and Thesleff, 1953; Paton and Perry, 1953; Krivoy and Wills, 1956; Wurzel et al., 1962). The ...
This study used the Frankenhaeuser-Huxley axonal model to analyze the effects of non-symmetric wa... more This study used the Frankenhaeuser-Huxley axonal model to analyze the effects of non-symmetric waveforms on conduction block of myelinated axons induced by high-frequency (10-300 kHz) biphasic electrical stimulation. The results predict a monotonic relationship between block threshold and stimulation frequency for symmetric waveform and a non-monotonic relationship for non-symmetric waveforms. The symmetric waveform causes conduction block by constantly activating both sodium and potassium channels at frequencies of 20-300 kHz, while the non-symmetric waveforms share the same blocking mechanism from 20 kHz up to the peak threshold frequency. At the frequencies above the peak threshold frequency the non-symmetric waveforms block axonal conduction by either hyperpolarizing the membrane (if the positive pulse is longer) or depolarizing the membrane (if the negative pulse is longer). This simulation study further increases our understanding of conduction block in myelinated axons induced by high-frequency biphasic electrical stimulation, and can guide future animal experiments as well as optimize stimulation parameters that might be used for electrically induced nerve block in clinical applications.
Objective: This paper reviews recent studies in animals that examined the effect on lower urinary... more Objective: This paper reviews recent studies in animals that examined the effect on lower urinary tract function of · 1 -adrenoceptor agonists and antagonists. Methods: Bladder reflexes were studied in vivo on anesthetized rats and cats using cystometrographic and electrophysiologic techniques. Neurally-evoked bladder contractions and release of acetylcholine (ACh) were also studied in rat bladder strips in vitro. Results: Administration of the · 1 -adrenoceptor agonist, phenylephrine (PE) to isolated strips of rat bladder enhanced neurally-evoked bladder contractions and increased basal tone. The former effects of PE were blocked by a selective · 1A antagonist and the latter by an · 1B antagonist. Activation of · 1A receptors by PE enhanced ACh release evoked by electrical field stimulation in bladder strips. PE also enhanced transmission in cat bladder ganglia. PE or noradrenaline act on ·-and ß-adrenoceptors on urothelial cells to release nitric oxide. It is concluded that facilitato-ry · 1A -adrenoceptors are located prejunctionally in the bladder, whereas · 1B adrenoceptors are located postjunctionally. In the central nervous system of the rat and cat facilitatory · 1 -adrenergic mechanisms can modulate the sympathetic, parasympathetic and somatic outflow to the urinary tract. In addition inhibitory · 1 adrenoceptor mechanisms have been detected in the rat spinal cord. Activation of these receptors with PE raises the intravesical pressure threshold for inducing micturition and decreases voiding frequency. Conclusions: · 1 -adrenoceptors are located at various sites in the bladder and in the neural pathways controlling lower urinary tract function. At most sites these receptors mediate facilitatory responses that enhance smooth muscle activity or facilitate storage or voiding reflexes. However, · 1 -adrenoceptor inhibitory mechanisms in the rat spinal cord, can also reduce the frequency of voiding reflexes. This effect is possibly mediated by an inhibition in the afferent limb of the micturition reflex pathway.
Two main functions of lower urinary tract, storage and periodic elimination of urine, are regulat... more Two main functions of lower urinary tract, storage and periodic elimination of urine, are regulated by a complex neural control system located in the brain and spinal cord which coordinates the activity of the reservoir (urinary bladder) and the outlet (bladder neck, urethra and urethral sphincter). These organs are regulated by three sets of peripheral nerves: sacral parasympathetic (pelvic nerves), thoracolumber sympathetic nerves (hypogastric nerves) which innervate the bladder trigone and prostate, and sacral somatic nerves (pudendal nerves) which innervate external urethral sphincter (EUS). The relationship between the bladder and EUS is controlled by reflex pathways in the lumbosacral spinal cord that are activated by primary afferent input from the bladder or the urethra. This study was conducted to examine the reflexes that mediate bladder and sphincter coordination. We compared the properties of the pelvic nerve afferent to pudendal nerve reflex (pelvic-to-pudendal nerve re...
Mathematics and Engineering Techniques in Medicine and Biological Scienes, 2004
The lower urinary tract has two main functions: storage and periodic elimination of urine. These ... more The lower urinary tract has two main functions: storage and periodic elimination of urine. These functions are regulated by a complex neural control system located in the brain and spinal cord which coordinates the activity of the two components of the lower urinary tract: (1) the reservoir (urinary bladder) and (2) the outlet (bladder neck, urethra and urethral sphincter).
Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 1997
Isometric torques were generated about the knee joint by microstimulation of the cat lumbar L6 sp... more Isometric torques were generated about the knee joint by microstimulation of the cat lumbar L6 spinal cord. Stimulation via a single microelectrode in the ventral part of the L6 spinal cord produced large knee joint extension torques. The extension torques were influenced by stimulus intensity, frequency and pulsewidth. Certain stimulation parameters (100 μA intensity, 40 Hz frequency and 0.20 ms
The afferent innervation of the urinary bladder consists primarily of small myelinated (Adelta) a... more The afferent innervation of the urinary bladder consists primarily of small myelinated (Adelta) and unmyelinated (C-fiber) axons that respond to chemical and mechanical stimuli. Immunochemical studies indicate that bladder afferent neurons synthesize several putative neurotransmitters, including neuropeptides, glutamic acid, aspartic acid, and nitric oxide. The afferent neurons also express various types of receptors and ion channels, including transient receptor potential channels, purinergic, muscarinic, endothelin, neurotrophic factor, and estrogen receptors. Patch-clamp recordings in dissociated bladder afferent neurons and recordings of bladder afferent nerve activity have revealed that activation of many of these receptors enhances neuronal excitability. Afferent nerves can respond to chemicals present in urine as well as chemicals released in the bladder wall from nerves, smooth muscle, inflammatory cells, and epithelial cells lining the bladder lumen. Pathological conditions...
1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation w... more 1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. [3H]NA and [14C]ACh release was greater during continuous stimulation (CS; 10 Hz, 100 shocks) or in the presence of eserine than during intermittent train stimulation (IS; 10 Hz, 10 shocks every 5 s, 10 times). Atropine (1 microM) or pirenzepine (0.05-0.1 microM) blocked the CS- or eserine-facilitated release. 3. The protein kinase C (PKC) activator phorbol dibutyrate (PDB; 0.05 and 0.5 microM) increased the release of both [3H]NA and [14C]ACh in a concentration-dependent manner. Atropine blocked the PDB-induced facilitation of ACh release but not the facilitation of NA release. 4. The protein kinase A (PKA) activator 8-Br-cAMP did not affect ACh release but enhanced NA release. 5. The PKC inhibitor H-7 (50-100 microM) inhibited the CS- or eserine-facilitated release of both ACh and NA, but did not affect the ...
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