[Show abstract][Hide abstract] ABSTRACT: This study aimed at understanding thermal effects on nerve conduction and developing new methods to produce a reversible thermal block of axonal conduction in mammalian myelinated nerves. In 13 cats under α-chloralose anesthesia, conduction block of pudendal nerves (N=20) by cooling (5-30°C) or heating (42-54 °C) a small segment (9 mm) of the nerve was monitored by the urethral striated muscle contractions and increases in intraurethral pressure induced by intermittent (5 sec on and 20 sec off) electrical stimulation (50 Hz, 0.2 ms) of the nerve. Cold block was observed at 5-15 °C while heat block occurred at 50-54 °C. A complete cold block up to 10 minutes was fully reversible, but a complete heat block was only reversible when the heating duration was less than 1.3±0.1 minutes. A brief (<1 minute) reversible complete heat block at 50-54 °C or 15 minutes of non-block mild heating at 46-48 °C significantly increased the cold block temperature to 15-30 °C. The effect of heating on cold block fully reversed within about 40 minutes. This study discovered a novel method to block mammalian myelinated nerves at 15-30 °C, providing the possibility to develop an implantable device to block axonal conduction and treat many chronic disorders. The effect of heating on cold block is of considerable interest because it raises many basic scientific questions that may help reveal the mechanisms underlying cold or heat block of axonal conduction.
Preview · Article · Jan 2016 · Journal of Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2 ms pulse width, 10-25 second duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (p < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS but not TNS inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.
No preview · Article · Dec 2015 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: Neuromodulation elicited by electrical stimulation of peripheral or spinal nerves is a U.S. Food and Drug Administered (FDA)-approved therapy for treating disorders of the pelvic viscera, including urinary urgency, urgency-frequency, nonobstructive urinary retention and fecal incontinence. The technique is also being tested experimentally for its efficacy in treating interstitial cystitis, chronic constipation and pelvic pain. The goal of neuromodulation is to suppress abnormal visceral sensations and involuntary reflexes and restore voluntary control. Although detailed mechanisms underlying the effects of neuromodulation are still to be elucidated, it is generally believed that effects are due to stimulation of action potentials in somatic afferent nerves. Afferent nerves project to the lumbosacral spinal cord, where they release excitatory neurotransmitters that activate ascending pathways to the brain or spinal circuits that modulate visceral sensory and involuntary motor mechanisms. Studies in animals revealed that different types of neuromodulation (for example, stimulation of a sacral spinal root, pudendal nerve or posterior tibial nerve) act by releasing different inhibitory and excitatory neurotransmitters in the central nervous system. In addition, certain types of neuromodulation inhibit visceral smooth muscle by initiating reflex firing in peripheral autonomic nerves or excite striated sphincter muscles by initiating reflex firing in somatic efferent nerves. This report will provide a brief summary of (a) neural control of the lower urinary tract and distal bowel, (b) clinical use of neuromodulation in the treatment of bladder and bowel dysfunctions
[Show abstract][Hide abstract] ABSTRACT: In α-chloralose anesthetized cats we examined the role of opioid receptor (OR) subtypes (µ, κ, and δ) in tibial nerve stimulation (TNS) induced inhibition of bladder overactivity elicited by intravesical infusion of 0.25% acetic acid (AA). The sensitivity of TNS inhibition to cumulative intravenous doses of selective OR antagonists (cyprodime for µ, nor-binaltorphimine for κ, or naltrindole for δ ORs) was tested. Naloxone (1 mg/kg, i.v., an antagonist for µ, κ, and δ ORs) was administered at the end of each experiment. AA caused bladder overactivity and significantly (P < 0.01) reduced bladder capacity to 21.1±2.6% of the saline control. TNS at 2 or 4 times threshold (T) intensity for inducing toe movement significantly (P < 0.01) restored bladder capacity to 52.9±3.6% or 57.4±4.6% of control, respectively. Cyprodime (0.3-1.0 mg/kg) completely removed TNS inhibition without changing AA control capacity. Nor-binaltorphimine (3-10 mg/kg) also completely reversed TNS inhibition and significantly (P < 0.05) increased AA control capacity. Naltrindole (1-10 mg/kg) reduced (P<0.05) TNS inhibition but significantly (P < 0.05) increased AA control capacity. Naloxone (1 mg/kg) had no effect in cyprodime pre-treated cats, but reversed the nor-binaltorphimine induced increase in bladder capacity and eliminated the TNS inhibition remaining in naltrindole pre-treated cats. These results indicate a major role of µ and κ ORs in TNS inhibition while δ ORs play a minor role. Meanwhile, κ and δ ORs also have an excitatory role in irritation-induced bladder overactivity.
No preview · Article · Sep 2015 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: This study examined the role of β-adrenergic and opioid receptors in spinal reflex bladder activity and in the inhibition induced by pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS). Spinal reflex bladder contractions were induced by intravesical infusion of 0.25% acetic acid in α-chloralose anesthetized cats after an acute spinal cord transection (SCT) at the thoracic T9/T10 level. PNS or TNS at 5 Hz was applied to inhibit these spinal reflex contractions at 2 and 4 times the threshold intensity (T) for inducing anal or toe twitch respectively. During a cystrometrogram (CMG) PNS at 2T and 4T significantly (p<0.05) increased bladder capacity from 58.0±4.7% to 85.8±10.3% and 96.5±10.7% respectively of saline control capacity, while TNS failed to inhibit spinal reflex bladder contractions. After administering propranolol (3 mg/kg i.v., a β1/β2-adrenergic receptor antagonist), the effects of 2T and 4T PNS on bladder capacity were significantly (p<0.05) reduced to 64.5±9.5% and 64.7±7.3% respectively of the saline control capacity. However, the residual PNS inhibition (about 10% increase in capacity) was still statistically significant (p<0.05). Propranolol treatment also significantly (p=0.0019) increased the amplitude of bladder contraction, but did not change the control bladder capacity. Naloxone (1 mg/kg i.v., an opioid receptor antagonist) had no effect on either spinal reflex bladder contractions or PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg i.v., a ganglionic blocker) significantly (p<0.05) reduced the amplitude of the reflex bladder contractions. This study indicates an important role of β1/β2-adrenergic receptors in pudendal inhibition and spinal reflex bladder activity.
No preview · Article · Nov 2014 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid (AA) was used to irritate bladder, activate nociceptive afferent C-fibers and trigger spinal reflex bladder contractions (amplitude 19.3±2.9 cmH2O). Hexamethonium (a ganglionic blocker, i.v.) significantly (p<0.01) reduced the amplitude of the reflex bladder contractions to 8.5±1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2±1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited the reflex bladder contractions, while tibial nerve stimulation (TNS) failed to inhibit the bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows for the first time that after acute spinal cord transection reflex bladder contractions can be triggered by activating the nociceptive bladder afferent C-fibers using AA irritation. Understanding the sites of action for PNS or TNS inhibition is important for clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions.
Preview · Article · Jul 2014 · American journal of physiology. Renal physiology
[Show abstract][Hide abstract] ABSTRACT: The effect of a non-symmetric waveform on nerve conduction block induced by high-frequency biphasic stimulation is investigated using a lumped circuit model of the unmyelinated axon based on Hodgkin-Huxley equations. The simulation results reveal that the block threshold monotonically increases with the stimulation frequency for the symmetric stimulation waveform. However, a non-monotonic relationship between block threshold and stimulation frequency is observed when the stimulation waveform is non-symmetric. Constant activation of potassium channels by the high-frequency stimulation results in the increase of block threshold with increasing frequency. The non-symmetric waveform with a positive pulse 0.4-0.8 μs longer than the negative pulse blocks axonal conduction by hyperpolarizing the membrane and causes a decrease in block threshold as the frequency increases above 12-16 kHz. On the other hand, the non-symmetric waveform with a negative pulse 0.4-0.8 μs longer than the positive pulse blocks axonal conduction by depolarizing the membrane and causes a decrease in block threshold as the frequency increases above 40-53 kHz. This simulation study is important for understanding the potential mechanisms underlying the nerve block observed in animal studies, and may also help to design new animal experiments to further improve the nerve block method for clinical applications.
No preview · Article · Jun 2014 · Journal of Computational Neuroscience
[Show abstract][Hide abstract] ABSTRACT: This study is aimed at determining the effect of duloxetine (a serotonin-norepinephrine reuptake inhibitor) on pudendal inhibition of bladder overactivity. Cystometrograms were performed on 15 cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, pudendal nerve stimulation (PNS) at 5 Hz was applied to the right pudendal nerve at 2 and 4 times the threshold (T) intensity for inducing anal twitch. Duloxetine (0.03-3 mg/kg) was administered intravenously to determine the effect on PNS inhibition. AA irritation significantly (p<0.01) reduced bladder capacity to 27.9±4.6% of saline control capacity. PNS alone at both 2T and 4T significantly (p<0.01) inhibited bladder overactivity and increased bladder capacity to 83.6±7.6% and 87.5±7.7% of saline control, respectively. Duloxetine at low doses (0.03-0.3 mg/kg) caused a significant reduction in PNS inhibition without changing bladder capacity. However, at high doses (1-3 mg/kg) duloxetine significantly increased bladder capacity but still failed to enhance PNS inhibition. WAY100635 (a 5-HT1A receptor antagonist, 0.5-1 mg/kg, i.v.) reversed the suppressive effect of duloxetine on PNS inhibition and significantly (p<0.05) increased the inhibitory effect of duloxetine on bladder overactivity but did not enhance the effect of PNS. These results indicate that activation of 5-HT1A auto-receptors on the serotonergic neurons in the raphe nucleus may suppress duloxetine and PNS inhibition, suggesting that the co-administration of a 5-HT1A antagonist drug might be useful in enhancing the efficacy of duloxetine alone and/or the additive effect of PNS-duloxetine combination for the treatment of overactive bladder symptoms.
No preview · Article · Mar 2014 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Picrotoxin, an antagonist for γ-aminobutyric acid receptor subtype A (GABAA), was used to investigate the role of GABAA receptors in nociceptive and non-nociceptive reflex bladder activities and pudendal inhibition of these activities in cats under α-chloralose anesthesia. Acetic acid (AA, 0.25%) was used to irritate the bladder and induce nociceptive bladder overactivity, while saline was used to distend the bladder and induce non-nociceptive bladder activity. To modulate the bladder reflex pudendal nerve stimulation (PNS) was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. AA irritation significantly (p<0.01) reduced bladder capacity to 34.3±7.1% of the saline control capacity; while PNS at 2T and 4T significantly (p<0.01) increased AA bladder capacity to 84.0±7.8% and 93.2±15.0%, respectively, of the saline control. Picrotoxin (0.4 mg, i.t.) did not change AA bladder capacity but completely removed PNS inhibition of AA-induced bladder overactivity. Picrotoxin (i.v.) only increased AA bladder capacity at a high dose (0.3 mg/kg) but significantly (p<0.05) reduced 2T PNS inhibition at low doses (0.01-0.1 mg/kg). During saline cystometry, PNS significantly (p<0.01) increased bladder capacity to 147.0±7.6% at 2T and 172.7±8.9% at 4T of control capacity; and picrotoxin (0.4 mg, i.t. or 0.03-0.3 mg/kg, i.v.) also significantly (p<0.05) increased bladder capacity. However, picrotoxin treatment did not alter PNS inhibition during saline infusion. These results indicate that spinal GABAA receptors have different roles in controlling nociceptive and non-nociceptive reflex bladder activities and in PNS inhibition of these activities.
No preview · Article · Feb 2014 · AJP Renal Physiology