Characterization of hyperpolarization-activated current (Ih) in dorsal root ganglion neurons innervating rat urinary bladder (original) (raw)
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The Journal of Physiology, 2012
• I h is a hyperpolarisation-activated current that influences neuronal excitability and is present in some sensory neurons. • The magnitude and properties of I h in different groups of sensory neurons that respond to painful stimuli (nociceptors) or to non-painful stimuli, such as low threshold mechanoreceptors (LTMs), were unknown. • We found that neurons with the greatest I h were the nociceptors and LTMs with the fastest conducting fibres. The highest I h of all was present in LTM neurons that sense muscle stretch and length (muscle spindle afferents). • The high levels of I h could fundamentally influence excitability of fast conducting sensory neurons which detect muscle stretch/length, touch and pressure, and painful stimuli. I h could thus influence sensations associated with all these. • The properties of I h are similar to those of HCN1-and HCN2-related I h , suggesting that these channels underlie the current.
Neurourology and Urodynamics, 2008
Aims: The role of I h channels at the spinal level in the control of bladder function was examined in urethane anesthetized female rats. Methods: Bladder activity was recorded via a transurethral catheter under isovolumetric conditions or via an intravesical catheter during continuous infusion cystometry. ZD7288, a selective I h channel inhibitor, was administered intrathecally at L6-S1 segmental levels of the spinal cord. Results: Under isovolumetric conditions, intrathecal 0.3 mg of ZD7288 was inactive, whereas 1 and 3 mg abolished bladder activity for 5.6 AE 1.8 and 20.7 AE 3.9 min, respectively. Three micrograms also tended to decrease the amplitude of the contractions when they reappeared. During continuous cystometry, an intrathecal injection of ZD7288 at 0.3-3 mg dose-dependently increased the intercontraction intervals by 7.5%, 33.1%, and 57.5% from pre-drug values. A higher dose of ZD7288 (3 mg) tended to increase the pressure threshold for inducing micturition by 16.6% and the maximum voiding pressure by 11.1%. On the other hand, cardiovascular parameters such as heart rate and mean blood pressure were not affected by 0.3-3 mg of intrathecal ZD7288. Conclusions: These results indicate that I h channels play an important role in the control of micturition. Because I h channel inhibition in the lumbosacral spinal cord reduced the frequency of the micturition reflex without significantly affecting the amplitude of reflex bladder contraction, I h channels might preferentially be involved in afferent processing in the spinal cord to control the micturition reflex.
The Journal of Physiology, 1997
1. Whole-cell patch-clamp recordings in combination with axonal tracing techniques were used to investigate the effects of chronic spinal cord injury on the electrical properties of dorsal root ganglion neurones innervating the urinary bladder or colon of the adult rat. 2. In spinal intact animals, the majority (73-74%) of bladder and colon neurones which were small in size exhibited high-threshold humped spikes mediated by tetrodotoxin (TTX)resistant Nae channels, whereas large neurones had low-threshold narrow spikes mediated by TTX-sensitive Nae channels.
Hyperpolarization-activated cation currents in human epileptogenic neocortex
Epilepsia, 2010
Background: To investigate the functions of the hyperpolarization-activated cation currents in medium-size dorsal root ganglion cells in a rat model of overactive bladder syndrome. Methods: Rats with OAB were screened using a urodynamic testing device. The whole-cell patch clamp technique was used to investigate changes in excitability and hyperpolarization-activated cation current (I h) of medium-size cells in the L6 dorsal root ganglia (DRG) of the OAB rats. Intrathecal injection of the specific I h inhibitor ZD7288 was used to investigate changes of voiding function and I h of medium-size cells in the L6 DRG. Results: The urinary bladder weight of the OAB rats was significantly increased (p < 0.01); However, 7 days after intrathecally administration of ZD7288 (2 μM), the weight of rat bladder was significantly reduced (p < 0.01). The excitability of the medium-size cells in the L6 DRG of the OAB rats was significantly increased, and the number of action potentials elicited by a 500 pA stimulus was also markedly increased. Furthermore, ZD7288 significantly reduced the excitability of the medium-size DRG cells. The medium-size cells in the DRG of the OAB rats had a significantly increased I h current density, which was blocked by ZD7288. Conclusions: The I h current density significantly increased in medium-size cells of the L6 DRG in the OAB model. A decrease of the I h current was able to significantly improve the voiding function of the OAB rats, in addition to lowering their urinary bladder weight. Our finding suggested that the observed increase of I h current in the medium-size DRG neurons might play an important role in the pathological processes of OAB.
Electrical and mechanical responses of guinea-pig bladder muscle to nerve stimulation
British Journal of Pharmacology, 1989
1 The electrical and mechanical responses to transmural stimulation of intrinsic nerves have been recorded from smooth muscle strips dissected from the dome of the guinea-pig bladder, by use of intracellular microelectrodes, and conventional tension recording techniques. 2 Stimulation of intrinsic nerves evoked action potentials in all cells studied. Hyperpolarization of the cells by extracellular current injection revealed subthreshold excitatory junction potentials (ej.ps) in about a quarter of the cells studied. 3 Action potentials could still be evoked in the presence of atropine and neostigmine, but were abolished after desensitization of the cells to a,#-methylene ATP, a stable analogue of ATP.
The Frequency-Dependence of Pre- and Postganglionic Nerve Stimulation of Pig and Rat Bladder
International Neurourology Journal
Purpose: The urinary bladder generates phasic contractions via action potentials generated in pre- and then postganglionic neurons. Whilst the frequency-dependence of postganglionic neurons to generate contractions has been quantified, the dynamic range of preganglionic neurons is less clear and if intramural ganglia exert frequency-dependent modulation of transmission between pre- and postganglionic neurons. The phosphodiesterase type 5 inhibitor sildenafil reduces neurotransmitter release from postganglionic fibres to detrusor smooth muscle and an additional question was if there was also a preganglionic action. This study aimed to compare the frequency range of bladder contractile activation by pre- and postganglionic stimulation in pig and rat bladders and if sildenafil exerted additional preganglionic actions.Methods: An arterially-perfused ex vivo pig bladder preparation was used for preganglionic (pelvic nerve) and mixed pre-and postganglionic (direct bladder wall) stimulatio...
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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.
Modulators of Calcium Influx Regulate Membrane Excitability in Rat Dorsal Root Ganglion Neurons
Anesthesia and Analgesia, 2008
Background-Chronic neuropathic pain resulting from neuronal damage remains difficult to treat, in part due to incomplete understanding of underlying cellular mechanisms. We have previously shown that inward Ca 2+ flux (I Ca ) across the sensory neuron plasmalemma is decreased in a rodent model of chronic neuropathic pain, but the direct consequence of this loss of I Ca on function of the sensory neuron has not been defined. We therefore examined the extent to which altered membrane properties after nerve injury, especially increased excitability that may contribute to chronic pain, are attributable to diminished Ca 2+ entry.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004
Sensory neurons express hyperpolarization-activated currents (I(H)) that differ in magnitude and kinetics within the populations. We investigated the structural basis for these differences and explored the functional role of the I(H) channels in sensory neurons isolated from rat nodose ganglia. Immunohistochemical studies demonstrated a differential distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) protein (HCN1, HCN2, HCN4) in sensory neurons and peripheral terminals. HCN2 and HCN4 immunoreactivity was present in all nodose neurons. In contrast, only 20% of the total population expressed HCN1 immunoreactivity. HCN1 did not colocalize with IB4 (a marker for C-type neurons), and only 15% of HCN1-positive neurons colocalized with immunoreactivity for the vanilloid receptor VR1, another protein associated primarily with C-type neurons. Therefore, most HCN1-containing neurons were A-type neurons. In further support, HCN1 was present in the mechanosensitive termin...