scholarly journals Endogenous Monoamine Receptor Activation Is Essential for Enabling Persistent Sodium Currents and Repetitive Firing in Rat Spinal Motoneurons

2006 ◽  
Vol 96 (3) ◽  
pp. 1171-1186 ◽  
Author(s):  
P. J. Harvey ◽  
X. Li ◽  
Y. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Sodium Channel ◽  
Receptor Activation ◽  
Repetitive Firing ◽  
Spinal Motoneurons ◽  
Sodium Currents ◽  
Receptor Antagonists ◽  
Channel Inactivation ◽  
Chronic Spinal Rats

The spinal cord and spinal motoneurons are densely innervated by terminals of serotonin (5-HT) and norepinephrine (NE) neurons arising mostly from the brain stem, but also from intrinsic spinal neurons. Even after long-term spinal transection (chronic spinal), significant amounts (10%) of 5-HT and NE (monoamines) remain caudal to the injury. To determine the role of such endogenous monoamines, we blocked their action with monoamine receptor antagonists and measured changes in the sodium currents and firing in motoneurons. We focused on persistent sodium currents (Na PIC) and sodium spike properties because they are critical for enabling repetitive firing in motoneurons and are facilitated by monoamines. Intracellular recordings were made from motoneurons in the sacrocaudal spinal cord of normal and chronic spinal rats (2 mo postsacral transection) with the whole sacrocaudal cord acutely removed and maintained in vitro (cords from normal rats termed acute spinal). Acute and chronic spinal rats had TTX-sensitive Na PICs that were respectively 0.62 ± 0.76 and 1.60 ± 1.04 nA, with mean onset voltages of −63.0 ± 5.6 and −64.1 ± 5.4 mV, measured with slow voltage ramps. Application of 5-HT2A, 5-HT2C, and α1-NE receptor antagonists (ketanserin, RS 102221, and WB 4101, respectively) significantly reduced the Na PICs, and a combined application of these three monoamine antagonists completely eliminated the Na PIC, in both acute and chronic spinal rats. Likewise, reduction of presynaptic transmitter release (including 5-HT and NE) with long-term application of cadmium also eliminated the Na PIC. Associated with the elimination of the Na PIC in monoamine antagonists, the motoneurons lost their ability to fire during slow current ramps. At this point, the spike evoked by antidromic stimulation was not affected, suggesting that activation of the transient sodium current was not impaired. However, the spike evoked after a slow ramp depolarization was slightly reduced in height and rate-of-rise, suggesting decreased sodium channel availability as a result of increased channel inactivation. These results suggest that endogenous monoamine receptor activation is critical for enabling the Na PIC and decreasing sodium channel inactivation, ultimately enabling steady repetitive firing in both normal and chronic spinal rats.

scholarly journals 5-HT2 Receptor Activation Facilitates a Persistent Sodium Current and Repetitive Firing in Spinal Motoneurons of Rats With and Without Chronic Spinal Cord Injury

2006 ◽  
Vol 96 (3) ◽  
pp. 1158-1170 ◽  
Author(s):  
P. J. Harvey ◽  
X. Li ◽  
Y. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Receptor Activation ◽  
Repetitive Firing ◽  
Persistent Sodium Current ◽  
Spinal Motoneurons ◽  
Spinal Transection ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats

We examined the modulation of persistent inward currents (PICs) by serotonin (5-HT) in spinal motoneurons of normal and chronic spinal rats. PICs are composed of both a TTX-sensitive persistent sodium current (Na PIC) and a nimodipine-sensitive persistent calcium current (Ca PIC), and we focused on quantifying the Na PIC (and its action on the total PIC), which is known to be critical in enabling repetitive firing. Intracellular recordings were made from motoneurons of the whole sacrocaudal spinal cord of normal adult rats after the cord was acutely transected at the S2 spinal level (acute spinal rat condition), removed from the animal, and then maintained in vitro. In vitro motoneuron recordings were likewise made from rats that had a sacral spinal transection 2 mo previously (chronic spinal rats). In motoneurons from acute spinal rats, moderately high doses of 5-HT (≥10 μM), or the 5-HT2 receptor agonist DOI (≥30 μM), significantly increased the total PIC, hyperpolarized the PIC onset voltage, and hyperpolarized the spike threshold, whereas lower doses had no effect. Both 5-HT and DOI specifically increased the Na PIC portion of the total PIC (tested with nimodipine blocking the Ca PIC). Additionally, 5-HT, but not DOI, depolarized the resting membrane potential ( Vm) and increased the input resistance ( Rm) in a dose-dependent manner. Therefore 5-HT2 receptor activation facilitated the Na PIC, whereas other 5-HT receptors modulated Vm and Rm. Motoneurons of chronic spinal rats responded to 5-HT and DOI in the same way, but with larger responses and at much lower doses (0.3–1 μM), thus exhibiting a 30-fold supersensitivity to 5-HT. Specifically the Na PIC was supersensitive to 5-HT2 receptor activation with DOI. Also, Rm and Vm were supersensitive to 5-HT. Consistent with the known critical role of the Na PIC in repetitive firing, enhancement of the Na PIC by DOI or 5-HT facilitated the repetitive firing evoked by steady current injection and enabled repetitive firing in a subpopulation of motoneurons of acute spinal rats that were initially unable to produce sustained repetitive firing. We suggest that after spinal transection, residual endogenous spinal sources of 5-HT help facilitate the Na PIC and repetitive firing. With chronic injury, the developed 5-HT supersensitivity more than compensates for lost brain stem 5-HT, so that the Na PIC is large and motoneurons are very excitable, thus contributing to spasticity.

scholarly journals Persistent Sodium Currents and Repetitive Firing in Motoneurons of the Sacrocaudal Spinal Cord of Adult Rats

2006 ◽  
Vol 96 (3) ◽  
pp. 1141-1157 ◽  
Author(s):  
P. J. Harvey ◽  
Y. Li ◽  
X. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Input Resistance ◽  
Calcium Currents ◽  
Repetitive Firing ◽  
Resting Membrane Potential ◽  
Sodium Currents ◽  
Adult Rats ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats

Months after sacral spinal transection in rats (chronic spinal rats), motoneurons below the injury exhibit large, low-threshold persistent inward currents (PICs), composed of persistent sodium currents (Na PICs) and persistent calcium currents (Ca PICs). Here, we studied whether motoneurons of normal adult rats also exhibited Na and Ca PICs when the spinal cord was acutely transected at the sacral level (acute spinal rats) and examined the role of the Na PIC in firing behavior. Intracellular recordings were obtained from motoneurons of acute and chronic spinal rats while the whole sacrocaudal spinal cord was maintained in vitro. Compared with chronic spinal rats, motoneurons of acute spinal rats were more difficult to activate because the input resistance was 22% lower and resting membrane potential was hyperpolarized 4.1 mV further below firing threshold (−50.9 ± 6.2 mV). In acute spinal rats, during a slow voltage ramp, a PIC was activated subthreshold to the spike (at −57.2 ± 5.0 mV) and reached a peak current of 1.11 ± 1.21 nA. This PIC was less than one-half the size of that in chronic spinal rats (2.79 ± 0.94 nA) and usually was not large enough to produce bistable behavior (plateau potentials and self-sustained firing not present), unlike in chronic spinal rats. The PIC was composed of two components: a TTX-sensitive Na PIC (0.44 ± 0.36 nA) and a nimodipine-sensitive Ca PIC (0.78 ± 0.82 nA). Both were smaller than in chronic spinal rats (but with similar Na/Ca ratio). The presence of the Na PIC was critical for normal repetitive firing, because no detectable Na PIC was found in the few motoneurons that could not fire repetitively during a slow ramp current injection and motoneurons that had large Na PICs more readily produced repetitive firing and had lower minimum firing rates compared with neurons with small Na PICs. Furthermore, when the Na PIC was selectively blocked with riluzole, steady repetitive firing was eliminated, even though transient firing could be evoked on a rapid current step and the spike itself was unaffected. In summary, only small Ca and Na PICs occur in acute spinal motoneurons, but the Na PIC is essential for steady repetitive firing. We discuss how availability of monoamines may explain the variability in Na PICs and firing in the normal and spinal animals.

scholarly journals Cervical spinal 5-HT2A and 5-HT2B receptors are both necessary for moderate acute intermittent hypoxia-induced phrenic long-term facilitation

2019 ◽  
Vol 127 (2) ◽  
pp. 432-443 ◽  
Author(s):  
Arash Tadjalli ◽  
Gordon S. Mitchell
Keyword(s):  
Receptor Antagonist ◽  
Broad Spectrum ◽  
Intermittent Hypoxia ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Erk Mapk ◽  
Long Term Facilitation

Serotonin (5-HT) is a key regulator of spinal respiratory motor plasticity. For example, spinal 5-HT receptor activation is necessary for the induction of phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity triggered by moderate acute intermittent hypoxia (mAIH). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum 5-HT-receptor antagonist, methysergide. However, methysergide does not allow distinctions between the relative contributions of different 5-HT receptor subtypes. Intravenous administration of the Gq protein-coupled 5-HT2A/2C receptor antagonist ketanserin blocks mAIH-induced pLTF when administered before, but not after, mAIH; thus, 5-HT2 receptor activation is necessary for the induction but not maintenance of mAIH-induced pLTF. However, systemic ketanserin administration does not identify the site of the relevant 5-HT2A/2C receptors. Furthermore, this approach does not differentiate between the roles of 5-HT2A versus 5-HT2C receptors, nor does it preclude involvement of other Gq protein-coupled metabotropic 5-HT receptors capable of eliciting long-lasting phrenic motor facilitation, such as 5-HT2B receptors. Here we tested the hypothesis that mAIH-induced pLTF requires cervical spinal 5-HT2 receptor activation and determined which 5-HT2 receptor subtypes are involved. Anesthetized, paralyzed, and ventilated adult male Sprague Dawley rats were pretreated intrathecally with cervical (~C3-C5) spinal injections of subtype selective 5-HT2A/2C, 5-HT2B, or 5-HT2C receptor antagonists before mAIH. Whereas cervical spinal 5-HT2C receptor inhibition had no impact on mAIH-induced pLTF, pLTF was no longer observed after pretreatment with either 5-HT2A/2C or 5-HT2B receptor antagonists. Furthermore, spinal pretreatment with an MEK/ERK MAPK inhibitor blocked phrenic motor facilitation elicited by intrathecal injections of 5-HT2A but not 5-HT2B receptor agonists. Thus, mAIH-induced pLTF requires concurrent cervical spinal activation of both 5-HT2A and 5-HT2B receptors. However, these distinct receptor subtypes contribute to phrenic motor facilitation via distinct downstream signaling cascades that differ in their requirement for ERK MAPK signaling. The demonstration that both 5-HT2A and 5-HT2B receptors make unique contributions to mAIH-induced pLTF advances our understanding of mechanisms that underlie 5-HT-induced phrenic motor plasticity. NEW & NOTEWORTHY Moderate acute intermittent hypoxia (mAIH) triggers a persistent enhancement in phrenic motor output, an effect termed phrenic long-term facilitation (pLTF). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum serotonin (5-HT) receptor antagonist methysergide, demonstrating the need for spinal 5-HT receptor activation. However, the exact type of 5-HT receptors required for initiation of pLTF remains unknown. To the best of our knowledge, the present study is the first to demonstrate that 1) spinal coactivation of two distinct Gq protein-coupled 5-HT2 receptor subtypes is necessary for mAIH-induced pLTF, and 2) these receptors contribute to pLTF via cascades that differ in their requirement for ERK MAPK signaling.

scholarly journals Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current

2014 ◽  
Vol 112 (4) ◽  
pp. 903-912 ◽  
Author(s):  
Ryan J. Schutte ◽  
Soleil S. Schutte ◽  
Jacqueline Algara ◽  
Eden V. Barragan ◽  
Jeff Gilligan ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Current ◽  
Dravet Syndrome ◽  
Repetitive Firing ◽  
Gabaergic Interneurons ◽  
Sodium Currents ◽  
Channel Gene ◽  
Sodium Channel Gene ◽  
Current Activity ◽  
Scn1a Mutation

Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene para results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.

scholarly journals Removal of sodium channel inactivation in squid axon by the oxidant chloramine-T.

1985 ◽  
Vol 86 (2) ◽  
pp. 289-302 ◽  
Author(s):  
G K Wang ◽  
M S Brodwick ◽  
D C Eaton
Keyword(s):  
Sodium Channel ◽  
Time Course ◽  
Removal Rate ◽  
Potassium Currents ◽  
Activation Process ◽  
Sodium Currents ◽  
Methionine Residue ◽  
Channel Inactivation ◽  
Sodium Channel Inactivation ◽  
Chloramine T

We have investigated the effects of a mild oxidant, chloramine-T(CT), on the sodium and potassium currents of squid axons under voltage-clamp conditions. Sodium channel inactivation of squid giant axons can be completely removed by CT at neutral pH. Internal and external CT treatment are both effective. CT apparently removes inactivation in an irreversible, all-or-none manner. The activation process of sodium channels is little affected, as judged from the voltage dependence of peak sodium currents, the rising phase of sodium currents, and the time course of tail currents following the repolarization. The removal of inactivation by CT is pH-dependent; higher pH decreases the removal rate, whereas lower pH increases it. Internal metabisulfite, a strong reductant, does not protect inactivation from the action of external CT, nor does external metabisulfite protect from internal CT application. CT slightly depresses the peak potassium currents at comparable concentrations but has no apparent effects on their kinetics. Our results suggest that the neutral form of CT modifies an embedded methionine residue that is involved in sodium channel inactivation.

scholarly journals Spastic Tail Muscles Recover From Myofiber Atrophy and Myosin Heavy Chain Transformations in Chronic Spinal Rats

2007 ◽  
Vol 97 (2) ◽  
pp. 1040-1051 ◽  
Author(s):  
R. Luke W. Harris ◽  
Charles T. Putman ◽  
Michelle Rank ◽  
Leo Sanelli ◽  
David J. Bennett
Keyword(s):  
Spinal Cord ◽  
Skeletal Muscles ◽  
Type I ◽  
Type Ii ◽  
Neuromuscular Activity ◽  
Cord Injury ◽  
Chronic Spinal Rats ◽  
Myofiber Type ◽  
Sacral Spinal Cord

Without intervention after spinal cord injury (SCI), paralyzed skeletal muscles undergo myofiber atrophy and slow-to-fast myofiber type transformations. We hypothesized that chronic spasticity-associated neuromuscular activity after SCI would promote recovery from such deleterious changes. We examined segmental tail muscles of chronic spinal rats with long-standing tail spasticity (7 mo after sacral spinal cord transection; older chronic spinals), chronic spinal rats that experienced less spasticity early after injury (young chronic spinals), and rats without spasticity after transection and bilateral deafferentation (spinal isolated). These were compared with tail muscles of age-matched normal rats. Using immunohistochemistry, we observed myofiber distributions of 15.9 ± 3.5% type I, 18.7 ± 10.7% type IIA, 60.8 ± 12.6% type IID(X), and 2.3 ± 1.3% type IIB (means ± SD) in young normals, which were not different in older normals. Young chronic spinals demonstrated transformations toward faster myofiber types with decreased type I and increased type IID(X) paralleled by atrophy of all myofiber types compared with young normals. Spinal isolated rats also demonstrated decreased type I myofiber proportions and increased type II myofiber proportions, and severe myofiber atrophy. After 4 mo of complete spasticity (older chronic spinals), myofiber type transformations were reversed, with no significant differences in type I, IIA, IID(X), or IIB proportions compared with age-matched normals. Moreover, after this prolonged spasticity, type I, IIA, and IIB myofibers recovered from atrophy, and type IID(X) myofibers partially recovered. Our results indicate that early after transection or after long-term spinal isolation, relatively inactive tail myofibers atrophy and transform toward faster myofiber types. However, long-term spasticity apparently produces neuromuscular activity that promotes recovery of myofiber types and myofiber sizes.

scholarly journals Incomplete Inactivation and Rapid Recovery of Voltage-Dependent Sodium Channels During High-Frequency Firing in Cerebellar Purkinje Neurons

2011 ◽  
Vol 105 (2) ◽  
pp. 860-871 ◽  
Author(s):  
Brett C. Carter ◽  
Bruce P. Bean
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
High Frequency ◽  
Interspike Interval ◽  
Channel Gating ◽  
Purkinje Neurons ◽  
Repetitive Firing ◽  
Channel Inactivation ◽  
Sodium Channel Inactivation ◽  
Channel Availability

Purkinje neurons can spike very rapidly for sustained periods. We examined the cycle of sodium channel gating during high-frequency firing of Purkinje neurons, focusing on the kinetics of sodium channel inactivation and recovery during and after spikes. To analyze sodium channel availability during spiking, we recorded the firing patterns of acutely dissociated Purkinje neurons in current clamp and used these records as command voltages in voltage-clamp experiments in the same cell, adding step depolarizations at various points to assay availability. Sodium channel availability decreased abruptly during the spike, as expected, but never reached zero. During spontaneous firing (∼40 Hz at 37°C), availability decreased from nearly 90% before the spike to about 10–20% after the spike. With fast steady firing stimulated by current injection (∼300 Hz at 37°C), the availability decreased from about 60% between spikes to roughly 15–20% after the spike. Thus even at the fastest firing rates, sodium channel inactivation is incomplete after a spike, leaving a substantial fraction of sodium channels immediately available for activation. Also, inactivation recovered quickly during the early interspike interval (time constant ∼1 ms at 37°C), but developed slowly during the depolarization of the late interspike interval, ensuring high availability until spike threshold. These features of sodium channel gating, especially the availability remaining after the spike, reduce the refractory period and facilitate rapid repetitive firing.

Long-Term Follow-Up After Spinal Cord Injury in Canada

2006 ◽  
Author(s):  
Mark I. Tonack ◽  
Sander L. Hitzig ◽  
B. Catharine Craven ◽  
Kent A. Campbell ◽  
Kathryn A. Boschen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cord Injury ◽  
Long Term Follow Up

OPEN HAEMORRHOIDS SURGERY IN SPINAL CORD INJURY PATIENTS

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Khaled Hassan
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Anal Fissure ◽  
Open Surgery ◽  
Anal Fissures ◽  
Cord Injury ◽  
Long Term Follow Up ◽  
Grade Iii

This Pilot retrospective research conducted on the results of open surgery in patients with Grade III and IV haemorrhoids With SCI. No major complications had arisen at 6 weeks post-operative and all wounds had healed, but 1 patient Anal fissure recurrence. 75% of patients reported a substantial increase in anorectal anorexia during long-term follow-up. With symptoms. Five patients reported recurrences: three haemorrhoids (18 percent) and two anal fissures (25 percent).   Keywords: Haemorrhoids, Pilot retrospective research, Anorectal Anorexia.

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