Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sodium Channel Blockers”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed2006

The role of sodium channels in chronic inflammatory and neuropathic pain.

UNLABELLED: Clinical and experimental data indicate that changes in the expression of voltage-gated sodium channels play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic. Clinical and experimental data also suggest that changes in voltage-gated sodium channels may play a role in inflammatory pain, and here too sodium-channel blockers may have therapeutic potential. The sodium-channel blockers of interest include local anesthetics, used at doses far below those that block nerve impulse propagation, and tricyclic antidepressants, whose analgesic effects may at least partly be due to blockade of sodium channels. Recent data show that local anesthetics may have pain-relieving actions via targets other than sodium channels, including neuronal G protein-coupled receptors and binding sites on immune cells. Some of these actions occur with nanomolar drug concentrations, and some are detected only with relatively long-term drug exposure. There are 9 isoforms of the voltage-gated sodium channel alpha-subunit, and several of the isoforms that are implicated in neuropathic and inflammatory pain states are expressed by somatosensory primary afferent neurons but not by skeletal or cardiovascular muscle. This restricted expression raises the possibility that isoform-specific drugs might be analgesic and lacking the cardiotoxicity and neurotoxicity that limit the use of current sodium-channel blockers. PERSPECTIVE: Changes in the expression of neuronal voltage-gated sodium channels may play a key role in the pathogenesis of both chronic neuropathic and chronic inflammatory pain conditions. Drugs that block these channels may have therapeutic efficacy with doses that are far below those that impair nerve impulse propagation or cardiovascular function.

Anesthetics, Local↗
PubMed2002

Effects of AMPA-receptor and voltage-sensitive sodium channel blockade on high potassium-induced glutamate release and neuronal death in vivo.

High extracellular potassium induces spreading depression-like depolarizations and elevations of extracellular glutamate. Both occur in the penumbra of a focal ischemic infarct, and may be responsible for the spread of cell death from the infarct core to the penumbra. We have modeled this situation with microdialysis of an isotonic high-potassium solution into the normal rat amygdala for 70 min. This elevates extracellular glutamate up to 8-fold or more and produces irreversibly damaged, acidophilic neurons. NMDA-receptor blockade protects neurons and reduces the elevation of extracellular glutamate. Here we investigated the effects of sodium channel blockade with the voltage-sensitive sodium channel blocker tetrodotoxin and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide disodium (NBQX disodium) on high potassium-induced neuronal death and extracellular glutamate elevations. The acidophilic neurons produced are necrotic by ultrastructural examination. Tetrodotoxin, at dialysate concentrations of 33, 330 and 3300 microM (only a small fraction is extracted by tissue), markedly reduced the elevations of glutamate in rat amygdala at nearly all time points during high-potassium perfusion, but it reduced tissue edema only at the highest concentration, and it was neuroprotective only if dialyzed prior to high-potassium microdialysis (at 330 microM concentration). Although both 250 microM (6.2% is extracted by tissue) and 500 microM NBQX reduced elevations of glutamate, neither was neuroprotective, and neuropil edema was not reduced by either concentration. Our results suggest that in vivo, sodium influx through voltage-sensitive sodium channels but not through ligand-gated AMPA receptor channels contributes to high potassium-induced neuronal necrosis.

Amygdala↗
PubMed2000

Voltage-dependent ion channels in CAD cells: A catecholaminergic neuronal line that exhibits inducible differentiation.

Cell lines derived from tumors engineered in the CNS offer promise as models of specific neuronal cell types. CAD cells are an unusual subclone of a murine cell line derived from tyrosine hydroxylase (TH) driven tumorigenesis, which undergoes reversible morphological differentiation on serum deprivation. Using single-cell electrophysiology we have examined the properties of ion channels expressed in CAD cells. Despite relatively low resting potentials, CAD cells can be induced to fire robust action potentials when mildly artificially hyperpolarized. Correspondingly, voltage-dependent sodium and potassium currents were elicited under voltage clamp. Sodium currents are TTX sensitive and exhibit conventional activation and inactivation properties. The potassium currents reflected two pharmacologically distinguishable populations of delayed rectifier type channels while no transient A-type channels were observed. Using barium as a charge carrier, we observed an inactivating current that was completely blocked by nimodipine and thus associated with L-type calcium channels. On differentiation, three changes in functional channel expression occurred; a 4-fold decrease in sodium current density, a 1.5-fold increase in potassium current density, and the induction of a small noninactivating barium current component. The neuronal morphology, excitability properties, and changes in channel function with differentiation make CAD cells an attractive model for study of catecholaminergic neurons.

Action Potentials↗
PubMed1996

A molecular basis for the therapy of the long QT syndrome.

The long QT syndrome (LQTS) is a familial disease characterized by abnormally prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmia. Recently, molecular biology studies brought major advancements in the understanding of the pathophysiologic mechanisms of this disease. The genes for the LQTS linked to chromosomes 3 (LQT3). 7 (LQT2) and 11 (LQT1) were identified as SCNSA, the cardiac sodium channel gene and as HERG and KVLQT1 potassium channel genes. We developed a cellular model in which ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. The effects of sodium channel blockade and rapid pacing were then studied showing a pronounced action potential shortening in response to mexlietine and during rapid pacing only in antopleurin-treated cells but no in dofetilide-treated cells. On this experimental basis, we tested the hypothesis that QT interval would behave differently during similar intervention in LQT3 and LQT2 patients. Results showed that 1) mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients and 2) LQT3 patients shortened their QT interal in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. They also suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cathecolamines with the insufficient adaptation of their QT interval when heart rate increases.

Action Potentials↗
PubMed1994

Potassium channel blockade amplifies cardiac instability numerical studies of torsades de pointes.

Suppression of responses to premature stimulation has been the guiding principle in managing many cardiac arrhythmias. Recent clinical trails revealed that sodium channel blockade increased the incidence of re-entrant cardiac arrhythmias resulting in sudden cardiac death, although the physiologic mechanism remains uncertain. Potassium channel blockade offers an alternative mechanism for suppressing responses to premature stimuli. We have developed a simple model of a 2D sheet of excitable cells. We can initiate re-entrant activation with stimuli timed to occur within a period of vulnerability (VP). Reducing the Na conductance increases the VP while reducing the K conductance increases the collective instability of the array, and arrhythmias similar to torsades de pointes seen in patients subjected to K channel blocked can be readily initiated. Thus, while K channel blockade may suppress excitability by prolonging the action potential duration, it appears to simultaneously exhibit proarrhythmic properties that result in complex re-entrant arrhythmias.

Action Potentials↗
PubMed1994

Electrophysiological properties of neonatal mouse cardiac myocytes in primary culture.

1. The increasing utility of transgenic mice in molecular studies of the cardiovascular system has motivated us to characterize the ionic currents in neonatal mouse ventricular myocytes. 2. Cell capacitance measurements (30 +/- 1 pF, n = 73) confirmed visual impressions that neonatal mouse ventricular myocytes in primary culture are considerably smaller than freshly isolated adult ventricular myocytes. With the use of electron microscopy, mitochondria and sarcoplasmic reticulum were found in close association with myofibrils, but transverse tubules were not observed. 3. Action potential durations, measured at 50 and 90% repolarization, were 23 +/- 1 and 42 +/- 2 ms respectively (n = 46). Application of 4-aminopyridine (4-AP; 5 mM) prolonged action potential duration at 50% repolarization by 26 +/- 5% (n = 3). The brevity of the action potential is explained by the rapid activation of a transient outward K+ current upon voltage-clamp depolarization to plateau potentials. 4. Potassium currents identified include an inward rectifier, a large 4-AP-sensitive transient outward, a slowly inactivating 4-AP-insensitive outward, a slowly activating delayed rectifier and a small rapidly activating E-4031 (10 microM)-sensitive delayed rectifier K+ current. 5. Sodium currents (-305 +/- 50 pA pF-1, n = 21) were recorded in 40 mM Na+ with Ni2+ (1 mM) to block Ca2+ currents and with K+ replaced by Cs+. The relative insensitivity of the Na+ current to block by tetrodotoxin (IC50 = 2.2 +/- 0.3 microM, n = 4) is distinctive of the cardiac Na+ channel isoform. 6. Nitrendipine-insensitive (10 microM) Ba2+ currents elicited during steps from -90 to -30 mV measured -25 +/- 5 pA pF-1 (n = 7, 30 mM Ba2+). Decay of these currents was complete during 180 ms depolarizations, even with Ba2+ as the charge carrier. These currents were not present when the holding potential was set at -50 mV. These data support the presence of a low threshold, T-type Ca2+ current. 7. The maximal nitrendipine-sensitive L-type Ca2+ current density was -10 +/- 2 pA pF-1 (n = 8) in 2 mM Ca2+ and -38 +/- 5 pA pF-1 (n = 9) in 30 mM Ba2+. Exposure to isoprenaline (1 microM) resulted in an 82% increase (n = 3) in the amplitude of the Ba2+ currents elicited at 0 mV. 8. Neonatal mouse cardiac myocytes in primary culture possess surprisingly large inward currents given the brevity of their action potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed2002

Voltage-gated ionic currents in an identified modulatory cell type controlling molluscan feeding.

An important modulatory cell type, found in all molluscan feeding networks, was investigated using two-electrode voltage- and current-clamp methods. In the cerebral giant cells of Lymnaea, a transient inward Na+ current was identified with activation at -58 +/- 2 mV. It was sensitive to tetrodotoxin only in high concentrations (approximately 50% block at 100 microm), a characteristic of Na+ channels in many molluscan neurons. A much smaller low-threshold persistent Na+ current (activation at < -90 mV) was also identified. Two purely voltage-sensitive outward K+ currents were also found: (i) a transient A-current type which was activated at -59 +/- 4 mV and blocked by 4-aminopyridine; (ii) a sustained tetraethylammonium-sensitive delayed rectifier current which was activated at -47 +/- 2 mV. There was also evidence that a third, Ca2+-activated, K+ channel made a contribution to the total outward current. No inwardly rectifying currents were found. Two Ca2+ currents were characterized: (i) a transient low-voltage (-65 +/- 2 mV) activated T-type current, which was blocked in NiCl2 (2 mm) and was completely inactivated at approximately -50 mV; (ii) A sustained high voltage (-40 +/- 1 mV) activated current, which was blocked in CdCl2 (100 microm) but not in omega-conotoxin GVIA (10 microm), omega-agatoxin IVA (500 nm) or nifedipine (10 microm). This current was enhanced in Ba2+ saline. Current-clamp experiments revealed how these different current types could define the membrane potential and firing properties of the cerebral giant cells, which are important in shaping the wide-acting modulatory influence of this neuron on the rest of the feeding network.

Action Potentials↗
PubMed1997

Neuronal synchronization and ionic mechanisms for propagation of excitation in the functional network of immortalized GT1-7 neurons: optical imaging with a voltage-sensitive dye.

Immortalized gonadotropin releasing hormone (GnRH) neurons (GT1 cell line) in culture release GnRH in a pulsatile manner, suggesting that GT1 cells form a functional neuronal network. Optical imaging techniques and a voltage-sensitive fluorescent dye (RH795) were used to study the mechanism of neuronal synchronization and intercellular communication in cultured GT1-7 cells (one of the subclones of the GT1 cell line). The majority (79%) of GT1-7 cells in contact with one another revealed synchronized fluctuations in spontaneous neuronal activity. When a cell in contact with other cells was electrically stimulated, the evoked excitation was propagated to neighbouring cells. The ionic mechanisms involved in the propagation of electrical signals between interconnected GT1-7 cells were investigated using various blockers of Na+, Ca2+ and K+ channels. The propagation of stimulus-evoked excitation was prevented by the voltage-dependent Na+ channel blocker tetrodotoxin. It was also prevented by the voltage-dependent Ca2+ channel blockers, Ni+ (nonselective), nimodipine (L-type) and flunarizine (T-type > L-type), but not apparently affected by omega-agatoxin IVA (P- and Q-type) and omega-conotoxin MVIIA (N-type). The propagation was not influenced by the K+ channel blockers, quinine, tetraethylammonium and Ba2+, but in some cases, it was enhanced by 4-aminopyridine (4-AP) and prevented by apamin. These results suggest that voltage-dependent Na+ channels and L- and T-type Ca2+ channels are involved in the propagation of electrical signals in the GT1-7 neuronal network. Ionic mechanisms, through 4-AP- or apamin-sensitive K+ channels, also seem to be involved in the regulation of signal propagation. These mechanisms may underlie the functioning of the neuronal network formed by immortalized GnRH neurons.

Animals↗
PubMed1995

Basic concepts in cellular cardiac electrophysiology: Part II: Block of ion channels by antiarrhythmic drugs.

Antiarrhythmic drugs have relative specificity for blocking each of the major classes of ion channels that control the action potential. The kinetics of block is determined by the state of the channel. Those channel states occupied at depolarized potentials generally have greater affinity for the blocking drugs. The kinetics of the drug-channel interaction is important in determining the blocking profile observed clinically. The increased mortality resulting from drug treatment in CAST and several atrial fibrillation trials has resulted in a shift in antiarrhythmic drug development from the Na+ channel blocking (Class I) drugs to the K+ channel blocking (Class III) drugs. While both Classes of drugs have a proarrhythmic potential, this may be less for the Class III agents. Their lack of negative inotropy also make them more attractive. It is important that the potential advantages of these agents be evaluated in controlled clinical trials. In several laboratories, the techniques of molecular biology and biophysics are being combined to determine the block site of available drugs. This information will aid in the future development of agents with greater specificity, and hopefully greater efficacy and safety than those currently in clinical use.

Action Potentials↗
PubMed2005

Effects of Na(+) and K(+) channel blockade on vulnerability to and termination of fibrillation in simulated normal cardiac tissue.

Na(+) and K(+) channel-blocking drugs have anti- and proarrhythmic effects. Their effects during fibrillation, however, remain poorly understood. We used computer simulation of a two-dimensional (2-D) structurally normal tissue model with phase I of the Luo-Rudy action potential model to study the effects of Na(+) and K(+) channel blockade on vulnerability to and termination of reentry in simulated multiple-wavelet and mother rotor fibrillation. Our main findings are as follows: 1) Na(+) channel blockade decreased, whereas K(+) channel blockade increased, the vulnerable window of reentry in heterogeneous 2-D tissue because of opposing effects on dynamical wave instability. 2) Na(+) channel blockade increased the cycle length of reentry more than it increased refractoriness. In multiple-wavelet fibrillation, Na(+) channel blockade first increased and then decreased the average duration or transient time ( ) of fibrillation. In mother rotor fibrillation, Na(+) channel blockade caused peripheral fibrillatory conduction block to resolve and the mother rotor to drift, leading to self-termination or sustained tachycardia. 3) K(+) channel blockade increased dynamical instability by steepening action potential duration restitution. In multiple-wavelet fibrillation, this effect shortened because of enhanced wave instability. In mother rotor fibrillation, this effect converted mother rotor fibrillation to multiple-wavelet fibrillation, which then could self-terminate. Our findings help illuminate, from a theoretical perspective, the possible underlying mechanisms of termination of different types of fibrillation by antiarrhythmic drugs.

Anti-Arrhythmia Agents↗
PubMed1996

The effects of verapamil and lidocaine on the duration of propofol and xylazine-ketamine anesthesia in broiler chickens.

The effects of verapamil, a calcium channel blocker, and lidocaine, a sodium channel blocker, administration on the duration of 1 mg propofol/kg i.v. or 5 mg xylazine/kg + 15 mg ketamine/kg i.m. anesthesia were examined in 1 and 6-w-old broiler chickens. The use of 2.5 or 1.25 mg verapamil/kg i.m. or 5 mg lidocaine/kg im prolonged the sleep time induced by the anesthetic agents. Administration of 5 mg verapamil/kg i.m. caused unexpected acute toxicity and mortality. This study suggests that propofol and xylazine + ketamine anesthesia in broilers may be modulated by calcium and sodium channels.

Aging↗
PubMed2005

Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.

Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal sodium channels can trigger axonal degeneration, recent studies have tested sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, sodium channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that sodium channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of sodium channel Nav1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for sodium channels in microglial activation, we show that tetrodotoxin, a specific sodium channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Nav1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Nav1.6 channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that sodium channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, sodium channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms.

Animals↗
PubMed1989

Cocaine stimulates rat hypothalamic corticotropin-releasing hormone secretion in vitro.

Acute or chronic cocaine administration exerts multiple behavioral and physiologic effects including stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Pharmacologically, cocaine shares major properties with at least 2 classes of pharmaceuticals. It is a local anesthetic and also a potent psychomotor stimulant. The psychomotor stimulant properties of cocaine are thought to be related to its ability to modify the metabolism and the activity of many neurotransmitter systems, such as acetylcholine (ACh), serotonin (5-HT), norepinephrine (NE), and dopamine (DA). We and others have shown that all these neurotransmitters are potent stimulants of hypothalamic corticotropin-releasing hormone (CRH) secretion. The present study was undertaken to examine whether cocaine stimulates hypothalamic CRH secretion and whether or not such an effect is mediated by any of the above neurotransmitters. To accomplish this task, we employed a rat hypothalamic organ culture system, in which CRH secretion form single explanted hypothalami was evaluated by specific radioimmunoassay (iCRH). Cocaine stimulated iCRH secretion in a dose-dependent fashion with peak of activity at 10(-8) M. Isolated or simultaneous pharmacologic blockade of cholinergic (atropine plus hexamethonium), serotonergic (ritanserin), alpha-adrenergic (phentolamine) and/or dopaminergic (compound SCH 23390) receptor subtypes failed to inhibit cocaine-induced iCRH secretion. On the other hand, cocaine-induced iCRH secretion was inhibited by GABA, a potent inhibitor of CRH secretion, dexamethasone, verapamil, a calcium channel blocker, tetrodotoxin, a sodium channel blocker, and carbamazepine, an antiepileptic and antidepressive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Capillary as a communicating medium in the microvasculature.

The preceding study (Dietrich and Tyml, 1992. Microvasc. Res. 43) demonstrated that a local application of norepinephrine (NE) on a capillary in a skeletal muscle produces a temporary reduction in blood flow within this capillary. The reduction is mediated via constriction of the supplying arteriole. The objective of the present study was to address the mechanism by which the local NE stimulus is propagated from the capillary to the arteriole. Using intravital video microscopy we measured red blood cell velocity in capillaries, and diameter of supplying arterioles, in the sartorius muscle in anesthetized frogs. Velocity responses were measured following iontophoretic application of NE (3 mM in the pipette) on the capillary, with or without pretreatment with 0.9 mM tetrodotoxin (nerve-specific sodium channel blocker), 30 mM lidocaine (nonspecific sodium channel blocker), and 30 mM yohimbine (alpha 2-receptor blocker). Diameter responses were measured before and after capillary damage introduced by microcautery. Tetrodotoxin did not block the NE-induced velocity reduction (i.e., from 0.2 to 0.07 mm/sec), while lidocaine attenuated it. Yohimbine blocked it only when applied on the same site as NE. Capillary damage abolished the NE-induced arteriolar constriction (i.e., from 27.8 to 21.5 microns). We conclude that the observed responses were not due to (1) direct diffusion of NE from the capillary to the arteriole, (2) conduction along adrenergic nerves, or (3) venous-arteriolar diffusional cross-talk. We interpret our data to indicate that the capillary itself could function as a communicating medium.

Animals↗
PubMed2006

Isolated perfused and paced guinea pig heart to test for drug-induced changes of the QT interval.

INTRODUCTION: One of the biomarkers for assessing the risk of a cardiac adverse event is drug-induced prolongation of the QT interval. A model is needed for evaluating the potential liability of test compounds on QT interval in vitro. Since QT intervals can be generated from paced or spontaneously beating hearts, data so generated can also be used for validating QT(c) correction equations. METHODS: Isolated guinea pig hearts were perfused in Locke's solution according to the Langendorff method. QT intervals were routinely measured from Lead II ECG waveforms. RESULTS: Compounds known to inhibit HERG channel, such as dofetilide, prolonged the QT interval in this model. (+/-)Bay K8644, a calcium channel activator, prolonged the QT interval, while verapamil, a calcium channel blocker, shortened it. Procainamide, a sodium channel blocker, also prolonged the QT interval. Many of the compounds, which prolonged the QT interval, also prolonged PR interval, suggesting dual inhibition of the Ikr channel, the rapid component of delayed rectifier potassium channel, and the calcium channel. The QT/RR intervals exhibited a curvilinear relationship, which could be corrected into nearly straight horizontal lines by using correction equations derived from linear, parabolic, and hyperbolic models. However, these correction equations yielded different results on the QT prolongation produced by sotalol, which also slowed down the heart rate. With the data set obtained in this investigation, correction equations derived from linear and parabolic models worked better than the equations derived from the hyperbolic model. The exponential model did not fit at all. CONCLUSION: QT intervals obtained under paced conditions provide the most direct and reliable QT information for a drug. The isolated perfused and paced guinea pig heart is a convenient model for studying the effect of compounds on QT interval in vitro.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Reversal of neuropathic pain by alpha-hydroxyphenylamide: a novel sodium channel antagonist.

Sodium (Na) channel blockers are known to possess antihyperalgesic properties. We have designed and synthesized a novel Na channel antagonist, alpha-hydroxyphenylamide, and determined its ability to inhibit both TTX-sensitive (TTX-s) and TTX-resistant (TTX-r) Na currents from small dorsal root ganglion (DRG) neurons. alpha-Hydroxyphenylamide tonically inhibited both TTX-s and TTX-r Na currents yielding an IC(50) of 8.2+/-2.2 microM (n=7) and 28.9+/-1.8 microM (n=8), respectively. In comparison, phenytoin was less potent inhibiting TTX-s and TTX-r currents by 26.2+/-4.0% (n=8) and 25.5+/-2.0%, respectively, at 100 microM. alpha-Hydroxyphenylamide (10 microM) also shifted equilibrium gating parameters of TTX-s Na channels to greater hyperpolarized potentials, slowed recovery from inactivation, accelerated the development of inactivation and exhibited use-dependent block. In the chronic constriction injury (CCI) rat model of neuropathic pain, intraperitoneal administration of alpha-hydroxyphenylamide attenuated the hyperalgesia by 53% at 100mg/kg, without affecting motor coordination in the Rotorod test. By contrast, the reduction in pain behavior produced by phenytoin (73%; 100mg/kg) was associated with significant motor impairment. In summary, we report that alpha-hydroxyphenylamide, a sodium channel antagonist, exhibits antihyperalgesic properties in a rat model of neuropathic pain, with favorable sedative and ataxic side effects compared with phenytoin.

Action Potentials↗
PubMed2006

Pharmacological characterization of ionic currents that regulate high-frequency spontaneous activity of electromotor neurons in the weakly electric fish, Apteronotus leptorhynchus.

The neural circuit that controls the electric organ discharge (EOD) of the brown ghost knifefish (Apteronotus leptorhynchus) contains two spontaneous oscillators. Both pacemaker neurons in the medulla and electromotor neurons (EMNs) in the spinal cord fire spontaneously at frequencies of 500-1,000 Hz to control the EOD. These neurons continue to fire in vitro at frequencies that are highly correlated with in vivo EOD frequency. Previous studies used channel blocking drugs to pharmacologically characterize ionic currents that control high-frequency firing in pacemaker neurons. The goal of the present study was to use similar techniques to investigate ionic currents in EMNs, the other type of spontaneously active neuron in the electromotor circuit. As in pacemaker neurons, high-frequency firing of EMNs was regulated primarily by tetrodotoxin-sensitive sodium currents and by potassium currents that were sensitive to 4-aminopyridine and kappaA-conotoxin SIVA, but resistant to tetraethylammonium. EMNs, however, differed from pacemaker neurons in their sensitivity to some channel blocking drugs. Alpha-dendrotoxin, which blocks a subset of Kv1 potassium channels, increased firing rates in EMNs, but not pacemaker neurons; and the sodium channel blocker muO-conotoxin MrVIA, which reduced firing rates of pacemaker neurons, had no effect on EMNs. These results suggest that similar, but not identical, ionic currents regulate high-frequency firing in EMNs and pacemaker neurons. The differences in the ionic currents expressed in pacemaker neurons and EMNs might be related to differences in the morphology, connectivity, or function of these two cell types.

Action Potentials↗