TTX-R Na+ current-reduction by celecoxib correlates with changes in PGE2 and CGRP within rat DRG neurons during acute incisional pain

The fast transient inward current elicited by depolarizations above about –60 mV in calf Purkinje fibres was found to be depressed by Cd in concentrations less than 1 mm. The Cd-sensitive current, which strongly depended on external Na, was recorded in the presence of 2 mm MnCl 2 and was blocked by TTX , indicating that a contamination from slow Ca-dependent currents could be discounted. The current reduction caused by Cd was also observed in nominally Ca-free solutions. The Cd-induced depression of the fast Na current was not accompanied by changes in the current kinetic parameters, as revealed by comparing inactivation curves and peak current voltage relations at different Cd concentrations, and could be attributed to a voltage-independent channel blocking action. Half-blockade occurred at 0.182±0.06 mm ( n = 4). Plots of peak current amplitude as a function of the Cd concentration showed that the cooperation of two Cd ions was required to block a single channel.

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Lidocaine suppresses subthreshold oscillations by inhibiting persistent Na+ current in injured dorsal root ganglion neurons

Physiological Research ◽

10.33549/physiolres.931164 ◽

2008 ◽

pp. 639-646

Author(s):

H Dong ◽

Y-H Fan ◽

Y-Y Wang ◽

W-T Wang ◽

S-J Hu

Keyword(s):

Dorsal Root Ganglion ◽

Voltage Clamp ◽

Dorsal Root ◽

Na Current ◽

Drg Neurons ◽

Current Clamp ◽

Low Concentration ◽

Current Clamp Mode ◽

Single Spike ◽

Ganglion Neurons

The aim of this study was to determine the effect and mechanism of low concentration of lidocaine on subthreshold membrane potential oscillations (SMPO) and burst discharges in chronically compressed dorsal root ganglion (DRG) neurons. DRG neurons were isolated by enzymatic dissociation method. SMPO, burst discharges and single spike were elicited by whole cell patchclamp technique in current clamp mode. Persistent Na+ current (INaP) and transient Na+ current (INaT) were elicited in voltage clamp mode. The results showed that SMPO was suppressed and burst discharges were eliminated by tetrodotoxin (TTX, 0.2 μmol/l) in current clamp mode, INaP was blocked by 0.2 μmol/l TTX in voltage clamp mode. SMPO, burst discharges and INaP were also suppressed by low concentration of lidocaine (10 μmol/l) respectively. However, single spike and INaT could only be blocked by high concentration of lidocaine (5 mmol/l). From these results, it is suggested that INaP mediates the generation of SMPO in injured DRG neurons. Low concentration of lidocaine (10 μmol/l) suppresses SMPO by selectively inhibiting INaP, but not INaT, in chronically compressed DRG neurons.

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Rapid Induction of P/C-type Inactivation Is the Mechanism for Acid-induced K+ Current Inhibition

The Journal of General Physiology ◽

10.1085/jgp.20028760 ◽

2003 ◽

Vol 121 (3) ◽

pp. 215-225 ◽

Cited By ~ 17

Author(s):

Shetuan Zhang ◽

Harley T. Kurata ◽

Steven J. Kehl ◽

David Fedida

Keyword(s):

Time Course ◽

Low Ph ◽

Sufficient Time ◽

Na Current ◽

Extracellular Acidification ◽

Current Time ◽

Rapid Induction ◽

Na Currents ◽

K Current ◽

Current Reduction

Extracellular acidification is known to decrease the conductance of many voltage-gated potassium channels. In the present study, we investigated the mechanism of H+o-induced current inhibition by taking advantage of Na+ permeation through inactivated channels. In hKv1.5, H+o inhibited open-state Na+ current with a similar potency to K+ current, but had little effect on the amplitude of inactivated-state Na+ current. In support of inactivation as the mechanism for the current reduction, Na+ current through noninactivating hKv1.5-R487V channels was not affected by [H+o]. At pH 6.4, channels were maximally inactivated as soon as sufficient time was given to allow activation, which suggested two possibilities for the mechanism of action of H+o. These were that inactivation of channels in early closed states occurred while hyperpolarized during exposure to acid pH (closed-state inactivation) and/or inactivation from the open state was greatly accelerated at low pH. The absence of outward Na+ currents but the maintained presence of slow Na+ tail currents, combined with changes in the Na+ tail current time course at pH 6.4, led us to favor the hypothesis that a reduction in the activation energy for the inactivation transition from the open state underlies the inhibition of hKv1.5 Na+ current at low pH.

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Persistent TTX-Resistant Na+ Current Affects Resting Potential and Response to Depolarization in Simulated Spinal Sensory Neurons

Journal of Neurophysiology ◽

10.1152/jn.2001.86.3.1351 ◽

2001 ◽

Vol 86 (3) ◽

pp. 1351-1364 ◽

Cited By ~ 201

Author(s):

R. I. Herzog ◽

T. R. Cummins ◽

S. G. Waxman

Keyword(s):

Sensory Neurons ◽

Dorsal Root ◽

Strong Influence ◽

Neuronal Excitability ◽

Sodium Current ◽

Current Model ◽

Resting Potential ◽

Slow Inactivation ◽

Na Current ◽

Drg Neurons

Small dorsal root ganglion (DRG) neurons, which include nociceptors, express multiple voltage-gated sodium currents. In addition to a classical fast inactivating tetrodotoxin-sensitive (TTX-S) sodium current, many of these cells express a TTX-resistant (TTX-R) sodium current that activates near −70 mV and is persistent at negative potentials. To investigate the possible contributions of this TTX-R persistent (TTX-RP) current to neuronal excitability, we carried out computer simulations using the Neuron program with TTX-S and -RP currents, fit by the Hodgkin-Huxley model, that closely matched the currents recorded from small DRG neurons. In contrast to fast TTX-S current, which was well fit using a m3h model, the persistent TTX-R current was not well fit by an m3h model and was better fit using an mh model. The persistent TTX-R current had a strong influence on resting potential, shifting it from −70 to −49.1 mV. Inclusion of an ultra-slow inactivation gate in the persistent current model reduced the potential shift only slightly, to −56.6 mV. The persistent TTX-R current also enhanced the response to depolarizing inputs that were subthreshold for spike electrogenesis. In addition, the presence of persistent TTX-R current predisposed the cell to anode break excitation. These results suggest that, while the persistent TTX-R current is not a major contributor to the rapid depolarizing phase of the action potential, it contributes to setting the electrogenic properties of small DRG neurons by modulating their resting potentials and response to subthreshold stimuli.

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Paired helical filaments (PHF) in rats: An experimental animal model for Alzheimer's disease

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128493 ◽

1987 ◽

Vol 45 ◽

pp. 842-843

Author(s):

V.J.A. Montpetit ◽

S. Dancea ◽

S.W. French ◽

D.F. Clapin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Model ◽

Paired Helical Filaments ◽

Ethanol Intoxication ◽

Drg Neurons ◽

Critical Difference ◽

Suitable Animal Model ◽

The Central Nervous System ◽

Chronic Ethanol Intoxication

A continuing problem in Alzheimer research is the lack of a suitable animal model for the disease. The absence of neurofibrillary tangles of paired helical filaments is the most critical difference in the processes by which the central nervous system ages in most species other than man. However, restricting consideration to single phenomena, one may identify animal models for specific aspects of Alzheimer's disease. Abnormal fibers resembling PHF have been observed in dorsal root ganglia (DRG) neurons of rats in a study of chronic ethanol intoxication and spontaneously in aged rats. We present in this report evidence that PHF-like filaments occur in ethanol-treated rats of young age. In control animals lesions similar in some respects to our observations of cytoskeletal pathology in pyridoxine induced neurotoxicity were observed.Male Wistar BR rats (Charles River Labs) weighing 350 to 400 g, were implanted with a single gastrostomy cannula and infused with a liquid diet containing 30% of total calories as fat plus ethanol or isocaloric dextrose.

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