scholarly journals The pH-dependent rate of action of local anesthetics on the node of Ranvier.

1977 ◽  
Vol 69 (4) ◽  
pp. 475-496 ◽  
Author(s):  
B Hille
Keyword(s):  
Membrane Permeability ◽  
Local Anesthetics ◽  
Time Course ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
Lipid Solubility ◽  
Myelinated Nerve ◽  
Degree Of Ionization ◽  
Hydrophobic Barrier ◽  
High Lipid Solubility

Local anesthetic solutions were applied suddenly to the outside of single myelinated nerve fibers to measure the time course of development of block of sodium channels. Sodium currents were measured under voltage clamp with test pulses applied several times per second during the solution change. The rate of block was studied by using drugs of different lipid solubility and of different charge type, and the external pH was varied from pH 8.3 to pH 6 to change the degree of ionization of the amine compounds. At pH 8.3 the half-time of action of amine anesthetics such as lidocaine, procaine, tetracaine, and others was always less than 2 s and usually less than 1 s. Lowering the pH to 6.0 decreased the apparent potency and slowed the rate of action of these drugs. The rate of action of neutral benzocaine was fast (1 s) and pH independent. The rate of action of cationic quaternary QX-572 was slow (greater than 200 s) and also pH independent. Other quaternary anesthetic derivatives showed no action when applied outside. The result is that neutral drug forms act much more rapidly than charged ones, suggesting that externally applied local anesthetics must cross a hydrophobic barrier to reach their receptor. A model representing diffusion of drug into the nerve fiber gives reasonable time courses of action and reasonable membrane permeability coefficients on the assumption that the hydrophobic barrier is the nodal membrane. Arguments are given that there may be a need for reinterpretation of many published experiments on the location of the anesthetic receptor and on which charge form of the drug is active to take into account the effects of unstirred layers, high membrane permeability, and high lipid solubility.

Gating currents in the node of Ranvier: voltage and time dependence

1975 ◽  
Vol 270 (908) ◽  
pp. 483-492 ◽  
Keyword(s):  
Membrane Potential ◽  
Time Constant ◽  
Time Course ◽  
Voltage Dependence ◽  
Sudden Change ◽  
Node Of Ranvier ◽  
Ionic Currents ◽  
Gating Currents ◽  
Myelinated Nerve ◽  
Sodium Conductance

Like the axolemma of the giant nerve fibre of the squid, the nodal membrane of frog myelinated nerve fibres after blocking transmembrane ionic currents exhibits asymmetrical displacement currents during and after hyperpolarizing and depolarizing voltage clamp pulses of equal size. The steady-state distribution of charges as a function of membrane potential is consistent with Boltzmann’s law (midpoint potential —33.7 mV; saturation value 17200 charges/(μm 2 ). The time course of the asymmetry current and the voltage dependence of its time constant are consistent with the notion that due to a sudden change in membrane potential the charges undergo a first order transition between two configurations. Size and voltage dependence of the time constant are similar to those of the activation of the sodium conductance assuming m 2 h kinetics, The results suggest the presence of ten times more sodium channels (5000/μm2) in the node of Ranvier than in the squid giant axon with similar sodium conductance per channel (2-3 pS),

scholarly journals Long-lasting increase in axonal excitability after epidurally applied DC

2017 ◽  
Vol 118 (2) ◽  
pp. 1210-1220 ◽  
Author(s):  
Elzbieta Jankowska ◽  
Dominik Kaczmarek ◽  
Francesco Bolzoni ◽  
Ingela Hammar
Keyword(s):  
Pain Control ◽  
Time Course ◽  
Nerve Fibers ◽  
Myelinated Nerve ◽  
Epidural Stimulation ◽  
Myelinated Nerve Fibers ◽  
Dorsal Columns ◽  
New Form ◽  
Axonal Excitability ◽  
Dc Polarization

The study indicates a new form of plasticity of myelinated fibers. The differences in time course of DC-evoked increases in the excitability of myelinated nerve fibers in the dorsal columns and in preterminal axonal branches suggest that distinct mechanisms are involved in them. The results show that combining epidural stimulation and transspinal DC polarization may dramatically improve their outcome and result in more effective pain control and the return of impaired motor functions.

scholarly journals The Inner Quaternary Ammonium Ion Receptor in Potassium Channels of the Node of Ranvier

1972 ◽  
Vol 59 (4) ◽  
pp. 388-400 ◽  
Author(s):  
Clay M. Armstrong ◽  
Bertil Hille
Keyword(s):  
Potassium Channels ◽  
Quaternary Ammonium ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
Ammonium Ion ◽  
Ammonium Ions ◽  
Myelinated Nerve ◽  
Quaternary Ammonium Ions ◽  
Activation Gate ◽  
Almost All

Quaternary ammonium ions were applied to the inside of single myelinated nerve fibers by diffusion from a cut end. The resulting block of potassium channels in the node of Ranvier was studied under voltage-clamp conditions. The results agree in almost all respects with similar studies by Armstrong of squid giant axons. With tetraethylammonium ion (TEA), pentyltriethylammonium ion (C5), or nonyltriethylammonium ion (C9) inside the node, potassium current during a depolarization begins to rise at the normal rate, reaches a peak, and then falls again. This unusual inactivation is more complete with C9 than with TEA. Larger depolarizations give more block. Thus the block of potassium channels grows with time and voltage during a depolarization. The block reverses with repolarization, but for C9 full reversal takes seconds at -75 mv. The reversal is faster in 120 mM KCl Ringer's and slower during a hyperpolarization to -125 mv. All of these effects contrast with the time and voltage-independent block of potassium, channels seen with external quaternary ammonium ions on the node of Ranvier. External TEA, C5, and C9 block without inactivation. The external quaternary ammonium ion receptor appears to be distinct from the inner one. Apparently the inner quaternary ammonium ion receptor can be reached only when the activation gate for potassium channels is open. We suggest that the inner receptor lies within the channel and that the channel is a pore with its activation gate near the axoplasmic end.

scholarly journals Time Course of Axon and Myelin Degeneration in Peripheral Nerves in Experimental Autoimmune Neuritis Rats

2019 ◽  
Vol 47 (4) ◽  
pp. 542-552 ◽  
Author(s):  
Emi Tomikawa ◽  
Mayu Mutsuga ◽  
Kojiro Hara ◽  
Chihiro Kaneko ◽  
Yuko Togashi ◽  
...  
Keyword(s):  
Peripheral Nerves ◽  
Time Course ◽  
Nerve Fibers ◽  
Neurological Symptoms ◽  
Experimental Autoimmune Neuritis ◽  
Histopathological Changes ◽  
Cell Cytoplasm ◽  
Myelinated Nerve ◽  
Transmission Electron ◽  
Experimental Autoimmune

Experimental autoimmune neuritis (EAN) is an animal model for Guillain–Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats. Axon and myelin degeneration was observed by light microscopy at onset, degeneration became severe at peak, and persisted at recovery. Densities of myelinated nerve fibers and myelin areas decreased from day 10 to a minimum on day 22. Slight axon and myelin degeneration, such as accumulation of vesicles in axons and focal myelin splitting and folding, was observed by transmission electron microscopy at onset; severe degeneration, such as axonal loss, myelin ovoid, and demyelination, increased at peak; and regenerative changes, such as remyelination and enlargement of Schwann cell cytoplasm, occurred at recovery. These results suggest that EAN rats have histopathological similarities to some types of GBS patients and that EAN rats are a useful model to understand the pathogenesis of GBS.

scholarly journals CHOLINESTERASE ACTIVITY OF NODAL AND INTERNODAL REGIONS OF MYELINATED NERVE FIBERS OF FROG

1967 ◽  
Vol 32 (3) ◽  
pp. 577-583 ◽  
Author(s):  
Miro Brzin ◽  
Wolf-D. Dettbarn
Keyword(s):  
Enzyme Activity ◽  
Esterase Activity ◽  
Cholinesterase Activity ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
Selective Inhibitors ◽  
Myelinated Nerve ◽  
Myelinated Nerve Fibers ◽  
Significant Difference ◽  
Saltatory Conduction

The distribution of cholinesterase (Ch-esterase) in isolated myelinated fibers of the frog has been investigated. Quantitative microgasometric measurements have confirmed the previous histochemical observations. Both approaches indicate that in frog nerve fibers acetylcholinesterase (ACh-esterase) is the only or the predominant enzyme when selective inhibitors and different substrates are used: acetylcholine (ACh), butyrylcholine, and acetyl-B-methylcholine (Mecholyl). By means of the microgasometric technique, a significant difference in ACh-esterase activity between axons isolated from ventral (37.2 ± 1.7 µmole x 10-5 ACh/mm2/hr) and dorsal roots (2.0 ± 0.9 µmole x 10-5 ACh/mm2/hr) was found. In the region of the node of Ranvier the enzyme activity (50.4 ± 4.4 µmole x 10-5 ACh/mm2/hr) appears to be considerably higher than in the internodal area (36.6 ± 2.1 µmole x 10-5 ACh/mm2/hr). The findings are discussed in relation to the theory of saltatory conduction and the ACh system.

scholarly journals The mechanosensitive ion channel TRAAK is localized to the mammalian node of Ranvier

2019 ◽  
Author(s):  
Stephen G. Brohawn ◽  
Weiwei Wang ◽  
Jürgen R. Schwarz ◽  
Annie Handler ◽  
Ernest B. Campbell ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Polyclonal Antibodies ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
Resting Membrane Potential ◽  
Myelinated Nerve ◽  
Myelinated Nerve Fibers ◽  
Behavioral Studies ◽  
Mechanosensitive Ion Channel

ABSTRACTTRAAK is a membrane tension-activated K+ channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the ‘leak’ K+ current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+ channel availability for action potential propagation. Mechanical gating in TRAAK might serve a neuroprotective role by counteracting mechanically-induced ectopic action potentials. Alternatively, TRAAK may open in response to mechanical forces in the nodal membrane associated with depolarization during saltatory conduction and thereby contribute to repolarization of the node for subsequent spikes.

scholarly journals Damage and repair of the peripheral myelin sheath and node of Ranvier after treatment with trypsin.

1975 ◽  
Vol 64 (1) ◽  
pp. 1-14 ◽  
Author(s):  
R C Yu ◽  
R P Bunge
Keyword(s):  
Schwann Cell ◽  
Light And Electron Microscopy ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
Myelinated Nerve ◽  
Nodal Region ◽  
Fetal Rat ◽  
The Matrix ◽  
Cell Processes

Cultures of whole fetal rat sensory ganglia which had matured and myelinated in culture were treated for 1-3 h with a pulse of 0.2% trypsin. The tissue was observed during the period of treatment and during subsequent weeks using both light and electron microscopy. Within minutes after trypsin addition the matrix of the culture was altered and the nerve fascicles loosened. Progressive changes included the retraction of Schwann cell processes from the nodal region the detachment of the myelin-related paranodal Schwann cell loops from the axon, and lengthening of the nodal region as the axon was bared. The retraction of myelin from nodal stabilized several hours after trypsin withdrawal. Breakdown of the altered myelin segments was rare. There were no discernable changes in neurons or their processes after this exposure to trypsin. The partial repair which occured over a period of several weeks included the reattachment of paranodal Schwann cell loops to the axolemma and the insertion of new myelin segments where a substantial length of axolemma had been bared. The significance of these observations to the characterization of the Schwann cell-axolemmal junctions on myelinated nerve fibers is discussed. The dramatic degree of myelin change that can occur without concomitant myelin breakdown is particularly noted, as is the observation that these altered myelin segments are, in part, repaired.

scholarly journals The mechanosensitive ion channel TRAAK is localized to the mammalian node of Ranvier

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Stephen G Brohawn ◽  
Weiwei Wang ◽  
Annie Handler ◽  
Ernest B Campbell ◽  
Jürgen R Schwarz ◽  
...  
Keyword(s):  
Action Potential ◽  
Polyclonal Antibodies ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
K Channel ◽  
Resting Membrane Potential ◽  
Na Channel ◽  
Nodes Of Ranvier ◽  
Myelinated Nerve ◽  
Myelinated Nerve Fibers

TRAAK is a membrane tension-activated K+ channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in what is likely an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the ‘leak’ K+ current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+ channel availability for action potential propagation. We speculate on why nodes of Ranvier contain a mechanosensitive K+ channel.

scholarly journals A LIGHT AND ELECTRON HISTOCHEMICAL APPROACH TO THE NODE OF RANVIER AND MYELIN OF PERIPHERAL NERVE FIBERS

1967 ◽  
Vol 15 (12) ◽  
pp. 722-731 ◽  
Author(s):  
O. K. LANGLEY ◽  
D. N. LANDON
Keyword(s):  
Osmium Tetroxide ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
Blue Pigment ◽  
Staining Reaction ◽  
Myelinated Nerve ◽  
Structural Localization ◽  
Axon Membrane ◽  
Specific Localization ◽  
Exchange Properties

The Hale staining reaction has been used to study the nature and distribution of acid mucopolysaccharides associated with mammalian peripheral myelinated nerve fibers. Histochemical blocking reactions were employed to determine the specificity of the method. Electron micrographs of parallel preparations were examined to discover the fine structural localization of the optically visible Prussian blue pigment. The observations reported suggest that there is a specific localization of a sulfated mucopolysaccharide in the region immediately surrounding the axolemma at the node of Ranvier. Other parts of the fiber, in particular the myelin sheath, show a preponderance of carboxyl groups. Attention is drawn to the variation in the form and distribution of the Hale stain product after differing fixation procedures. The effect of osmium tetroxide on ferrocyanide-treated material is examined and discussed. Attention is directed to possible physiologic implications of the presence of material with the known ion exchange properties of a sulfated mucopolysaccharide in the immediate environment of the ionically active nodal axon membrane.

scholarly journals Local anesthetics potently block a potential insensitive potassium channel in myelinated nerve.

1995 ◽  
Vol 105 (4) ◽  
pp. 485-505 ◽  
Author(s):  
M E Bräu ◽  
C Nau ◽  
G Hempelmann ◽  
W Vogel
Keyword(s):  
Local Anesthetics ◽  
Single Channel ◽  
Distribution Coefficients ◽  
Nerve Fibers ◽  
K Channel ◽  
Na Channel ◽  
Myelinated Nerve ◽  
Time Constants ◽  
Channel Inactivation ◽  
Ic50 Values

Effects of some local anesthetics were studied in patch clamp experiments on enzymatically demyelinated peripheral amphibian nerve fibers. Micromolar concentrations of external bupivacaine depolarized the excised membrane considerably. The flicker K+ channel was found to be the most sensitive ion channel to local anesthetics in this preparation. Half-maximum inhibiting concentrations (IC50) for extracellular application of bupivacaine, ropivacaine, etidocaine, mepivacaine, lidocaine, and QX-314 were 0.21, 4.2, 8.6, 56, 220, and > 10,000 microM, respectively. The corresponding concentration-effect curves could be fitted under the assumption of a 1:1 reaction. Application from the axoplasmic side resulted in clearly lower potencies with IC50 values of 2.1, 6.6, 16, 300, 1,200, and 1,250 microM, respectively. The log(IC50)-values of the local anesthetics linearly depended on the logarithm of their octanol:buffer distribution coefficients with two regression lines for the piperidine derivatives and the standard amino-amides indicating an inherently higher potency of the cyclic piperidine series. Amide-linked local anesthetics did not impair the amplitude of the single-channel current but prolonged the time of the channel to be in the closed state derived as time constants tau c from closed-time histograms. With etidocaine and lidocaine tau c was 133 and 7.2 ms, and proved to be independent of concentration. With the most potent bupivacaine time constants of wash in and wash out were 1.8 and 5.2 s for 600 nM bupivacaine. After lowering the extracellular pH from 7.4 to 6.6, externally applied bupivacaine showed a reduced potency, whereas at higher pH of 8.2 the block was slightly enhanced. Intracellular pH of 6.4, 7.2, 8.0 had almost no effect on internal bupivacaine block. It is concluded that local anesthetics block the flicker K+ channel by impeding its gating but not its conductance. The slow blocker bupivacaine and the fast blocker lidocaine compete for the same receptor. Lipophilic interactions are of importance for blockade but besides a hydrophobic pathway, there exists also a hydrophilic pathway to the binding site which could only be reached from the cytoplasmic side of the membrane. Under physiological conditions, blockade of the flicker K+ channel which is more sensitive to bupivacaine than the Na+ channel might lead via membrane depolarization and the resulting sodium channel inactivation to a pronounced block of conduction in thin fibers.

Sign in / Sign up

Export Citation Format

Share Document