Effects of deuterium oxide on the rate and dissociation constants for saxitoxin and tetrodotoxin action. Voltage-clamp studies on frog myelinated nerve.

Hahin, Richard; Strichartz, Gary R.

doi:10.1085/jgp.78.2.113

Cited by 36 publications

(35 citation statements)

References 32 publications

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“…The diffusion of toxin molecules to and away from the nodal membrane is governed by this source sink . Delays in the onset and reversal of the effects of anemone toxin in frog node have been previously reported (Ulbricht and Schmidtmayer, 1981 ;Ulbricht, 1983), although no such lags were seen with the smaller cationic organic molecules TTX and STX (Ulbricht and Wagner, 1975;Hahin and Strichartz, 1981) .…”

Section: Rates Of Action and Equilibrium Affinity Of Leiurus Toxinmentioning

confidence: 55%

“…The maintained currents determined after prolonged depolarization will be referred to in this report as steady state Na currents (or noninactivating currents). Both peak Na currents and steady state currents are blocked by STX with an apparent KD of 1 .1 nM, a value that is comparable to that of normal frog nerve fibers (K D = 1 .2 nM ; Hille, 1968 ;Hahin and Strichartz, 1981).…”

Section: General Descriptions Ofthe Effects Oflqiia On Na Currentsmentioning

confidence: 75%

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Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

Wang¹,

Strichartz²

1985

The Journal of General Physiology

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A BS T R A C T The effects of a neurotoxin, purified from the venom of the scorpion Leiurus quinquestriatus, on the ionic currents of toad single myelinated fibers were studied under voltage-clamp conditions. Unlike previous investigations using crude scorpion venom, purified Leiurus toxin IIa at high concentrations (200-400 nM) did not affect the K currents, nor did it reduce the peak Na current in the early stages of treatment. The activation of the Na channel was unaffected by the toxin, the activation time course remained unchanged, and the peak Na current vs. voltage relationship was not altered. In contrast, Na channel inactivation was considerably slowed and became incomplete . As a result, a steady state Na current was maintained during prolonged depolarizations of several seconds. These steady state Na currents had a different voltage dependence from peak Na currents and appeared to result from the opening of previously inactivated Na channels . The opening kinetics of the steady state current were exponential and had rates -100-fold slower than the normal activation processes described for transitions from the resting state to the open state. In addition, the dependence of the peak Na current on the potential of preceding conditioning pulses was also dramatically altered by toxin treatment; this parameter reached a minimal value near a membrane potential of -50 mV and then increased continuously to a "plateau" value at potentials greater than +50 mV. The amplitude of this plateau was dependent on toxin concentration, reaching a maximum value equal to -50% of the peak current; voltagedependent reversal of the toxin's action limits the amplitude of the plateauing effect . The measured plateau effect was half-maximum at a toxin concentration of 12 nM, a value quite similar to the concentration producing half of the maximum slowing of Na channel inactivation . The results of Hill plots for these actions suggest that one toxin molecule binds to one Na channel. Thus, the binding of a single toxin molecule probably both produces the steady state currents and slows the Na channel inactivation . We propose that Leiurus toxin inhibits the conversion of the open state to inactivated states in a voltagedependent manner, and thereby permits a fraction of the total Na permeability to remain at membrane potentials where inactivation is normally complete .

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Section: Rates Of Action and Equilibrium Affinity Of Leiurus Toxinmentioning

confidence: 55%

Section: General Descriptions Ofthe Effects Oflqiia On Na Currentsmentioning

confidence: 75%

Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

Wang¹,

Strichartz²

1985

The Journal of General Physiology

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“…The sciatic nerves were excised, desheathed and split longitudinally into two bundles. Each preparation was mounted in a sucrose-gap chamber as previously described (Strong et al, 1978;Hahin & Strichartz, 1981 were measured in frog Ringer solution containing (mM): NaCl 110, KCl 2.5, CaCl2 2.0, morpholino-propanesulphonic acid 5.0, the pH was adjusted to 7.2 with NaOH. Inhibition in the presence of drug was expressed as a fraction of the initial control compound action potential amplitude.…”

Section: Generalmentioning

confidence: 99%

Investigation of the specificity of FK 888 as a tachykinin NK₁ receptor antagonist

Wang¹,

Tung²,

Strichartz³

et al. 1994

British J Pharmacology

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“…The action of local anesthetics is curtailed by obstacles to their penetration to nerves, as evidenced by the large difference in concentrations required to achieve nerve blockade in isolated nerves and in vivo (6)(7)(8)(9)(10). We have hypothesized that chemical permeation enhancers (CPEs), such as those used to enhance transdermal drug delivery, might increase drug flux across those barriers, resulting in longer-duration nerve blocks.…”

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confidence: 99%

Prolonged sensory-selective nerve blockade

Sagie

Kohane

2010

Proc. Natl. Acad. Sci. U.S.A.

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Sensory-selective local anesthesia has long been a key goal in local anesthetic development. For example, it allows women to be painfree during labor without compromising their ability to push. Here we show that prolonged sensory-selective nerve block can be produced by specific concentrations of surfactants-such as are used to enhance drug flux across skin-in combination with QX-314, a lidocaine derivative that has relative difficulty penetrating nerves. For example, injection of 25 mM QX-314 in 30 mM octyltrimethylammonium bromide (OTAB) lasted up to 7 h. Sensory selectivity was imparted to varying degrees by cationic, neutral, and anionic surfactants, and also was achieved with another lidocaine derivative, QX-222. Simultaneous injection of OTAB at a s.c. injection site remote from the sciatic nerve did not result in prolonged sensory-specific nerve blockade from QX-314, suggesting that the observed effect is due to a local interaction between the surfactant and the lidocaine derivative, not a systemic effect.analgesia | quaternary lidocaine derivative | sensory | surfactant | local anesthetics P eripheral nerves contain separate populations of axons that serve specific functions, including sensation and movement. The development of local anesthetics that would block sensory nerves without impairing motor nerve function has long been a key goal. One notable example of its potential applicability is in labor analgesia; such blockade would allow the parturient to push effectively without feeling pain. There are recent reports of local anesthetic formulations with varying degrees of sensory selectivity, albeit of relatively brief duration. One report described a combination of QX-314 with the vanilloid receptor agonist capsaicin (1). QX-314, QX-222, and similar compounds are quaternary lidocaine derivatives with obligate positive charges (2, 3) that thus have greater difficulty reaching their targets on the inner surface of the cell membranes than do their uncharged counterparts. According to that report, capsaicin opens the TRPV1 channel on sensory nerves alone, allowing QX-314 to enter sensory cells only. Another report described an increase in the relative proportion of sensory block from a combination of lidocaine (the nonquaternary parent molecule of QX-314) with capsaicin (4). Lidocaine itself can open the TRPV1 channel and has been shown to produce sensory-predominant nerve blockade in the presence of QX-314 (5).The action of local anesthetics is curtailed by obstacles to their penetration to nerves, as evidenced by the large difference in concentrations required to achieve nerve blockade in isolated nerves and in vivo (6-10). We have hypothesized that chemical permeation enhancers (CPEs), such as those used to enhance transdermal drug delivery, might increase drug flux across those barriers, resulting in longer-duration nerve blocks. Recently, we demonstrated that a wide range of surfactant CPEs dramatically increased the duration of rat sciatic nerve blockade from tetrodotoxin, but had little or no effe...

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Effects of deuterium oxide on the rate and dissociation constants for saxitoxin and tetrodotoxin action. Voltage-clamp studies on frog myelinated nerve.

Cited by 36 publications

References 32 publications

Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

Investigation of the specificity of FK 888 as a tachykinin NK₁ receptor antagonist

Prolonged sensory-selective nerve blockade

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Effects of deuterium oxide on the rate and dissociation constants for saxitoxin and tetrodotoxin action. Voltage-clamp studies on frog myelinated nerve.

Cited by 36 publications

References 32 publications

Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

Investigation of the specificity of FK 888 as a tachykinin NK1 receptor antagonist

Prolonged sensory-selective nerve blockade

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Investigation of the specificity of FK 888 as a tachykinin NK₁ receptor antagonist