In vivo potency of different ligands on voltage-gated sodium channels (original) (raw)
Related papers
Local Anesthetic Neurotoxicity Does Not Result from Blockade of Voltage-Gated Sodium Channels
Anesthesia & Analgesia, 1995
To investigate whether local anesthetic neurotoxicity results from sodium channel blockade, we compared the effects of intrathecally administered lidocaine, bupivacaine, and tetrodotoxin (TTX), the latter a highly selective sodium channel blocker, on sensory function and spinal cord morphology in a rat model. First, to determine relative anesthetic potency, 25 rats implanted with intrathecal catheters were subjected to infusions of lidocaine (n = 8), bupivacaine (n = 81, or TTX (n = 9). The three drugs produced parallel dose-effect curves that differed significantly from one another: the EC,, values for lidocaine, bupivacaine, and TTX were 28.2 mM (0.66%), 6.6 mM (0.19%), and 462 nM, respectively. Twenty-five additional rats were then given intrathecal lidocaine (n = 8), bupivacaine (n = 8), or TTX (n = 9) at concentrations 10 times the calculated EC,, for sensory block. Lidocaine and bupivacaine induced persistent sensory impairment, whereas TTX did not. Finally, 28 rats were given either intrathecal bupivacaine (n = 10) or TTX (n = 9) at 10 times the EC,,, or normal saline (n = 9). Significant sensory impairment again occurred after infusion of bupivacaine, but not after infusion of TTX or saline. Neuropathologic evaluation revealed moderate to severe nerve root injury in bupivacaine-treated animals; histologic changes in TTX-and saline-treated animals were minimal, similar, and restricted to the area adjacent to the catheter. These results indicate that local anesthetic neurotoxicity does not result from blockade of the sodium channel, and suggest that development of a safer anesthetic is a realistic goal.
Anesthesiology, 2008
Background-Transient receptor potential vanilloid 1 channels integrate nociceptive stimuli and are predominantly expressed by unmyelinated C-fiber nociceptors, but not low-threshold mechanoreceptive sensory or motor fibers. A recent report showed that the transient receptor potential vanilloid 1 channel agonist capsaicin allows a hydrophilic quaternary ammonium derivative of lidocaine, QX-314, to selectively block C fibers without motor block. The authors tested whether a similar differential block would be produced using amphipathicN-methyl amitriptyline, amitriptyline, bupivacaine, or lidocaine, either alone or together with 0.05% capsaicin, in a rat sciatic nerve block model.
Pflügers Archiv - European Journal of Physiology, 2010
The generation of action potentials in nociceptive neurons is accomplished by the tetrodotoxin-resistant (TTXr) Na+ channel Na(v)1.8. Following nerve injury, a redistribution of Na(v)1.8 from dorsal root ganglion (DRG) neurons into peripheral axons contributes to hyperexcitability and possibly to neuropathic pain. Na(v)1.8 has been reported to display a lower sensitivity to block by Na+ channel blockers as compared to TTX-sensitive (TTXs) Na(v) subunits. Furthermore, the antinociceptive efficacy of lidocaine is increased in Na(v)1.8-knockout mice. Here, we asked if Na(v)1.8 expression can reduce the susceptibility of sensory neurons to block by lidocaine. Employing wild-type and Na(v)1.8-knockout mice, we examined C-fibers in the skin-nerve preparation and Na+ currents in DRG neurons by patch-clamp recordings. Deletion of Na(v)1.8 resulted in an enhanced tonic block of Na+ currents in DRG neurons held at -80 mV but not at -140 mV. Accordingly, lower concentrations of lidocaine were required for a conduction block of C-fibers from Na(v)1.8-knockout as compared to wild-type mice. The efficacy of lidocaine on neurons lacking Na(v)1.8 was further increased by cold temperatures, due to a synergistic hyperpolarizing shift of the slow inactivation of TTXs Na+ channels by lidocaine and cooling. Finally, the approximately 90% reduction of TTXr Na+ currents in injured neurons from mice with a peripheral nerve injury was accompanied with an enhanced tonic block by lidocaine. In conclusion, our data demonstrate that the expression of Na(v)1.8 in sensory neurons can confine the antinociceptive efficacy of lidocaine and other Na+ channel blockers employed for pain treatment.
British Journal of Pharmacology, 2004
Voltage-gated Na þ channels are transmembrane proteins that are essential for the propagation of action potentials in excitable cells. Na v 1.7 and Na v 1.8 dorsal root ganglion Na þ channels exhibit different kinetics and sensitivities to tetrodotoxin (TTX). We investigated the properties of both channels in the presence of lidocaine, a local anesthetic (LA) and class I anti-arrhythmic drug. 2 Na v 1.7 and Na v 1.8 Na þ channels were coexpressed with the b 1-subunit in Xenopus oocytes. Na þ currents were recorded using the two-microelectrode voltage-clamp technique. 3 Dose-response curves for both channels had different EC 50 (dose producing 50% maximum current inhibition) (450 mM for Na v 1.7 and 104 mM for Na v 1.8). Lidocaine enhanced current decrease in a frequency-dependent manner. Steady-state inactivation of both channels was also affected by lidocaine, Na v 1.7 being the most sensitive. Only the steady-state activation of Na v 1.8 was affected while the entry of both channels into slow inactivation was affected by lidocaine, Na v 1.8 being affected to a larger degree. 4 Although the channels share homology at DIV S6, the LA binding site, they differ in their sensitivity to lidocaine. Recent studies suggest that other residues on DI and DII known to influence lidocaine binding may explain the differences in affinities between Na v 1.7 and Na v 1.8 Na þ channels. 5 Understanding the properties of these channels and their pharmacology is of critical importance to developing drugs and finding effective therapies to treat chronic pain.
Effect of Adjuvant Drugs on the Action of Local Anesthetics in Isolated Rat Sciatic Nerves
Regional Anesthesia and Pain Medicine, 2012
Background and Objectives-There is increasing clinical use of adjuvant drugs to prolong the duration of local anesthetic-induced block of peripheral nerves. However, the mechanistic understanding regarding drug interactions between these compounds in the periphery is quite limited. Accordingly, we undertook this study to determine whether selected adjuvants are efficacious in blocking action potential propagation in peripheral nerves at concentrations used clinically, and whether these drugs influence peripheral nerve block produced by local anesthetics. Methods-Isolated rat sciatic nerves were used to assess (1) the efficacy of buprenorphine, clonidine, dexamethasone, or midazolam, alone and in combination, on action potential propagation; and (2) their influence on the blocking actions of local anesthetics ropivacaine and lidocaine. Compound action potentials (CAPs) from A-and C-fibers were studied before and after drug application. Results-At estimated clinical concentrations, neither buprenorphine nor dexamethasone affected either A-or C-waves of the CAP. Clonidine produced a small, but significant attenuation of the C-wave amplitude. Midazolam attenuated both A-and C-wave amplitudes, but with greater potency on the C-wave. The combination of clonidine, buprenorphine, and dexamethasone had no influence on the potency or duration of local anesthetic-or midazolam-induced block of A-and Cwaves of the CAP. Conclusions-These results suggest that the reported clinical efficacy of clonidine, buprenorphine, and dexamethasone influence the actions of local anesthetics via indirect mechanisms. Further identification of these indirect mechanisms may enable the development of novel approaches to achieve longer duration, modality-specific peripheral nerve block.
Journal of Clinical Investigation, 2008
Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na + channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene-related peptide (CGRP) from isolated skin and peripheral nerve.
Anesthesiology, 2009
Background: Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314 -mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia.
Membrane-Mediated Activity of Local Anesthetics
Molecular Pharmacology
The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins, far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins, just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels, based on LAs' amphiphilicity. It is possible that LAs act in one of the following ways: they (a) dissolve raft-like membrane micro-domains, (b) impede nerve impulse propagation by lowering the lipid phase transition temperature, or (c) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LA besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum, between unspecific membrane mediated activity on one end, and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics, and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics.
Evidence of presynaptic and postsynaptic action of local anesthetics in rats
Acta Cirurgica Brasileira, 2013
To assess the probable actions of ropivacaine, 50% enantiomeric excess bupivacaine mixture (S75-R25) and levobupivacaine on neuromuscular transmission in vitro. METHODS: Thirty rats were distributed into groups (n=5) according to the drug used: ropivacaine, bupivacaine (S75-R25) and levobupivacaine. The concentration used for the three local anesthetics (LA) was 5 µg.mL.-1 The following parameters were evaluated: 1) LA effects on membrane potential (MP) and miniature end plate potential (MEPP). A chick biventer cervicis preparation was also used to evaluate LA effects on the contracture response to acetylcholine. RESULTS: LA did not alter MP values and decreased the frequency and amplitude of MEPP. In a chick biventer cervicis preparation, bupivacaine (S75-R25) and levobupivacaine decreased the contracture response to acetylcholine with statistical significance, in comparison to ropivacaine. CONCLUSIONS: In the concentrations used, levobupivacaine and bupivacaine (S75-R25) exhibited presynaptic and postsynaptic actions evidenced by alterations in miniature end plate potentials and contracture response to acetylcholine. Ropivacaine only had a presynaptic action.