Suppression of Potassium Conductance by Droperidol Has Influence on Excitability of Spinal Sensory Neurons

Background: During spinal and epidural anesthesia with opioids, droperidol is added to prevent nausea and vomiting. The mechanisms of its action on spinal sensory neurons are not well understood. It was previously shown that droperidol selectively blocks a fast component of the Na+ current. The authors studied the action of droperidol on voltage-gated K+ channels and its effect on membrane excitability in spinal dorsal horn neurons of the rat.

Methods: Using a combination of the patch-clamp technique and the "entire soma isolation" method, the action of droperidol on fast-inactivating A-type and delayed-rectifier K+ channels was investigated. Current-clamp recordings from intact sensory neurons in spinal cord slices were performed to study the functional meaning of K+ channel block for neuronal excitability.

Results: Droperidol blocked delayed-rectifier K+ currents in isolated somata of dorsal horn neurons with a half-maximum inhibiting concentration of 20.6 [mu]m. The A-type K+ current was insensitive to up to 100 [mu]m droperidol. At droperidol concentrations insufficient for suppression of an action potential, the block of delayed-rectifier K+ channels led to an increase in action potential duration and, as a consequence, to lowering of the discharge frequency in the neuron.     

Differential block of fast and slow inactivating tetrodotoxin-sensitive sodium channels by droperidol in spinal dorsal horn neurons

BACKGROUND: Dorsal horn neurons of the spinal cord participate in neuronal pain transmission. During spinal and epidural anesthesia, dorsal horn neurons are exposed to local anesthetics and opioids. Droperidol is usually given with opioids to avoid nausea and vomiting. A recently developed method of "entire soma isolation" has made it possible to study directly the action of droperidol on different components of Na+ current in dorsal horn neurons. METHODS: Using a combination of the whole-cell patch-clamp recording from spinal cord slices and the entire soma isolation method, we studied the direct action of droperidol on two types of Na+ currents in dorsal horn neurons of young rats. RESULTS: The tetrodotoxin-sensitive Na+ current in isolated somata consisted of a fast inactivating (tauF, 0.5-2 ms; 80-90% of the total amplitude) and a slow inactivating (tauS, 6-20 ms; 10-20% of the total amplitude) component. Droperidol, at concentrations relevant for spinal and epidural anesthesia, selectively and reversibly suppressed the fast component with a half-maximum inhibiting concentration (IC50) of 8.3 microm. The slow inactivating component was much less sensitive to droperidol; the estimated IC50 value was 809 microm. CONCLUSIONS: Droperidol selectively blocks fast Na+ channels, the fast and slow components of the Na+ current in dorsal horn neurons are carried through pharmacologically distinct types of Na+ channels, and the effects of droperidol differ from those of local anesthetics and tetrodotoxin, which equipotently suppress both components. Droperidol may be suggested as a pharmacologic tool for separation of different types of inactivating tetrodotoxin-sensitive Na+ channel.     

Meperidine suppresses the excitability of spinal dorsal horn neurons

BACKGROUND: In addition to local anesthetics, meperidine has been successfully used for local anesthesia. When applied intrathecally, the dorsal horn neurons of the superficial laminae are exposed to high concentrations of meperidine. These cells represent an important point for the transmission of pain information. This study investigated the blocking effects of meperidine on different ionic currents of spinal dorsal horn neurons and, in particular, its impact on the generation of action potentials. METHODS: Using a combination of the patch clamp technique and the entire soma isolation method, the action of meperidine on voltage-gated Na+ and K+ currents in spinal dorsal horn neurons of rats was described. Current clamp recordings from intact neurons showed the functional relevance of the ion current blockade for the generation of action potentials. RESULTS: Externally applied meperidine reversibly blocked voltage-gated Na+ currents with a half-maximum inhibiting concentration (IC50) of 112 microM. During repetitive stimulation, a slight phasic block occurred. In addition, A-type K+ currents and delayed-rectifier K+ currents were affected in a dose-dependent manner, with IC50 values of 102 and 52 microM, respectively. In the current clamp mode, single action potentials were suppressed by meperidine. The firing frequency was lowered to 54% at concentrations (100 microM) insufficient for the suppression of a single action potential. CONCLUSIONS: Meperidine inhibits the complex mechanism of generating action potentials in spinal dorsal horn neurons by the blockade of voltage-gated Na+ and K+ channels. This can contribute to the local anesthetic effect of meperidine during spinal anesthesia.     

Meperidine Suppresses the Excitability of Spinal Dorsal Horn Neurons

Background: In addition to local anesthetics, meperidine has been successfully used for local anesthesia. When applied intrathecally, the dorsal horn neurons of the superficial laminae are exposed to high concentrations of meperidine. These cells represent an important point for the transmission of pain information. This study investigated the blocking effects of meperidine on different ionic currents of spinal dorsal horn neurons and, in particular, its impact on the generation of action potentials.

Methods: Using a combination of the patch clamp technique and the entire soma isolation method, the action of meperidine on voltage-gated Na+ and K+ currents in spinal dorsal horn neurons of rats was described. Current clamp recordings from intact neurons showed the functional relevance of the ion current blockade for the generation of action potentials.

Results: Externally applied meperidine reversibly blocked voltage-gated Na+ currents with a half-maximum inhibiting concentration (IC50) of 112 [mu]m. During repetitive stimulation, a slight phasic block occurred. In addition, A-type K+ currents and delayed-rectifier K+ currents were affected in a dose-dependent manner, with IC50 values of 102 and 52 [mu]m, respectively. In the current clamp mode, single action potentials were suppressed by meperidine. The firing frequency was lowered to 54% at concentrations (100 [mu]m) insufficient for the suppression of a single action potential.     

Blockade of Na sup + and K sup + Currents by Local Anesthetics in the Dorsal Horn Neurons of the Spinal Cord

Background: The dorsal horn of the spinal cord is a pivotal point for transmission of neuronal pain. During spinal and epidural anesthesia, the neurons of the dorsal horn are exposed to local anesthetics. Unfortunately, little is known about the action of local anesthetics on the major ionic conductances in dorsal horn neurons. In this article, the authors describe the effects of bupivacaine, lidocaine, and mepivacaine on voltage-gated Na sup + and K sup + currents in the membranes of these neurons.

Methods: The patch-clamp technique was applied to intact dorsal horn neurons from laminae I-III identified in 200-micro meter slices of spinal cord from newborn rats. Under voltage-clamp conditions, the whole-cell Na sup + and K sup + currents activated by depolarization were recorded in the presence of different concentrations of local anesthetics.

Results: Externally applied bupivacaine, lidocaine, and mepivacaine produced tonic block of Na sup + currents with different potencies. Half-maximum inhibiting concentrations (IC50) were 26, 112, and 324 micro Meter, respectively. All local anesthetics investigated also showed a phasic, that is, a use-dependent, block of Na sup + channels. Rapidly inactivating K sup + currents (KA currents) also were sensitive to the blockers with IC50 values for tonic blocks of 109, 163, and 236 micro Meter, respectively. The block of KA currents was not use dependent. In contrast to Na sup + and KA currents, delayed-rectifier K sup + currents were almost insensitive to the local anesthetics applied.     

Differential Block of Fast and Slow Inactivating Tetrodotoxin-sensitive Sodium Channels by Droperidol in Spinal Dorsal Horn Neurons

Background: Dorsal horn neurons of the spinal cord participate in neuronal pain transmission. During spinal and epidural anesthesia, dorsal horn neurons are exposed to local anesthetics and opioids. Droperidol is usually given with opioids to avoid nausea and vomiting. A recently developed method of "entire soma isolation" has made it possible to study directly the action of droperidol on different components of Na+ current in dorsal horn neurons.

Methods: Using a combination of the whole-cell patch-clamp recording from spinal cord slices and the entire soma isolation method, we studied the direct action of droperidol on two types of Na+ currents in dorsal horn neurons of young rats.

Results: The tetrodotoxin-sensitive Na+ current in isolated somata consisted of a fast inactivating ([tau]F, 0.5-2 ms; 80-90% of the total amplitude) and a slow inactivating ([tau]S, 6-20 ms; 10-20% of the total amplitude) component. Droperidol, at concentrations relevant for spinal and epidural anesthesia, selectively and reversibly suppressed the fast component with a half-maximum inhibiting concentration (IC50) of 8.3 [mu]m. The slow inactivating component was much less sensitive to droperidol; the estimated IC50 value was 809 [mu]m.     

Characteristics of ropivacaine block of Na+ channels in rat dorsal root ganglion neurons

When used for epidural anesthesia, ropivacaine can produce a satisfactory sensory block with a minor motor block. We investigated its effect on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na(+) currents in rat dorsal root ganglion (DRG) neurons to elucidate the mechanisms underlying the above effects. Whole-cell patch-clamp recordings were made from enzymatically dissociated neurons from rat DRG. A TTX-S Na(+) current was recorded preferentially from large DRG neurons and a TTX-R Na(+) current preferentially from small ones. Ropivacaine shifted the activation curve for the TTX-R Na(+) channel in the depolarizing direction and the inactivation curve for both types of Na(+) channel in the hyperpolarizing direction. Ropivacaine blocked TTX-S and TTX-R Na(+) currents, but its half-maximum inhibitory concentration (IC(50)) was significantly lower for the latter current (116 +/- 35 vs 54 +/- 14 microM; P: < 0.01); similar IC(50) values were obtained with the (R)-isomer of ropivacaine. Ropivacaine produced a use-dependent block of both types of Na(+) channels. Ropivacaine preferentially blocks TTX-R Na(+) channels over TTX-S Na(+) channels. We conclude that because TTX-R Na(+) channels exist mainly in small DRG neurons (which are responsible for nociceptive sensation), such selective action of ropivacaine could underlie the differential block observed during epidural anesthesia with this drug. Implications: Whole-cell patch-clamp recordings of tetrodotoxin-sensitive and tetrodotoxin-resistant Na(+) currents in rat dorsal root ganglion neurons showed ropivacaine preferentially blocked tetrodotoxin-resistant Na(+) channels over tetrodotoxin-sensitive Na(+) channels. This could provide a desirable differential sensory blockade during epidural anesthesia using ropivacaine.     

Molecular interaction of droperidol with human ether-a-go-go-related gene channels: prolongation of action potential duration without inducing early afterdepolarization

BACKGROUND: The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes. METHODS: Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique. RESULTS: Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 microM. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nM prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed. CONCLUSIONS: Droperidol is a high-affinity blocker of HERG channels. Amino acid residues typically involved in high-affinity block mediate droperidol effects. Patch clamp results and computational modeling allow the hypothesis that interaction with calcium currents may explain why droperidol at antiemetic concentrations prolongs the action potential without inducing early afterdepolarizations.     

Augmented activity of adenosine triphosphate-sensitive K+ channels induced by droperidol in the rat aorta

Droperidol produces the inhibition of K+ channels in cardiac myocytes. However, the effects of droperidol on K+ channels have not been studied in blood vessels. Therefore, we designed the present study to determine whether droperidol modulates the activity of adenosine triphosphate (ATP)-sensitive K+ channels in vascular smooth muscle cells. Rat aortic rings without endothelium were suspended or used for isometric force and membrane potential recordings, respectively. Vasorelaxation and hyperpolarization induced by levcromakalim (10(-8) to 10(-5) M or 10(-5) M, respectively) were completely abolished by the ATP-sensitive K+ channel antagonist glibenclamide (10(-5) M). Droperidol (10(-7) M) and an alpha-adrenergic receptor antagonist phentolamine (3 x 10(-9) M) caused a similar vasodilator effect (approximately 20% of vasorelaxation compared with maximal vasorelaxation induced by papaverine [3 x 10(-4) M]), whereas glibenclamide did not alter vasorelaxation induced by droperidol. Droperidol (3 x 10(-8) M to 10(-7) M) augmented vasorelaxation and hyperpolarization produced by levcromakalim, whereas phentolamine (3 x 10(-9) M) did not alter this vasorelaxation. Glibenclamide (10(-5) M) abolished the vasodilating and hyperpolarizing effects of levcromakalim in the aorta treated with droperidol (10(-7) M). These results suggest that droperidol augments vasodilator activity via ATP-sensitive K+ channels. However, it is unlikely that this augmentation is mediated by the inhibition of alpha-adrenergic receptors in vascular smooth muscles.     

Molecular Interaction of Droperidol with Human Ether-a-go-go-related Gene Channels: Prolongation of Action Potential Duration without Inducing Early Afterdepolarization

Background: The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes.

Methods: Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique.

Results: Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 [mu]m. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nm prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed.     

全身麻醉药在脊髓内的作用机制

脊髓是全身麻醉药抑制伤害性刺激体动反应和抗伤害效应的重要作用部位,含有不同配体门控离子受体等多个可能介导麻醉效应的靶点.不同药物在脊髓内经各自特异靶点通过多种分子机制发挥作用.现就全身麻醉药制动和镇痛效应在脊髓内的作用位点和分子机制作一综述.     

Spinally administered epinephrine suppresses noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord

This study was designed to determine if spinally administered epinephrine is capable of suppressing noxiously evoked activity of wide dynamic range (WDR) neurons in the dorsal horn of the spinal cord. Extracellular activity was recorded from single WDR neurons in the dorsal horn of decerebrate, spinal cord-transected (T-12) cats. Activity was evoked by the presentation of a noxious radiant heat stimulus (51 degrees C) to the cells' receptive fields on the hind paws. Evoked activity was monitored both before and after the spinal administration of either 50 micrograms (n = 6) or 100 micrograms (n = 6) epinephrine. Both doses of epinephrine produced a significant suppression of noxiously evoked activity, which was dose-dependent. In addition, the 100-microgram dose produced a suppression that was of longer duration than that seen following the 50-microgram dose. Recovery from suppression was recorded following both the 50- and 100-microgram dose. These results indicate that spinally administered epinephrine is capable of suppressing noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Since WDR neurons have been identified as cells of origin for the spinothalamic tract, such an action may block the central transmission of afferent pain information. This may be a mechanism by which spinally administered epinephrine enhances the duration or intensity of spinal anesthesia produced by local anesthetics and may also explain spinal analgesia resulting from the spinal administration of adrenergic agonists. Interactions between spinally administered epinephrine and spinally administered opioids also were studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Actions of midazolam on excitatory transmission in dorsal horn neurons of adult rat spinal cord

BACKGROUND: Although intrathecal administration of midazolam, a water-soluble imidazobenzodiazepine derivative, has been found to produce analgesia, how it exerts this effect at the neuronal level in the spinal cord is not fully understood. METHODS: The effects of midazolam on electrically evoked and spontaneous excitatory transmission were examined in lamina II neurons of adult rat spinal cord slices using the whole cell patch clamp technique. RESULTS: Bath-applied midazolam (1 microm) diminished Adelta- and C-fiber evoked polysynaptic excitatory postsynaptic currents in both amplitude and integrated area. However, it affected neither Adelta- and C-fiber evoked monosynaptic excitatory postsynaptic currents in amplitude nor miniature excitatory postsynaptic currents in amplitude, frequency, and decay time constant. In the presence of a benzodiazepine receptor antagonist, flumazenil (5 microm), midazolam (1 microm) did not diminish Adelta-fiber evoked polysynaptic excitatory postsynaptic currents, suggesting that midazolam modulate the gamma-aminobutyric acid interneurons in the dorsal horn. CONCLUSIONS: Midazolam reduced excitatory synaptic transmission by acting on the gamma-aminobutyric acid type A/benzodiazepine receptor in interneurons, leading to a decrease in the excitability of spinal dorsal horn neurons. This may be a possible mechanism for the antinociception by midazolam in the spinal cord.     

Effects of ketamine on low intensity tactile sensory input are not dependent upon a spinal site of action

The development of a technique for studying spinal dorsal horn electrophysiology in intact, awake, drug-free cats enables the study of spinal sites and mechanisms of action of anesthetic and analgesic agents in a system that more closely reflects normal physiology. Using this technique, we reevaluated the effect of ketamine on spinal dorsal horn sensory transmission. The results of our study confirm previous work done in acute preparations. Ketamine (maximum dose 20 mg/kg) did not significantly reduce the response of low threshold (n = 11) dorsal horn neurons to low intensity sensory stimulation. However, that same dose of ketamine did suppress noxiously evoked activity of the two wide dynamic range neurons encountered in the study, while having a varied effect on neurons responsive to proprioceptive input (n = 7). These findings confirm that, in the intact animal with all modulatory systems intact, ketamine "dissociation" of low intensity tactile stimuli does not appear to involve a spinal mechanism of action. The results also support the importance of spinal sites of action for the analgesia produced by ketamine, as well as the importance of distinguishing between the anesthetic and analgesic effects of that drug.     

Loss of T-type calcium current in sensory neurons of rats with neuropathic pain

BACKGROUND: Pathophysiology in the primary sensory neuron may contribute to chronic neuropathic pain. Ca channels play a central role in neuronal processes, and sensory neurons are rich in low-voltage-activated calcium channels (LVACCs). However, the physiologic function of these channels is unknown. Their possible role in rebound burst firing makes them a candidate for increased excitability after neuropathic injury. METHODS: This study uses pharmacological methods to isolate LVACC in cells from the dorsal root ganglia of neuropathic and sham-operated rats, including the blockade of high-voltage-activated Ca channels with fluoride and selective toxins. LVACCs were examined with conventional whole cell patch clamp electrophysiology techniques. RESULTS: After chronic constriction injury of the peripheral axon, LVACC was significantly reduced compared to sham rats as shown by a 60% reduction in peak current density and an 80% reduction in total calcium influx. A depolarizing shift in the voltage dependence of activation and an increase in the rate of deactivation and inactivation appear to cause this reduction of LVACC. Either Ni2+ or mibefradil, blockers of LVACC, applied in the bath to normal dorsal root ganglion cells during current clamp significantly and reversibly increased excitability. CONCLUSIONS: These results suggest that loss of LVACC may contribute to decreased spike frequency adaptation and increased excitability after injury to sensory neurons. Through decreased Ca2+ influx, the cell becomes less stable and more likely to initiate or transmit bursts of action potentials. Consequently, modulation of Ca2+ currents at the dorsal root ganglion may be a potential method of therapeutic intervention.     

Droperidol inhibits GABA(A) and neuronal nicotinic receptor activation

BACKGROUND: Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors. METHODS: gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists. RESULTS: Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant. CONCLUSIONS: Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.     

Inhibitory action of sensory transmission by inhalational anesthetics in the spinal cord

This review article focuses on the suppression of sensory transmission by inhalational anesthetics at the spinal cord level. Volatile anesthetics (e.g. halothane and isoflurane) suppress neuronal responses evoked by both noxious and non-noxious stimuli. This suppression is mediated largely by activation of GABAA and glycine receptors systems in the spinal dorsal horn. Depression of spinal glutamate receptor systems is also probably involved. The analgesic action of nitrous oxide is produced by activation of supra-spinal descending inhibitory systems, not by direct action on the spinal cord. Activation of the descending inhibitory systems by nitrous oxide causes release of noradrenaline in the spinal dorsal horn, and activates alpha 2 adrenergic receptor systems, resulting in depression of neuronal responses evoked by noxious stimuli. GABAA and glycine receptor systems in the spinal dorsal horn are also important components of nitrous oxide anesthesia in depressing neuronal responses evoked by non-noxious stimuli. Although excitation or inhibition of GABAA, glycine, alpha 2 adrenergic and glutamate receptors systems is an important action of inhalational anesthetics, influence of inhalational anesthetics on interactions among these receptor systems has yet to be studied.     

Local anesthetic inhibition of voltage-activated potassium currents in rat dorsal root ganglion neurons

BACKGROUND: Local anesthetic actions on the K+ channels of dorsal root ganglion (DRG) and dorsal horn neurons may modulate sensory blockade during neuraxial anesthesia. In dorsal horn neurons, local anesthetics are known to inhibit transient but not sustained K+ currents. The authors characterized the effects of local anesthetics on K+ currents of isolated DRG neurons. METHODS: The effects of lidocaine, bupivacaine, and tetracaine on K+ currents in isolated rat DRG neurons were measured with use of a whole cell patch clamp method. The currents measured were fast-inactivating transient current (I(Af)), slow-inactivating transient current (I(As)), and noninactivating sustained current (I(Kn)). RESULTS: One group of cells (type 1) expressed I(Af) and I(Kn). The other group (type 2) expressed I(As) and I(Kn). The diameter of type 2 cells was smaller than that of type 1 cells. Lidocaine and bupivacaine inhibited all three K+ currents. Tetracaine inhibited I(As) and I(Kn) but not I(Af) For bupivacaine, the concentration for half-maximal inhibition (IC50) of I(Kn) in type 2 cells was lower than that for I(Kn) in type 1 cells (57 vs. 121 microM). Similar results were obtained for tetracaine (0.6 vs. 1.9 mM) and for lidocaine (2.2 vs. 5.1 mM). CONCLUSIONS: Local anesthetics inhibited both transient and sustained K+ currents in DRG neurons. Because K+ current inhibition is known to potentiate local anesthetic-induced impulse inhibition, the lower IC50 for I(Kn) of small type 2 cells may reflect preferential inhibition of impulses in nociceptive neurons. The overall modulatory actions of local anesthetics probably are determined by their differential effects on presynaptic (DRG) and postsynaptic (dorsal horn neurons) K+ currents.     

Local Anesthetic Inhibition of Voltage-activated Potassium Currents in Rat Dorsal Root Ganglion Neurons

Background: Local anesthetic actions on the K+ channels of dorsal root ganglion (DRG) and dorsal horn neurons may modulate sensory blockade during neuraxial anesthesia. In dorsal horn neurons, local anesthetics are known to inhibit transient but not sustained K+ currents. The authors characterized the effects of local anesthetics on K+ currents of isolated DRG neurons.

Methods: The effects of lidocaine, bupivacaine, and tetracaine on K+ currents in isolated rat DRG neurons were measured with use of a whole cell patch clamp method. The currents measured were fast-inactivating transient current (IAf), slow-inactivating transient current (IAs), and noninactivating sustained current (IKn).

Results: One group of cells (type 1) expressed IAf and IKn. The other group (type 2) expressed IAs and IKn. The diameter of type 2 cells was smaller than that of type 1 cells. Lidocaine and bupivacaine inhibited all three K+ currents. Tetracaine inhibited IAs and IKn but not IAf. For bupivacaine, the concentration for half-maximal inhibition (IC50) of IKn in type 2 cells was lower than that for IKn in type 1 cells (57 vs. 121 [mu]m). Similar results were obtained for tetracaine (0.6 vs. 1.9 mm) and for lidocaine (2.2 vs. 5.1 mm).     

Tonic blocking action of meperidine on Na+ and K+ channels in amphibian peripheral nerves

BACKGROUND: Among opioids, meperidine (pethidine) also shows local anesthetic activity when applied locally to peripheral nerve fibers and has been used for this effect in the clinical setting for regional anesthesia. This study investigated the blocking effects of meperidine on different ion channels in peripheral nerves. METHODS: Experiments were conducted using the outside-out configuration of the patch-clamp method applied to enzymatically prepared peripheral nerve fibers of Xenopus laevis. Half-maximal inhibiting concentrations were determined for Na+ channels and different K+ channels by nonlinear least-squares fitting of concentration-inhibition curves, assuming a one-to-one reaction. RESULTS: Externally applied meperidine reversibly blocked all investigated channels in a concentration-dependent manner, i.e., voltage-activated Na+ channel (half-maximal inhibiting concentration, 164 microM), delayed rectifier K+ channels (half-maximal inhibiting concentration, 194 microM), the calcium-activated K+ channel (half-maximal inhibiting concentration, 161 microM), and the voltage-independent flicker K+ channel (half-maximal inhibiting concentration, 139 microM). Maximal block in high concentrations of meperidine reached 83% for delayed rectifier K+ channels and 100% for all other channels. Meperidine blocks the Na+ channel in the same concentration range as the local anesthetic agent lidocaine (half-maximal inhibiting concentration, 172 microM) but did not compete for the same binding site as evaluated by competition experiments. Low concentrations of meperidine (1 nM to 1 microM) showed no effects on Na+ channels. The blockade of Na+ and delayed rectifier K+ channels could not be antagonized by the addition of naloxone. CONCLUSIONS: It is concluded that meperidine has a nonselective inhibitory action on Na+ and K+ channels of amphibian peripheral nerve. For tonic Na+ channel block, neither an opioid receptor nor the the local anesthetic agent binding site is the target site for meperidine block.