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Suppression of Potassium Conductance by Droperidol Has Anesthesiology 2001; 94:280–9 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Suppression of Potassium Conductance by Droperidol Has Influence on Excitability of Spinal Sensory Neurons Andrea Olschewski, Dr.med.,* Gunter Hempelmann, Prof., Dr.med., Dr.h.c.,† Werner Vogel, Prof., Dr.rer.nat.,‡ Boris V. Safronov, P.D., Ph.D.§ Background: During spinal and epidural anesthesia with opi- Naϩ conductance.5–8 The sensitivity of different compo- oids, droperidol is added to prevent nausea and vomiting. The nents of Naϩ current to droperidol has further been mechanisms of its action on spinal sensory neurons are not studied in spinal dorsal horn neurons9 by means of the well understood. It was previously shown that droperidol se- 10,11 lectively blocks a fast component of the Na؉ current. The au- “entire soma isolation” (ESI) method. The ESI Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/280/403011/0000542-200102000-00018.pdf by guest on 25 September 2021 thors studied the action of droperidol on voltage-gated K؉ chan- method allowed a visual identification of the sensory nels and its effect on membrane excitability in spinal dorsal neurons within the spinal cord slice and further pharma- horn neurons of the rat. cologic study of ionic channels in their isolated somata Methods: Using a combination of the patch-clamp technique and the “entire soma isolation” method, the action of droperi- under conditions in which diffusion of the drug mole- -dol on fast-inactivating A-type and delayed-rectifier K؉ chan- cules is not impeded by the connective tissue surround nels was investigated. Current-clamp recordings from intact ing the neuron.9 It has been found that droperidol selec- sensory neurons in spinal cord slices were performed to study ϩ ؉ tively suppresses the fast inactivating component of Na the functional meaning of K channel block for neuronal current, while the slowly inactivating one remained re- excitability. 9 Results: Droperidol blocked delayed-rectifier K؉ currents in sistant to the drug. The effect of droperidol on spinal isolated somata of dorsal horn neurons with a half-maximum neurons may not only be restricted to the action on the ؉ ϩ inhibiting concentration of 20.6 ␮M. The A-type K current was fast inactivating Na current, because some blockers of insensitive to up to 100 ␮M droperidol. At droperidol concen- Naϩ channels were also shown to potently suppress trations insufficient for suppression of an action potential, the 12–14 -؉ different types of voltage-gated as well as back block of delayed-rectifier K channels led to an increase in ϩ 15–17 action potential duration and, as a consequence, to lowering of ground K channels. the discharge frequency in the neuron. In the present study, the action of the neuroleptic Conclusions: Droperidol blocks delayed-rectifier K؉ channels droperidol on voltage-gated Kϩ channels in spinal dorsal ؉ in a concentration range close to that for suppression of Na horn neurons as well as its functional meaning were channels. The block of delayed-rectifier K؉ channels by droperidol enhances the suppression of activity in spinal sen- studied. sory neurons at drug concentrations insufficient for complete conduction block. Materials and Methods DORSAL horn neurons located in laminae I–II of the spinal cord receive most of their primary sensory input Preparation from myelinated A␦-and nonmyelinated C-fibers and are Experiments were performed by means of the patch- 18 involved in nociception.1,2 During epidural and spinal clamp technique on 200-␮m thin slices cut from the anesthesia, these neurons are exposed to high concen- lumbar enlargement (L3–L6) of the spinal cord of 8–17- trations of local anesthetics or opioids.3 Application of day-old rats.14,19,20 Animals were rapidly decapitated, opioids is usually accompanied by side effects such as and the spinal cords were carefully removed in ice-cold nausea, emesis, and pruritus. To reduce nausea and eme- preparation solution bubbled with 95% O2–5% CO2. Af- sis and to prolong analgesia, the neuroleptic droperidol ter removal of the pial membrane with fine forceps, the is applied together with opioids.4 spinal cord was embedded in a preparation solution At the cellular level, droperidol was shown to act on containing 2% agar cooled down to 39°C. To accelerate dopaminergic receptors (D2) as well as voltage-gated solidification of the agar, the beaker with preparation was placed in ice-cold water. The agar block containing the lumbar enlargement of the spinal cord was cut out * Anesthesiologist, Departments of Anesthesiology and Intensive Care Medi- cine and Physiology, † Professor and Chair of Anesthesia, Department of Anes- and glued to a glass stage fixed in the chamber of the thesiology and Intensive Care Medicine, ‡ Professor, § Physiologist, Department tissue slicer. The spinal cord was sliced in ice-cold prep- of Physiology. aration solution under continuous bubbling. The slices Received from the Departments of Anesthesiology and Intensive Care Medi- cine and Physiology, Justus-Liebig-University, Giessen, Germany. Submitted for were thereafter incubated for1hat32°C. The standard publication January 10, 2000. Accepted for publication September 1, 2000. procedure of cell cleaning by repetitive blowing and Supported in part by Grant Vo. 188/16 from the Deutsche Forschungsgemein- schaft, Bonn, Germany. suction of the bath solution through a broken patch Address correspondence to Dr. Safronov: Physiologisches Institut, Justus-Liebig-Uni- pipette was not used because each slice contained nu- versität, Aulweg 129, D-35392 Giessen, Germany. Address electronic mail to: [email protected]. Reprints will not be available from the authors. Individual article merous dorsal horn neurons with clean surfaces. reprints may be purchased through the Journal Web site, www.anesthesiology.org. The procedures of animal decapitation were reported Anesthesiology, V 94, No 2, Feb 2001 280 DROPERIDOL BLOCKS DELAYED-RECTIFIER Kϩ CHANNELS 281 to the local veterinarian authority and are in accordance clamped potential evoked by the series resistance of the with German guidelines. electrode were not corrected. In experiments per- formed on the isolated somata, voltage errors caused by Solutions resistance in series did not exceed 4 mV in most cases. Preparation and experimental solution contained 115 mM All experiments were conducted at room temperature NaCl, 5.6 mM KCl, 2 mM CaCl2,1mM MgCl2,11mM glucose, (21–23°C). 1mM NaH2PO4, and 25 mM NaHCO3 (pH 7.4 when bubbled To make the action potentials or trains of action po- 2ϩ 2ϩ with 95% O2–5% CO2). Low-Ca –high-Mg solution con- tentials comparable, we kept the membrane potential at taining 100 nM charybdotoxin and 1 ␮M apamin used to pre- approximately Ϫ70 mV in current-clamp experiments by vent activation of Ca2ϩ and Ca2ϩ-dependent Kϩ currents was injecting sustained depolarizing or hyperpolarizing cur- obtained from the preparation solution by setting the concen- rents through the recording electrode. 2ϩ 2ϩ tration of Ca to 0.1 mM, increasing Mg to5mM, and Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/280/403011/0000542-200102000-00018.pdf by guest on 25 September 2021 addition of 100 nM charybdotoxin and 1 ␮M apamin. The study Identification of Dorsal Horn Neurons of Kϩ channels was conducted in Naϩ-free choline-Cl solution The dorsal horn neurons were identified in spinal cord ␮ containing 141 mM choline-Cl, 0.6 mM KCl, 0.1 mM CaCl2, slices as multipolar cells with a soma (8–12- m diame- 10 5mM MgCl2,11mM glucose, and 5 mM HEPES (pH 7.4 ad- ter) located in laminae I–III. Neurons were distin- justed with 5 mM KOH). Tetrodotoxin 0.2 ␮M was added to guished from glial cells in voltage-clamp mode on the this solution to block voltage-gated Naϩ channels. basis of a procedure described previously.10 All neurons ϩ Stock solution of droperidol (20 mM) was obtained by studied possessed a large Na current exceeding 1 nA, dissolving the drug in dimethyl-sulfoxide. It was added to were able to generate action potentials, and showed spon- bath solution to achieve the desired drug concentration. taneous synaptic activity. The resting potentials measured Tetrodotoxin and tetraethylammonium were directly in intact neurons were between Ϫ78 and Ϫ55 mV. added to the bath solution. Bovine serum albumin (0.05%) was added to charybdotoxin- and apamin-con- The Entire Soma Isolation Method taining solution to prevent an unspecific adhesion of A detailed description of the ESI method has been blocker molecules to the walls of the experimental given elsewhere.9–11 Briefly, in whole-cell recording chamber and the tubings. The experimental chamber mode, the entire soma of the neuron was isolated from with a volume of 0.4 ml was continuously perfused by the slice by slow withdrawal of the recording pipette. external solution at a rate of 2–3 ml/min. Droperidol and The isolated structure was classified as soma (“soma”) if apamin were purchased from Sigma (Deisenhofen, Ger- it had lost all of its processes during isolation and pre- many), tetrodotoxin and charybdotoxin from Latoxan served only 10–20% of original Naϩ current recorded (Rosans, France), and tetraethylammonium from Merck from the neuron in the slice before its isolation. The (Darmstadt, Germany). isolated structure was classified as “somaϩaxon” com- The pipette solution used in ESI experiments con- plex if it contained one process and preserved more than ϩ tained 5 mM NaCl, 144.4 mM KCl, 1 mM MgCl2,3mM 90% of the original Na current. The good physiologic EGTA, and 10 mM HEPES (pH 7.3 by 10 mM NaOH). The state of the isolated structures was confirmed by a con- pipette solution in all other experiments contained 5 mM siderable increase in their input resistances (reflecting a NaCl, 144.4 mM KCl, 1 mM MgCl2,3mM EGTA, and decrease in membrane leakage conductance), by stable 10 mM HEPES (pH 7.3 adjusted with 10.6 mM KOH).
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