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The Effects of Transcranial Electrical Stimulation on Opiate-Induced Analgesia in Rats

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The Effects of Transcranial Electrical Stimulation on Opiate-Induced Analgesia in Rats Kabalak.qxd 23/11/2004 9:28 AM Page 203 ORIGINAL ARTICLE The effects of transcranial electrical stimulation on opiate-induced analgesia in rats Ayla A Kabalak MD1, Oytun O Senel DVM2, Nermin Gogus MD1 AA Kabalak, OO Senel, N Gogus. The effects of transcranial Les effets de l’électrostimulation crânienne sur electrical stimulation on opiate-induced analgesia in rats. une analgésie aux opiacés chez des rats Pain Res Manage 2004;9(4):203-206. HISTORIQUE ET OBJECTIFS : Des expériences récentes démontrent BACKGROUND AND OBJECTIVES: Recent experiments have que la stimulation électrique transcrânienne augmente considérablement shown that transcranial electrical stimulation significantly increases la puissance et la durée des effets analgésiques des opiacés chez les the potency and duration of the analgesic effects of opioids in humains et les rats. Dans la présente étude, l’influence d’une électrosti- humans and rats. In the present study, the influence of transcranial mulation crânienne (ESC) sur l’effet analgésique de l’hydrochlorure de electrical stimulation (TCES) on the analgesic effect of remifentanil rémifentanil (HCR) chez les rats a été déterminée. hydrochloride (HCl) in rats was determined. MÉTHODOLOGIE : Des expériences ont été exécutées sur 80 rats METHODS: Experiments were performed on 80 albino male Wistar Wistar mâles albinos. Les rats ont été divisés aléatoirement en quatre rats. Rats were randomly assigned to four groups: remifentanil HCl, groupes : HCR, HCR et ESC, ESC et groupe témoin (n=20 par groupe). remifentanil HCl and TCES, TCES, and control (n=20/group). L’HCR a été injecté à la 55e minute. L’analgésie a été évaluée au moyen Remifentanil HCl was injected on the 55th minute. Analgesia was du test de latence de rétraction de la queue. assessed using the wet tail-flick latency test. RÉSULTATS : Dans le groupe HCR, l’analgésie (10,85±1,04 s) a été e RESULTS: In the remifentanil HCl group, analgesia (10.85±1.04 s) obtenue à la 5 minute et a été élevée pendant les 10 premières minutes. was reached at the fifth minute, and the analgesia was high for the Dans le groupe HCR et ESC, la période de latence a atteint un sommet e first 10 min. In the remifentanil HCl and TCES group, the latency (16,60±1,19 s) la 5 minute. Ce sommet était 150 % plus élevé que dans le groupe HCR, et 251 % plus élevé que dans les groupes témoin et ESC. time peaked (16.60±1.19 s) at the fifth minute. This peak was 150% L’analgésie dans le groupe HCR et ESC a été maintenue 20 minutes à un higher than that for the remifentanil HCl group, and 251% higher taux statistiquement plus élevé que dans les autres groupes de traitement than the control or TCES groups. Analgesia in the remifentanil HCl (P<0,001). and TCES group was sustained for 20 min at a statistically higher rate CONCLUSIONS : L’ESC augmentait de manière considérable la durée than the other treatment groups (P<0.001). et la puissance analgésique du HCR chez les rats. Cet effet semblait relié CONCLUSIONS: TCES markedly increased the duration and anal- à la libération d’enképhalines dans les structures cérébrales, qui accroissait gesic potency of remifentanil HCl in rats. This effect appeared to be l’analgésie aux opiacés. related to the release of enkephalins from brain structures, thus enhancing opioid analgesia. Key Words: Analgesia; Remifentanil; Transcranial electrical stimulation istorically, electrical pulses have been used for pain inhi- significantly increases the analgesic effects of morphine and Hbition in animals. Different models and new techniques of dexamethasone in humans and rats. Undesirable side effects electrical stimulation have been employed in both animals and attributable to TCES have not been reported in these studies. humans using ‘transcranial electrical stimulation (TCES)’, The preliminary results obtained from TCES in the field of which involves low-frequency electrical currents. However, clinical anesthesia seem to be promising. A better quality of low-frequency electrical currents have always been associated anesthesia, a faster recovery from anesthesia, and a long-lasting with severe side effects such as apnea, cardiac accidents and postoperative analgesic period can be obtained in especially convulsions (1,2); therefore, different stimulation methods high-risk patients by decreasing analgesic requirements (2-6). were developed. High-frequency TCES consists of low- In the present study, we used remifentanil hydrochloride frequency trains of high-frequency current. This method (HCl), which is used in acute pain relief, to test the effects of allows for an increase in current intensity without the reduc- opioids because it had not been previously studied with respect tion of tissue conductivity that is normally associated with to TCES. In addition, remifentanil HCl is a new, ultrashort- low-frequency currents. This type of TCES is called ‘Limoge’s acting mu-opioid agonist that is metabolized by plasma and tis- current’ (3). Recent experiments (3,4) have shown that TCES sue esterases. The elimination half-life of remifentanil HCl is 1Department of Anaesthesiology and Reanimation, Ankara Numune Research and Training Hospital; 2Department of Surgery, Faculty of Veterinary Medicine, Ankara University, Ankara, Turkey Correspondence: Dr Ayla A Kabalak, Cigdem Mah, 337 sok, Tugba apartment, 5/2, Balgat, 06530, Ankara, Turkey. Telephone 90-312-286-12-85, fax 90-312-286-12-85, e-mail [email protected] Pain Res Manage Vol 9 No 4 Winter 2004 ©2004 Pulsus Group Inc. All rights reserved 203 Kabalak.qxd 23/11/2004 9:28 AM Page 204 Kabalak et al TABLE 1 Groups and experimental procedure Remifentanil hydrochloride (R) Group (n=20) TCES or saline treatment TFL R – 1 µg/kg 5 min intervals R+TCES Limoge’s current (5 min) 1 µg/kg 5 min intervals TCES Limoge’s current (5 min) Isotonic saline 5 min intervals Control* – Isotonic saline 5 min intervals *Drug and stimulation-free. TCES Transcranial electrical stimulation; TFL Tail-flick latency (3). Electrodes were connected to an electrical generator with thin and flexible cables. TCES The stimulation was provided by a home-made generator calibrated with a digital oscilloscope (Multimeter, Hewlett Packard 973 A, USA). The electrical currents (Limoge’s current) consisted of low- frequency trains of high-frequency current (high-frequency inter- mittent bursts of bidirectional balanced currents: 166 kHz, low frequency; 4 ms at 100 Hz; current intensity: 100 mA). In each high-frequency cycle, the current was positive for 2 µs and nega- tive for 4 µs (Figure 1). The frontal electrode was connected to the negative pole of the generator and received the negative impulse of weak intensity of 33 mA (long duration 4 µs). The two posterior Figure 1) Characteristics of transcranial electrical stimulation with electrodes were connected to the positive pole and received the Limoge’s current. (A) High frequency 166 kHz, 2 µs+, 4 µs– and (B) positive impulse of 67 mA (short duration 2 µs) (3). The average intermittent low frequency 100 KHz, 4 ms intensity was zero, which completely eliminated electrode burns from electrolysis. A constant current circuit was added to main- tain the same intensity whenever the electrodes interfaced imped- approximately 10 min to 20 min (7). Intraperitoneal remifen- ance change. After the placement of the electrodes, the TCES tanil HCl reaches its peak effect in 5 min, and its duration of and R+TCES groups were stimulated for 60 min. The stimulation action is approximately 10±5 min in rats (8). was continued in on-and-off 5 min cycles until the end of the The aim of the present study was to determine the influ- experiment. The electrodes were placed in all groups, but the R ence of TCES with Limoge’s current on the analgesic effect and control groups were not exposed to electrical stimulation. and duration of short-acting remifentanil HCl in rats. Analgesia METHODS Remifentanil HCl was dissolved in isotonic saline and injected Animals intraperitoneally (1 µg/kg) with a 25 gauge needle (total volume The present study was approved by the Committee for Research of 1 mL) (Table 1). Groups R and R+TCES received remifentanil and Ethical Issues of Ankara University’s Veterinary Faculty HCl on the 55th minute of stimulation, whereas the TCES and (Ankara, Turkey). Experiments were performed on 80 albino male control groups were injected with only 1 mL of isotonic saline to Wistar rats (Hifzisihha Institute, Ankara, Turkey) weighing 140 g equalize the painful stimulus effect of injection. to 180 g. Rats were housed on a 12 h:12 h alternating light/dark cycle with food and water ad libitum. The study rats had no prior Measurement of analgesia exposure to electric stimulation or analgesics. A day before each Analgesia was assessed using the wet tail-flick latency (TFL) test experiment, the rats were placed in a transparent pliant box for (9). The terminal third of the rat’s tail was immersed in a thermo- 60 min to acclimate them to the experimental conditions. stat water bath (50°C), and the time required for initiating the Experiments took place between 16:00 and 20:00. Rats were ran- retreat reflex time (seconds) was measured. For TFL measure- domly assigned to four study groups, each consisting of 20 rats: the ments, the rats were disconnected from the stimulator for a short remifentanil HCl group (R), the remifentanil HCl and TCES period. The time required for the retreat reflex was measured with group (R+TCES), the TCES group and the control group (C). a chronometer in the immersion TFL as previously desecribed (10). The first tail movement imposed a time count interrupt. If Electrode placement the tail retreat reflex did not occur after 20 s, the tail was manually Each rat was confined to a transparent pliant box designed to keep withdrawn from the water to avoid tissue damage.
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