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Effects of succinylcholine on spinal antinociception with lidocaine in rats
Acute Pain (2005) 7, 37—40
Effects of succinylcholine on spinal antinociception with lidocaine in rats Weian Zeng a, ∗, Haichun Ma b, Hongying Tan c, Shuji Dohi d a
Department of Anesthesiology, Tumor Hospital, Cancer Center, Sun Yat-sen University, 651 Dong Feng Road East, Guangzhou City, Guangzhou 510060, China b Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China c Department of Anesthesiology, Tumor Hospital, Cancer Center, Sun Yat-sen University, Guangzhou, China d Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Japan Received 22 March 2004 ; received in revised form 5 January 2005; accepted 17 January 2005 Available online 25 February 2005 KEYWORDS Acetylcholine; Local anesthetics; Spinal analgesia
Summary Aim: In this study we investigated the antinociceptive effect of intrathecally administered succinylcholine, a muscle relaxant, and examine its potential interaction with lidocaine. Methods: Using rats chronically implanted with lumbar intrathecal catheters, the ability of intrathecal succinylcholine and lidocaine, and the mixtures of succinylcholine—lidocaine to alter tail-flick latency was examined. Motor function was assessed using a modified Langerman’s scale. Results: Intrathecal lidocaine (25—300 g) alone showed the prolongation of tail-flick latency in a time- and dose-dependent manner. Although intrathecal succinylcholine (50 and 100 g) alone demonstrated neither sensory nor motor block, the combination of lidocaine (100 or 200 g) and succinylcholine (100 g) significantly increased the tail-flick threshold. The combination of succinylcholine (100 g) and lidocaine (200 g) did not affect motor function when compared with lidocaine alone. Conclusion: These results indicated that the intrathecal succinylcholine potentiates spinal anesthesia with lidocaine. © 2005 Elsevier B.V. All rights reserved.
1. Introduction * Corresponding author. Tel.: +86 20 87343060; fax: +86 20 87343392. E-mail address: [email protected] (W. Zeng).
Activation of cholinergic pathways by muscarinic and nicotinic receptor agonists produces antinociceptive effects in a variety of species [1]. Neuromuscular blockers commonly used in anesthetic
1366-0071/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2005.01.003
38 practice interacted with muscarinic and nicotinic receptors [2]. Neuromuscular blockers given intravenously for a sufficient time and dose can enter the cerebrospinal fluid eventually. Succinylcholine, a neuromuscular blocker and an analog of acetylcholine, can inhibit postsynaptic current [3] and at a low concentration (1 M) can enhance evoked acetylcholine release [4]. Moreover, both of lidocaine and succinylcholine can cause or promote desensitization of cholinergic receptors [5]. Several studies indicated that spinal administration of neostigmine lessened the hypotensive effect induced by intrathecal local anesthetics in animals [6]. However, the interactions of cholinergic agonists succinylcholine and local anesthetics on the antinociception at the spinal cord level have not been reported. In the present study, on conscious rats, we examined whether intrathecal succinylcholine modulates the antinociceptive action of spinal lidocaine on somatic nociception.
2. Methods 2.1. Animal preparation and surgical procedure With approval from Gifu University Animal Care and Use Committee, studies were carried out on male Sprague-Dawley rats weighing 250—350 g (n = 5—7). All surgical procedures were performed with the rats under intraperitoneal midazolam (2 mg/kg) and ketamine (40 mg/kg) anesthesia. Using the method described by Zeng et al. [7], an intrathecal catheter (PE-10, 8.5 cm) was inserted through an opening in the cisternal magna to the lumbar subarachnoid space. After surgery, animals were allowed to recover for 1 week before the administration of drugs.
2.2. Nociceptive and motor function test Nociceptive threshold was assessed by means of the tail-flick (TF) test. The mean baseline value for TF latency was 3.5 s (3.3—3.8 s). A cut-off time of 10.0 s was imposed to minimize damage to the skin of the tail during the experiment. TF latencies were determined 5, 10, 15, 20, 30, 40, 50, and 60 min after intrathecal administration of drugs. Motor blockade was graded, according to the scale proposed by Langerman et al. [8] for rabbits, which we modified for the rat model as follows: 0 = free movement of hind limbs without limitation; 1 = limited or asymmetrical movement of the hinds to support the body and walk; 2 = inability to move the limbs and respond to a pain stimulus; and 3 = total paralysis of the hind limbs.
W. Zeng et al.
2.3. Drugs and injections After baseline measurements for TF latency had been obtained, each animal received an intrathecal injection of succinylcholine (50 and 100 g), lidocaine (25, 50, 100, 200, or 300 g), or succinylcholine plus lidocaine. Physiologic saline (20 l) served as a control. The behaviour and motor function of intraperitoneal injection of succinylcholine (300 g/kg) were also examined. All drugs were administered in a total volume of 10 l followed by 10 l of physiologic saline solution to flush out the contents of the catheter.
2.4. Statistical analysis All data are presented as mean ± S.E.M. The response in the TF test is expressed as the percentage of the maximum possible effect (%MPE) where %MPE = (postdrug TF latency − baseline TF latency)/(10 s − baseline TF latency) × 100. The effects of drugs on TF latency were evaluated for linearity and deviation from parallelism by a one-way analysis of variance and Scheffe’s PLSD test. Other comparisons between groups were analyzed using a two-way analysis of variance and Scheffe’s F-test. A P value < 0.05 was considered as statistically significant.
3. Results Intrathecal administration of lidocaine (25—300 g) alone produced a significant dose-dependent antinociception in the TF test (Figs. 1 and 2). The peak effects were observed at 5 min after drug administration. Intrathecal administration of succinylcholine (50 and 100 g) alone did not produce the antinociception in the TF test (Fig. 2). However, intrathecal succinylcholine (100 g) synergistically enhanced the antinociceptive effect of intrathecal lidocaine (Figs. 2 and 3). The motor functions revealed no differences in the scores on the modified scale whether observations were made before and after intrathecally administered succinylcholine during the observation period (data not shown). Intrathecal administration of lidocaine (200 g) combined with succinylcholine (100 g) also did not affect the motor function scales when compared with intrathecal administration of lidocaine (200 g) alone (Fig. 4). Succinylcholine (300 g/kg) injected intraperitoneally, no changes in behaviour were observed within 5 min.
Effects of succinylcholine on spinal antinociception with lidocaine in rats
Fig. 1 Time course of the antinociceptiove effect (%MPE) of intrathecally administered lidocaine (lido) in TF tests. Each point represents mean ± S.E.M. from 5 or 7 rats.
4. Discussion The current study demonstrates that spinal antinociceptive effects of lidocaine were significantly potentiated and prolonged by the concomitantly administered succinylcholine, a muscle relaxant, in the TF test. Spinal cholinergic system is important in spinal nociceptive modulation. Cholinergic binding was found in spinal cord level. Intrathecally admin-
Fig. 2 Log dose-response curves for the effects of intrathecally administered lidocaine (lido), succinylcholine (succ), and lidocaine-succcinylcholine ([succ] 100 g) on the thermal nociceptive threshold. Data are plotted as percentage maximal possible effect (%MPE) vs. log dose in g. Each point represents the mean ± S.E.M. from 5 or 7 rats.
39
Fig. 3 Effect of 100 g or 200 g lidocaine plus 100 g succinylcholine in TF tests. The combination produced a significant prolongation of TF latency. * P < 0.05 or ** P < 0.01 compared with the baseline preadministration values. Each point represents the mean ± S.E.M. from 5 or 7 rats.
istered nicotine and cholinergic agonists and acetylcholinesterase inhibitors produced analgesia in humans and animals [1]. In the present study spinal antinociceptive effects of lidocaine were significantly potentiated and prolonged by the concomitantly administered succinylcholine, a muscle relaxant, in the TF test in rats. The underlying mechanism of succinylcholine potentiating the spinal antinociception of lidocaine is not clear. Succinylcholine, an analog of acetylcholine,
Fig. 4 Effect of the combination of lidocaine (L) and succinylcholine (S) on motor function test. Lidocaine 200 g combined with succinylcholine 100 g did not affect on the motor function scales when compared with lidocaine alone. Each point represents the mean ± S.E.M. from 5 rats.
40 inhibits postsynaptic current [3], opens K+ channels [9], and at a low concentration (1 M) enhances evoked acetylcholine release [9]. Inman et al. [10] reported that succinylcholine dilated both preand post-glomerular vessels and this dilation was blocked by atropine, indicating succinylcholine has muscarinic actions. A previous study showed that the effect of lidocaine could be reduced by pretreatment with intraspinally administered atropine or mecamylamine suggesting that the antinociceptive effect produced by lidocaine was mediated through an action on muscarinic and nicotinic receptors [11]. Both succinylcholine and lidocaine may promote the shift of receptors from a normal state to a desensitized state or may react with desensitized molecules to prevent them from returning to normal [5]. Thus, one possible mechanism of the interaction is that the drug combination effectively inhibits overall neuronal excitability at the level of ionic channels by inhibiting Na+ channels with lidocaine and reducing postsynaptic current with both succinylcholine and lidocaine. Another possible mechanism of the interaction may be succinylcholine, an analog of acetylcholine, producing inhibition of the dorsal horn neuron through cholinergic mechanism enhancing spinal antinociception with lidocaine. Previous observation suggested that muscle relaxants were not inert when they appear in the cerebrospinal fluid. For example, muscle relaxants administered directly into rat brain and intraventricular caused seizures and neuronal death [12]. Pancuronium into the cerebrospinal fluid caused autonomic dysfunction and/or weakness [13]. In the present study intrathecal succinylcholine itself had no effect on antinociception and motor block, although the succinylcholine, like acetylcholine, binds and activates the nicotinic and muscarinic acetylcholine receptors in the spinal cord [14]. One possible explanation for this apparent discrepancy could be the existence of electrophysiologic differences in drug sensitivity between central and peripheral subclasses of acetylcholine receptors; another possible explanation for the result could be a plasma concentration of succinylcholine too low to produce neuromuscular blockade. In conclusion, intrathecal administration of succinylcholine alone causes no antinociception to a noxious heat stimulus in awake rats, but synergistically potentiates spinal antinociception
W. Zeng et al. with lidocaine, suggesting exogenous structure like cholinomimetics may be important in spinal antinociception.
References [1] Naguib M, Yaksh TL. Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with m and a2 receptor systems. Anesthesiology 1994;80:1338—48. [2] Nedoma J, Dorofeeva NA, Tucek S, Shelkovnikov SA, Danilov AF. Interaction of the neuromuscular blocking drugs alcuronium, decamethonium, gallamine, pancuronium, ritebronium, tercuronium and d-tubocurarine with muscarinic acetylcholine receptors in the heart and ileum. NaunynSchmiedebergs Arch Pharmacol 1985;329:176—81. [3] Adam LP, Henderson EG. Augmentation of succinylcholineinduced neuromuscular blockade by calcium channel antagonists. Neurosci Lett 1986;70:148—53. [4] Kimura I, Okazaki M, Uwano T, Kobayahi S, Kimura M. Succinylcholine-induced acceleration and suppression of electrically evoked acetylcholine release from mouse phrenic nerve-hemidiaphragm muscle preparation. Japan J Pharmacol 1991;57:397—403. [5] Miller RD. Anesthesia. fourth ed. Churchill Livingstone Inc.; 1994. p. 742—4. [6] Carp H, Jayaram A, Morrow D. Intrathecal cholinergic agonists lessen bupivacaine spinal block-induced hypotension in rats. Anesth Analg 1994;79:112—6. [7] Zeng W, Dohi S, Shimonaka H, Asano T. Spinal antinociceptive action of Na+ —K+ pump inhibitor ouabain and its interaction with morphine and lidocaine in rats. Anesthesiology 1999;90:500—8. [8] Langerman L, Grant GJ, Zakkowaki M, Golomb E, Ramanathan S, Turndorf H. Prolongation of epidural anesthesia using a lipid drug carrier with procaine, lidocaine, and tetracaine. Anesth Analg 1992;75:900—5. [9] Naguib M, Magboul MA. Adverse effects of neuromuscular blockers and their antagonists. Drug Safety 1998;18:99—116. [10] Inman SR, Stowe NT, Albanese J, Meehan M, Ryckman J, Zanettin GG, et al. Contrasting effects of vecuronium and succinylcholine on the renal microcirculation in rodents. Anesth Analg 1994;78:682—6. [11] Abelson KS, Hoglund AU. Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats. Neurosci Lett 2002;317:93—6. [12] Szenohradszky J, Trevor AJ, Bickler P, Caldwell JE, Sharma ML, Rampil IJ, et al. Central nerveous system effects of intrathecal muscle relaxants in rats. Anesth Analg 1993;76:11304—9. [13] Mesry S, Baradaran J. Accidental intrathecal injection of gallamine triethiodide. Anesthesia 1974;29:301—4. [14] Lauretti GR, de Oliveira R, Reis MP, et al. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999;90:1534—8.
Effects of succinylcholine on spinal antinociception with lidocaine in rats Weian Zeng a, ∗, Haichun Ma b, Hongying Tan c, Shuji Dohi d a
Department of Anesthesiology, Tumor Hospital, Cancer Center, Sun Yat-sen University, 651 Dong Feng Road East, Guangzhou City, Guangzhou 510060, China b Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China c Department of Anesthesiology, Tumor Hospital, Cancer Center, Sun Yat-sen University, Guangzhou, China d Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Japan Received 22 March 2004 ; received in revised form 5 January 2005; accepted 17 January 2005 Available online 25 February 2005 KEYWORDS Acetylcholine; Local anesthetics; Spinal analgesia
Summary Aim: In this study we investigated the antinociceptive effect of intrathecally administered succinylcholine, a muscle relaxant, and examine its potential interaction with lidocaine. Methods: Using rats chronically implanted with lumbar intrathecal catheters, the ability of intrathecal succinylcholine and lidocaine, and the mixtures of succinylcholine—lidocaine to alter tail-flick latency was examined. Motor function was assessed using a modified Langerman’s scale. Results: Intrathecal lidocaine (25—300 g) alone showed the prolongation of tail-flick latency in a time- and dose-dependent manner. Although intrathecal succinylcholine (50 and 100 g) alone demonstrated neither sensory nor motor block, the combination of lidocaine (100 or 200 g) and succinylcholine (100 g) significantly increased the tail-flick threshold. The combination of succinylcholine (100 g) and lidocaine (200 g) did not affect motor function when compared with lidocaine alone. Conclusion: These results indicated that the intrathecal succinylcholine potentiates spinal anesthesia with lidocaine. © 2005 Elsevier B.V. All rights reserved.
1. Introduction * Corresponding author. Tel.: +86 20 87343060; fax: +86 20 87343392. E-mail address: [email protected] (W. Zeng).
Activation of cholinergic pathways by muscarinic and nicotinic receptor agonists produces antinociceptive effects in a variety of species [1]. Neuromuscular blockers commonly used in anesthetic
1366-0071/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2005.01.003
38 practice interacted with muscarinic and nicotinic receptors [2]. Neuromuscular blockers given intravenously for a sufficient time and dose can enter the cerebrospinal fluid eventually. Succinylcholine, a neuromuscular blocker and an analog of acetylcholine, can inhibit postsynaptic current [3] and at a low concentration (1 M) can enhance evoked acetylcholine release [4]. Moreover, both of lidocaine and succinylcholine can cause or promote desensitization of cholinergic receptors [5]. Several studies indicated that spinal administration of neostigmine lessened the hypotensive effect induced by intrathecal local anesthetics in animals [6]. However, the interactions of cholinergic agonists succinylcholine and local anesthetics on the antinociception at the spinal cord level have not been reported. In the present study, on conscious rats, we examined whether intrathecal succinylcholine modulates the antinociceptive action of spinal lidocaine on somatic nociception.
2. Methods 2.1. Animal preparation and surgical procedure With approval from Gifu University Animal Care and Use Committee, studies were carried out on male Sprague-Dawley rats weighing 250—350 g (n = 5—7). All surgical procedures were performed with the rats under intraperitoneal midazolam (2 mg/kg) and ketamine (40 mg/kg) anesthesia. Using the method described by Zeng et al. [7], an intrathecal catheter (PE-10, 8.5 cm) was inserted through an opening in the cisternal magna to the lumbar subarachnoid space. After surgery, animals were allowed to recover for 1 week before the administration of drugs.
2.2. Nociceptive and motor function test Nociceptive threshold was assessed by means of the tail-flick (TF) test. The mean baseline value for TF latency was 3.5 s (3.3—3.8 s). A cut-off time of 10.0 s was imposed to minimize damage to the skin of the tail during the experiment. TF latencies were determined 5, 10, 15, 20, 30, 40, 50, and 60 min after intrathecal administration of drugs. Motor blockade was graded, according to the scale proposed by Langerman et al. [8] for rabbits, which we modified for the rat model as follows: 0 = free movement of hind limbs without limitation; 1 = limited or asymmetrical movement of the hinds to support the body and walk; 2 = inability to move the limbs and respond to a pain stimulus; and 3 = total paralysis of the hind limbs.
W. Zeng et al.
2.3. Drugs and injections After baseline measurements for TF latency had been obtained, each animal received an intrathecal injection of succinylcholine (50 and 100 g), lidocaine (25, 50, 100, 200, or 300 g), or succinylcholine plus lidocaine. Physiologic saline (20 l) served as a control. The behaviour and motor function of intraperitoneal injection of succinylcholine (300 g/kg) were also examined. All drugs were administered in a total volume of 10 l followed by 10 l of physiologic saline solution to flush out the contents of the catheter.
2.4. Statistical analysis All data are presented as mean ± S.E.M. The response in the TF test is expressed as the percentage of the maximum possible effect (%MPE) where %MPE = (postdrug TF latency − baseline TF latency)/(10 s − baseline TF latency) × 100. The effects of drugs on TF latency were evaluated for linearity and deviation from parallelism by a one-way analysis of variance and Scheffe’s PLSD test. Other comparisons between groups were analyzed using a two-way analysis of variance and Scheffe’s F-test. A P value < 0.05 was considered as statistically significant.
3. Results Intrathecal administration of lidocaine (25—300 g) alone produced a significant dose-dependent antinociception in the TF test (Figs. 1 and 2). The peak effects were observed at 5 min after drug administration. Intrathecal administration of succinylcholine (50 and 100 g) alone did not produce the antinociception in the TF test (Fig. 2). However, intrathecal succinylcholine (100 g) synergistically enhanced the antinociceptive effect of intrathecal lidocaine (Figs. 2 and 3). The motor functions revealed no differences in the scores on the modified scale whether observations were made before and after intrathecally administered succinylcholine during the observation period (data not shown). Intrathecal administration of lidocaine (200 g) combined with succinylcholine (100 g) also did not affect the motor function scales when compared with intrathecal administration of lidocaine (200 g) alone (Fig. 4). Succinylcholine (300 g/kg) injected intraperitoneally, no changes in behaviour were observed within 5 min.
Effects of succinylcholine on spinal antinociception with lidocaine in rats
Fig. 1 Time course of the antinociceptiove effect (%MPE) of intrathecally administered lidocaine (lido) in TF tests. Each point represents mean ± S.E.M. from 5 or 7 rats.
4. Discussion The current study demonstrates that spinal antinociceptive effects of lidocaine were significantly potentiated and prolonged by the concomitantly administered succinylcholine, a muscle relaxant, in the TF test. Spinal cholinergic system is important in spinal nociceptive modulation. Cholinergic binding was found in spinal cord level. Intrathecally admin-
Fig. 2 Log dose-response curves for the effects of intrathecally administered lidocaine (lido), succinylcholine (succ), and lidocaine-succcinylcholine ([succ] 100 g) on the thermal nociceptive threshold. Data are plotted as percentage maximal possible effect (%MPE) vs. log dose in g. Each point represents the mean ± S.E.M. from 5 or 7 rats.
39
Fig. 3 Effect of 100 g or 200 g lidocaine plus 100 g succinylcholine in TF tests. The combination produced a significant prolongation of TF latency. * P < 0.05 or ** P < 0.01 compared with the baseline preadministration values. Each point represents the mean ± S.E.M. from 5 or 7 rats.
istered nicotine and cholinergic agonists and acetylcholinesterase inhibitors produced analgesia in humans and animals [1]. In the present study spinal antinociceptive effects of lidocaine were significantly potentiated and prolonged by the concomitantly administered succinylcholine, a muscle relaxant, in the TF test in rats. The underlying mechanism of succinylcholine potentiating the spinal antinociception of lidocaine is not clear. Succinylcholine, an analog of acetylcholine,
Fig. 4 Effect of the combination of lidocaine (L) and succinylcholine (S) on motor function test. Lidocaine 200 g combined with succinylcholine 100 g did not affect on the motor function scales when compared with lidocaine alone. Each point represents the mean ± S.E.M. from 5 rats.
40 inhibits postsynaptic current [3], opens K+ channels [9], and at a low concentration (1 M) enhances evoked acetylcholine release [9]. Inman et al. [10] reported that succinylcholine dilated both preand post-glomerular vessels and this dilation was blocked by atropine, indicating succinylcholine has muscarinic actions. A previous study showed that the effect of lidocaine could be reduced by pretreatment with intraspinally administered atropine or mecamylamine suggesting that the antinociceptive effect produced by lidocaine was mediated through an action on muscarinic and nicotinic receptors [11]. Both succinylcholine and lidocaine may promote the shift of receptors from a normal state to a desensitized state or may react with desensitized molecules to prevent them from returning to normal [5]. Thus, one possible mechanism of the interaction is that the drug combination effectively inhibits overall neuronal excitability at the level of ionic channels by inhibiting Na+ channels with lidocaine and reducing postsynaptic current with both succinylcholine and lidocaine. Another possible mechanism of the interaction may be succinylcholine, an analog of acetylcholine, producing inhibition of the dorsal horn neuron through cholinergic mechanism enhancing spinal antinociception with lidocaine. Previous observation suggested that muscle relaxants were not inert when they appear in the cerebrospinal fluid. For example, muscle relaxants administered directly into rat brain and intraventricular caused seizures and neuronal death [12]. Pancuronium into the cerebrospinal fluid caused autonomic dysfunction and/or weakness [13]. In the present study intrathecal succinylcholine itself had no effect on antinociception and motor block, although the succinylcholine, like acetylcholine, binds and activates the nicotinic and muscarinic acetylcholine receptors in the spinal cord [14]. One possible explanation for this apparent discrepancy could be the existence of electrophysiologic differences in drug sensitivity between central and peripheral subclasses of acetylcholine receptors; another possible explanation for the result could be a plasma concentration of succinylcholine too low to produce neuromuscular blockade. In conclusion, intrathecal administration of succinylcholine alone causes no antinociception to a noxious heat stimulus in awake rats, but synergistically potentiates spinal antinociception
W. Zeng et al. with lidocaine, suggesting exogenous structure like cholinomimetics may be important in spinal antinociception.
References [1] Naguib M, Yaksh TL. Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with m and a2 receptor systems. Anesthesiology 1994;80:1338—48. [2] Nedoma J, Dorofeeva NA, Tucek S, Shelkovnikov SA, Danilov AF. Interaction of the neuromuscular blocking drugs alcuronium, decamethonium, gallamine, pancuronium, ritebronium, tercuronium and d-tubocurarine with muscarinic acetylcholine receptors in the heart and ileum. NaunynSchmiedebergs Arch Pharmacol 1985;329:176—81. [3] Adam LP, Henderson EG. Augmentation of succinylcholineinduced neuromuscular blockade by calcium channel antagonists. Neurosci Lett 1986;70:148—53. [4] Kimura I, Okazaki M, Uwano T, Kobayahi S, Kimura M. Succinylcholine-induced acceleration and suppression of electrically evoked acetylcholine release from mouse phrenic nerve-hemidiaphragm muscle preparation. Japan J Pharmacol 1991;57:397—403. [5] Miller RD. Anesthesia. fourth ed. Churchill Livingstone Inc.; 1994. p. 742—4. [6] Carp H, Jayaram A, Morrow D. Intrathecal cholinergic agonists lessen bupivacaine spinal block-induced hypotension in rats. Anesth Analg 1994;79:112—6. [7] Zeng W, Dohi S, Shimonaka H, Asano T. Spinal antinociceptive action of Na+ —K+ pump inhibitor ouabain and its interaction with morphine and lidocaine in rats. Anesthesiology 1999;90:500—8. [8] Langerman L, Grant GJ, Zakkowaki M, Golomb E, Ramanathan S, Turndorf H. Prolongation of epidural anesthesia using a lipid drug carrier with procaine, lidocaine, and tetracaine. Anesth Analg 1992;75:900—5. [9] Naguib M, Magboul MA. Adverse effects of neuromuscular blockers and their antagonists. Drug Safety 1998;18:99—116. [10] Inman SR, Stowe NT, Albanese J, Meehan M, Ryckman J, Zanettin GG, et al. Contrasting effects of vecuronium and succinylcholine on the renal microcirculation in rodents. Anesth Analg 1994;78:682—6. [11] Abelson KS, Hoglund AU. Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats. Neurosci Lett 2002;317:93—6. [12] Szenohradszky J, Trevor AJ, Bickler P, Caldwell JE, Sharma ML, Rampil IJ, et al. Central nerveous system effects of intrathecal muscle relaxants in rats. Anesth Analg 1993;76:11304—9. [13] Mesry S, Baradaran J. Accidental intrathecal injection of gallamine triethiodide. Anesthesia 1974;29:301—4. [14] Lauretti GR, de Oliveira R, Reis MP, et al. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999;90:1534—8.