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Anesth Analg 2001;92:725-732
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

The Analgesic Interaction Between Intrathecal Clonidine and Glutamate Receptor Antagonists on Thermal and Formalin-Induced Pain in Rats

Tomoki Nishiyama, MD, PhD*{dagger}, Laszlo Gyermek, MD, PhD*, Chingmuh Lee, MD*, Sachiko Kawasaki-Yatsugi, PhD{ddagger}, Tokio Yamaguchi, PhD{ddagger}, and Kazuo Hanaoka, MD, PhD§

*Department of Anesthesiology, Harbor-University of California, Los Angeles Medical Center, Torrance, California, {dagger}The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, {ddagger}Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan, §Department of Anesthesiology, The University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332-0015, Japan. Address e-mail to nishiyam{at}ims.u-tokyo.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Clonidine, an {alpha}2 adrenergic receptor agonist, inhibits glutamate release from the spinal cord. We studied the interaction of intrathecally administered clonidine and glutamate receptor antagonists on acute thermal or formalin induced nociception. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their tail withdrawal response by the tail flick test and paw flinches produced by formalin injection after intrathecal administration of saline, clonidine, AP-5 (a N-methyl-D-aspartate receptor antagonist), or YM872 (an {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist). The combinations of clonidine and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed as side effects. The ED50 values of clonidine decreased from 0.26 µg (tail flick), 0.12 µg (Phase 1) and 0.13 µg (Phase 2) to 0.036 µg, 0.006 µg, and 0.013 µg with AP-5, and 0.039 µg, 0.057 µg, and 0.133 µg with YM872, respectively. Side effects were attenuated in both combinations. In conclusion, spinally administered clonidine and AP-5 or YM872 exhibited potent synergistic analgesia on acute thermal and formalin-induced nociception with decreased side effects in rats.

Implications: Combinations of a spinally administered {alpha}2 adrenergic receptor agonist and an a N-methyl-D-aspartate receptor antagonist or an {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist exhibited potent synergistic analgesia in acute thermal and inflammatory-induced nociception with decreased side effects.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Glutamate plays an essential role in nociceptive mechanisms in the spinal cord. N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the facilitated states of pain processing but have little effect on acute pain (1). In contrast, an {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM872 inhibits both acute pain and inflammation-induced facilitated pain (2). However, because of the adverse effects e.g., neurotoxicity and psychotomimetic effects of NMDA receptor antagonists (3) and nephrotoxicity of the AMPA receptor antagonists (4), they are not clinically available. The NMDA receptor antagonist and AMPA receptor antagonist we used also induce motor disturbance, muscle weakness, or agitation/allodynia when administered alone intrathecally to rats to provide sufficient analgesia (2,5).

Intrathecally administered clonidine, an {alpha}2 adrenergic receptor agonist, produces analgesia and is important in the control of acute and chronic pain (6). However, hypotension and bradycardia occur with intrathecal clonidine (6), which sometimes complicates its clinical application.

{alpha}2 adrenergic receptor agonists alter the release of neurotransmitters in the spinal dorsal horn (7) and hyperpolarize dorsal horn wide dynamic range neurons (8). Clonidine inhibits glutamate release from the spinal cord synaptoneurosomes (9). From this evidence, we expected some interactive effects between {alpha}2 adrenergic receptor agonists and glutamate receptor antagonists in the spinal cord. Thus, answering the question as to whether the combination of clonidine and glutamate receptor antagonists would produce powerful analgesia with fewer side effects is important for clinical pain management. In the present study, interaction of intrathecally administered clonidine and NMDA- or AMPA receptor antagonist on acute thermal or formalin-induced nociception was studied using the rat model with intrathecal catheterization.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The protocol was approved by the Research and Education Institute of Harbor-UCLA Medical Center. Sprague-Dawley rats (280–300g; B K Universal, Fremont, CA) were implanted with chronic lumbar intrathecal catheters under halothane (2%) anesthesia according to the method described by Yaksh and Rudy (10). Briefly, a 8.5 cm polyethylene (PE-10; Clay Adams, Parsippany, NJ) catheter was advanced caudally through an incision in the atlantooccipital membrane, to the thoracolumbar level of the spinal cord. The external part of the catheter was tunneled subcutaneously to exit on the top of the skull and plugged with a 28-gauge stainless steel wire. Only rats with normal motor function and behavior 5 days after surgery were used. The position of the catheter was checked by the aspiration of cerebrospinal fluid at the implantation and was directly verified after killing the rat. A total of 176 rats for the tail flick test and behavioral study and 176 rats for the formalin test were used. The tail flick test and behavioral study were performed simultaneously using the same rat. Each rat was used only once.

Clonidine (Sigma Chemical, St. Louis, MO) 0.1, 0.3, 1, and 3 µg, and AP-5 (2-amino-5-phosphonovaleic acid, Sigma, St. Louis, MO) 1, 3, 10, and 30 µg were dissolved in saline 10 µL. YM872 {[2,3-Dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl] acetic acid, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Japan} 10 mg was dissolved in 0.97 mL distilled water with 30 µL 1N NaOH to adjust pH to 7.3–7.5. Solutions of 0.3 (0.86), 1 (2.86), 3 (8.59), 10 (28.63), or 30 (85.89) µg (nMol) per 10 µL were made using normal saline. Normal saline 10 µL was used as control. After each intrathecal drug injection, the catheter was flushed with a subsequent injection of 10 µL of normal saline to clear the dead space of the catheter (7 ± 0.4 µL, mean ± SE). Microinjector syringes were used for all injections. In each dose group, eight randomly selected rats were used.

Nociceptive test
The rats were placed in a clear plastic cylindrical cage with their tails extending through a slot provided in the rear of the tube. Noxious stimulation was provided by a beam of high intensity light (Tail-flick Analgesia Meter 0570–001L; Columbus Instruments International Co. Ltd., Columbus, OH) focused on the tail 2 to 3 cm proximal to the end. The response time was measured and defined as the interval between the onset of the thermal stimulation and the abrupt flick of the tail. The cut-off time in the absence of a response was set to 14 s, to prevent tissue injury.

Ten minutes after the intrathecal administration of the agent, the rats were anesthetized with 3% halothane until transient loss of spontaneous movements was observed and then quickly removed from the anesthesia box. Fifty µL of 5% formalin was injected subcutaneously into the dorsal surface of the right hindpaw with a 30-gauge needle. Immediately after injection, the rat was placed in an open Plexiglas chamber and observed for 60 min. Quantification of pain behavior was made by counting the incidence of spontaneous flinches/shaking of the injected paw at 1–2 min, 5–6 min and at 5 min intervals during a period of 10–60 min after formalin injection. The animals were then killed with an overdose of halothane. As previously described (5), two distinct phases were observed after formalin injection: Phase 1, during 0–6 min interval after injection, and Phase 2, beginning approximately 10 min after injection.

Behavioral and Motor Function Test
The general behavior (including agitation and allodynia), motor function, flaccidity, pinna reflex, and corneal reflex were examined by the blinded investigator. They were judged as present or absent. Agitation was judged as spontaneous irritable movement and/or vocalization. The presence of allodynia was examined by looking for agitation (escape and/or vocalization) evoked by lightly stroking the flank of the rat with a small probe. Motor function was evaluated by the placing/stepping reflex and the righting reflex. The former was evoked by drawing the dorsum of either hind paw across the edge of the table. Normally rats try to put the paw ahead into a position to walk. The latter was assessed by placing the rat horizontally with its back on the table, which normally causes an immediate, coordinated twisting of the body to an upright position. The disturbance of the righting reflex also shows impairment of function of the central nervous system. Flaccidity was judged as a muscle weakness in putting the forepaw on 3 to 5 cm higher than the hindpaw. Normally a rat will walk up. The lack of movement to walk up was judged as flaccid. Pinna and corneal reflexes were examined with a paper string. When a paper string was put into the ear canal or touched to the cornea rats normally shake their heads or blink, respectively.

The first series of experiments were performed to determine the dose-dependency and time course of the analgesic actions of intrathecally administered clonidine, AP-5, and YM872 in the tail flick test and the formalin test. The tail flick test, behavioral test, and motor function test were performed before and 5, 10, 15, 30, 60, 90, 120 min after drug injection and at 1 h intervals until the response time returned to the baseline (maximum 360 min).

To investigate the interaction between clonidine and AP-5 or YM872, an isobolographic analysis was used. The method is based on comparisons of dose ratios that were determined to be equally effective. First, the respective 50% effective dose (ED50) values were determined from the dose response curves of the drug alone. Subsequently, a dose-response curve is obtained by simultaneous coadministration of the two drugs in a constant dose ratio based on the ED50 values of the single drugs. The total volume of the combination was 10 µL. For the formalin test, the ED50 values in Phase 2 response were used. From the dose-response curve of the combined drugs, the ED50 value of the mixture was calculated.

Tail flick response latency was converted to %MPE (percent maximum possible effect) according to the formula: %MPE = [(postdrug latency-baseline latency)/(cutoff time-baseline latency)] x100. The ED50 was calculated by a computer program as the dose that produces a value of 50% MPE.

To describe the magnitude of interaction between the drugs, a total fractional dose value was calculated as follows: [(ED50 dose of drug 1 in combination)/(ED50 value for drug 1 alone)] + [(ED50 dose of drug 2 in combination)/(ED50 value for drug 2 alone)]. The values were normalized by assigning the ED50 values of the drugs given alone a value of 1. Values near 1 indicate an additive interaction, values greater than 1 imply an antagonistic interaction, and values <1 indicate a synergistic interaction. To compare the theoretical additive point with experimentally derived ED50, isobolographic analysis was used.

Differences between doses were analyzed with two-way analysis of variance followed by the Newman-Keuls test. The comparison between theoretical additive point and experimentally derived ED50 was performed with Student’s t-test. A P value <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The baseline latency (before drug injection) in the tail flick test was 3.1 ± 0.3 s (mean ± SE). Intrathecal administration of clonidine, AP-5, and YM872 resulted in dose-dependent increases in the tail flick latency ( Fig. 1). The ED50 values are shown in the Table 1 (Table 1).



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  		Figure 1. Time course of intrathecal clonidine ({alpha}2 adrenergic receptor agonist), AP-5 (N-methyl-D-aspartate receptor antagonist), YM872 ({alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist), AP-5 + clonidine, and YM872 + clonidine on the tail flick latency expressed as the peak %MPE (percent maximum possible effect). Each point presents the mean ± SEM of eight animals. Doses are shown as µg. AP = AP-5; Cl = clonidine; YM = YM872.

 

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  		Table 1. ED50 (50% effective dose) Values (µg) in the Tail Flick Test
 
Intrathecal administration of clonidine, AP-5, and YM872 decreased the number of flinches dose-dependently both in Phase 1 and Phase 2 of the formalin test ( Fig. 2). The ED50 values are shown in Table 2.



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  		Figure 2. Time course of intrathecal clonidine ({alpha}2 adrenergic receptor agonist), AP-5 (N-methyl-D-aspartatereceptor antagonist), YM872 ({alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist), AP-5 + clonidine, and YM872 + clonidine in the formalin test expressed as the number of flinches per minute. Each point presents the mean ± SEM of eight animals. Doses are shown as µg. AP = AP-5; Cl = clonidine; YM = YM872.

 

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  		Table 2. ED50 (50% effective dose) Values (µg) in the Formalin Test
 
Intrathecal coadministration of clonidine and AP-5 or YM872 induced dose-dependent increases in the thermal escape latency (Fig. 1) and showed a significant decrease of the ED50 values in each drug ( Fig. 3, Table 2). The total fractional dose value of the combination was calculated to be 0.28 ± 0.11 for clonidine + AP-5 and 0.30 ± 0.23 for clonidine + YM872, both of which indicate synergistic interactions.



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  		Figure 3. Isobologram for the intrathecal interaction of AP-5 and clonidine and YM872 + clonidine in the tail flick test. Horizontal and vertical bars indicate SEM. The oblique line between the x axis and y axis is the theoretical additive line. The point in the middle of this line is the theoretical additive point calculated from the separate ED50 values. The experimental point lies far below the additive line, indicating a significant synergism (P = 0.041 in AP-5 + Clonidine, P = 0.048 in YM872 + Clonidine).

 
Intrathecal coadministration of clonidine and AP-5 or YM872 induced dose-dependent decreases in the number of paw flinches of both Phase 1 and Phase 2 (Fig. 2) and showed a significant decrease of the ED50 values in each drug ( Fig. 4, Table 2). The total fractional dose value of the combination was calculated to be 0.012 ± 0.009 (Phase 1) and 0.19 ± 0.10 (Phase 2) for clonidine + AP-5, and 0.032 ± 0.016 (Phase 1) and 0.072 ± 0.031 (Phase 2) for clonidine + YM872, all of these indicate synergistic interactions.



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  		Figure 4. Isobologram for the intrathecal interaction of AP-5 and clonidine and YM872 + clonidine in the formalin test. Horizontal and vertical bars indicate SEM. The oblique line between the x axis and y axis is the theoretical additive line. The point in the middle of this line is the theoretical additive point calculated from the separate ED50 values. The experimental point lies far below the additive line, indicating a significant synergism (P < 0.01 in Phase 1 and P = 0.046 in Phase 2 of AP-5 + Clonidine, P = 0.023 in Phase 1 and P = 0.035 in Phase 2 of YM872 + Clonidine).

 
Clonidine >= 0.3 µg and AP-5 >= 10 µg induced agitation and allodynia. Motor disturbances (tested by the placing/stepping reflex and by the righting reflex) occurred with clonidine 3 µg, AP-5 >= 10 µg or YM872 >= 10 µg. Flaccidity was seen in the rats with YM872 >= 10 µg. AP-5 10 µg induced loss of corneal reflex and 30 µg induced loss of pinna reflex. In contrast, the combination of clonidine + AP-5 or YM872 in the dose range used in the present study induced no observable side effects ( Table 3).


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  		Table 3. Behavioral and Motor Function
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have found that intrathecally administered clonidine (an {alpha}2 adrenergic receptor agonist), AP-5 (NMDA receptor antagonist), and YM872 (AMPA receptor antagonist) produced dose-dependent increases in the tail flick latency and decreases in the number of paw flinches in both Phase 1 and Phase 2 of the formalin test. Clonidine showed synergistic antinociceptive effects with both AP-5 and YM872 on acute thermal and formalin-induced nociception with decreased side effects.

NMDA receptor antagonists are therefore the most effective against the tonic state of nociception, induced, for example, by formalin (1). Generally, they are ineffective on acute nociception, although Kristensen et al. (11) showed analgesic effects of NMDA receptor antagonists on acute thermal stimuli. In the present study, AP-5 (NMDA receptor antagonist) produced dose-dependent analgesic effects on acute thermal nociception though the ED50 value was relatively high. In a previous study, AP-5 had only weak analgesic effects at the maximum usable dose in the hot plate test (5). Considered together, NMDA antagonists might have some analgesic effects on acute nociception depending on the nociceptive stimulus. Yet the clinical application of NMDA receptor antagonists is limited by their adverse effects (e.g., psychotomimetic effects, cognitive impairment, and neurotoxicity (3)). Correspondingly AP-5 also induced motor disturbance and behavioral changes in our study.

AMPA receptors are thought to mediate acute excitation from primary afferent fibers to dorsal horn neurons evoked by high intensity stimuli. Intrathecal application of AMPA receptor antagonists produces dose-dependent antinociception on acute pain in animals (5). The clinical application of AMPA receptor antagonists has also been limited because of poor water solubility and nephrotoxicity (4). YM872 used in our study is a new competitive AMPA receptor antagonist. It is much more water soluble than the other formulations of AMPA receptor antagonists (12) and nephrotoxicity is not observed in animal experiments. In the present study, larger doses of YM872 induced transient motor disturbance and flaccidity, which completely recovered in 120 minutes. YM872 had no neurotoxicity in cat brain in cerebral ischemia model (13), or in rat and monkey brains in toxicological studies (unpublished data). However, further studies should be performed before applying it in human spinal cord.

At larger doses, intrathecal injection of clonidine results in peripheral vasoconstriction and increased blood pressure as a result of systemic absorption. At smaller doses, it decreases blood pressure as a result of inhibiting sympathetic outflow at sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord (14). We did not measure blood pressure because our main purpose was to study the analgesic effects and behavioral side effects. However, we can expect smaller changes in blood pressure when smaller doses are administered. Intrathecal administration of clonidine induced no detectable neurotoxic changes in the spinal cord and in nerve roots (15).

Although in the present study motor disturbance and flaccidity were observed in some of the rats, the animals still produced a vigorous tail flick response when the nociceptive stimulus was applied, indicating that the sedation did not interfere with the ability to respond to thermal stimulus.

From the above it appears that no single drug of these classes, administered alone, will be effective enough to block nociception without any adverse effects. One reason is that pain is not mediated by a single receptor or a single neurotransmitter. The other is that the receptors and/or neurotransmitters mediating pain are also connected to other neuronal networks in the central nervous system that may induce adverse effects. Thus a combination of drugs acting through different mechanisms may be one feasible way to arrive at a better analgesic method.

There are many studies on the analgesic interaction between different classes of antinociceptive drugs. In our previous study (5), neither NMDA receptor-nor NMDA receptor-glycine site antagonists showed any synergistic antinociception with morphine on acute thermal nociception, whereas in the other study (16), NMDA receptor glycine site antagonists and morphine synergistically reduced nociceptive transmission, evoked by carrageenin at the spinal cord. An AMPA receptor antagonist showed a significant synergistic analgesic effect with morphine on acute thermal nociception. This synergism was considered to be mediated by µ-opioid receptors (5). However there are no studies on the interaction between NMDA or AMPA receptor antagonists and {alpha}2 adrenergic receptor agonists.

{alpha}2 adrenergic receptor agonists bind pre- and postsynaptically to the primary afferent neurons in the spinal dorsal horn (17). They can alter pain transmission by activating presynaptically on the primary afferent fibers to release neurotransmitters (7). They also can act postsynaptically to hyperpolarize dorsal horn wide dynamic range neurons (18). The {alpha}2 adrenergic receptor agonists also activate K+ channels and inhibit voltage-dependent Ca2+ channels (19). Clonidine inhibits the activity of the preganglionic sympathetic neurons (20). Intrathecal administration of small doses of clonidine to rats produces significant reductions in neuronal firing rates of the lumbar sympathetic chain (21) and in efferent sympathetic activity (22). The inhibition of glutamate release in the spinal cord (9) may be an underlying mechanism of antinociception by clonidine.

The mechanism of the antinociceptive interaction between an {alpha}2 adrenergic receptor agonist and NMDA or AMPA receptor antagonists remains to be elucidated. Possible mechanisms of the synergy observed are as follows: First, change in the pharmacokinetics of each drug may occur when they are coadministered. Clonidine may decrease spinal blood flow with vasoconstriction, thereby it can affect the pharmacokinetics for example, of local anesthetics (23). Second, the difference of the sites of action between {alpha}2 adrenergic receptor agonists and NMDA or AMPA receptor antagonists would contribute to the synergistic interaction, because such interaction occurs when drugs affect different critical points along a common pathway (24). Third, as mentioned above, glutamate release might be inhibited by clonidine and the inhibition could be effectively enhanced by NMDA- or AMPA receptor antagonist.

With regard to the side effects, clonidine + AP-5 and clonidine + YM872 decreased behavioral changes and motor dysfunction while enhancing analgesia. Therefore these combinations could enhance the therapeutic efficacy and safety of pain treatment.

In conclusion, spinally administered {alpha}2 adrenergic receptor agonist and NMDA receptor or AMPA receptor antagonists exhibited potent synergistic analgesia on acute thermal and formalin-induced nociception in rats. Side effects, shown by behavioral changes and motor disturbance, decreased with the combination of these drugs. Our results are supportive of a new clinical approach, combining {alpha}2 adrenergic receptor agonists and NMDA or AMPA receptor antagonists, in the management of acute and inflammatory pain.


   Acknowledgments
 
Supported, in part, by the fund of the Department of Anesthesiology, Harbor-University of California, Los Angeles Medical Center, Los Angeles, California.

We thank to Dr. Ang Ji, Young-moon Cho, and Nguyen B. Nguyen, Department of Anesthesiology, Harbor/UCLA Medical Center for their assistance.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication November 20, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press