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Anesth Analg 1999;89:416
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

The Non-NMDA Glutamate Receptor Antagonist CNQX Augments Lidocaine Antinociception Through a Spinal Action in Rats

Noritaka Imamachi, MD, Yoji Saito, MD, Kaoru Hara, MD, Shinichi Sakura, MD, and Yoshihiro Kosaka, MD

Department of Anesthesiology, Shimane Medical University, Izumo, Japan

Address correspondence to Y. Saito, MD, Department of Anesthesiology, Shimane Medical University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. Address e-mail to ysaito{at}shimane -med.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Non-NMDA glutamate receptor antagonists produce antinociceptive effects, but the antinociceptive interaction between non-NMDA glutamate receptor antagonists and local anesthetics has not been demonstrated. We designed this study to evaluate the antinociceptive effects of a non-NMDA glutamate receptor antagonist and its interaction with lidocaine in rats. Intrathecal catheters were implanted at the L4-5 level in rats. The tail flick (TF) and colorectal distension (CD) tests were used to assess somatic and visceral antinociceptive effects, respectively. The TF latency and CD threshold were measured before and for 180 min after the intrathecal administration of lidocaine (20–100 µg), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (0.4–4.0 µg), a combination of CNQX (0.2–0.6 µg) and lidocaine (10–30 µg), or isotonic sodium chloride solution. The TF latency and CD threshold were converted to the percent maximal possible effect (%MPE). To determine synergistic interaction, isobolographic analysis was used. Lidocaine or CNQX increased %MPEs in both the TF and CD tests. The coadministration of CNQX 0.4 µg and lidocaine 20 µg, which had no effect by alone, significantly increased %MPEs in the TF and CD tests for 30 min and 10 min, respectively. Isobolographic analysis revealed the synergistic antinociception of CNQX and lidocaine in the TF test. Motor impairment was not observed after that combination. We conclude that CNQX and lidocaine produce synergistic analgesia on somatic and visceral pain at the spinal level.

Implications: We investigated the antinociceptive effects of 6-cyano-7-nitroquinoxaline-2,3-dione and its interaction with lidocaine at the spinal level in rats. Intrathecal 6-cyano-7-nitroquinoxaline-2,3-dione produced both somatic and visceral antinociception, and its coadministration with lidocaine showed synergistic antinociceptive effects.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Nociceptive stimulation increases the extracellular concentrations of glutamate in the spinal cord (1). The intrathecal administration of glutamate induces pain behavior, and this reaction is attenuated by glutamate receptor antagonists (2,3). These observations support the assumption that glutamate, as an excitatory amino acid, has an important role in a nociceptive processing at the spinal cord level. The ionotropic glutamate receptor involves three major subtypes: N-methyl-D-aspartate (NMDA), {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), and kainate receptors. Of these receptors, the role of the NMDA receptor in the nociceptive transmission is well characterized, but there is a little information regarding the role of non-NMDA glutamate (AMPA/kainate) receptors. Other studies have demonstrated that non-NMDA glutamate receptor antagonists, including 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), can produce antinociceptive effects on noxious stimuli in physiological (4,5) and hyperalgesic states (6–9).

Although the exact mechanisms of antinociceptive effects of non-NMDA glutamate receptor antagonists are unclear, they do decrease intracellular sodium (10) and intracellular calcium concentrations (11). This suggests that non-NMDA glutamate receptor antagonists, at least in part, may produce antinociceptive effects by inhibiting sodium and calcium influx. However, lidocaine produces antinociceptive effects by blocking sodium and calcium channels, leading to axonal conduction block (12), and it can inhibit sodium currents in the spinal dorsal horn neurons (13). We therefore hypothesized that non-NMDA glutamate receptor antagonists might have an antinociceptive interaction with local anesthetics through sodium and/or calcium channels at the spinal level.

The control of visceral pain is important in clinical practice because components of acute or chronic pain are of visceral origin (14). Some animal studies support the notion of visceral antinociceptive effects by local anesthetics (15,16). However, there is little information regarding the visceral antinociceptive effects at the spinal level of non-NMDA glutamate receptor antagonists, not to mention their antinociceptive interactions with local anesthetic.

We designed our study to evaluate antinociceptive effects of a non-NMDA glutamate receptor antagonist and its interaction with lidocaine on somatic and visceral noxious stimuli in the rat.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol for this experiment was approved by our animal care and use committee. The animals were maintained on a 12-h light/dark schedule (lights on from 8:00 AM to 8:00 PM) and were housed individually with free access to food and water.

To reduce the influences of handling on nociceptive responses, all animals were handled in the test situation for at least 4–6 days before intrathecal catheterization and testing. Under pentobarbital anesthesia, male Sprague-Dawley rats weighing 280–380 g were implanted with intrathecal catheters (double-stretched PE-10 joined to normal PE-10, then to PE-20) in the rostral direction at the level of L4-5. The effectiveness of the catheter was confirmed by injection of 20 µL of 2% lidocaine. After catheterization, at least 5 days were allowed for recovery before study. Rats that had motor deficits as a result of catheter placement, infection, or other health problems were excluded.

The tail flick (TF) test was performed to measure the response to a noxious somatic stimuli by monitoring latency to withdrawal from a heat source focused on the tail approximately 5 cm from the tip. The apparatus (model DS 20; Ugo Basile, Comerio-Varese, Italy) was calibrated to give an average baseline latency of approximately 4 s. The cutoff latency was 10 s.

The colorectal distension (CD) test was used to measure noxious visceral stimulus. The CD test involves air inflation of an 8-cm flexible latex balloon. The system consists of two parts: a large proximal stimulating balloon and a small distal sensing balloon. Pressure within the intracolonic stimulating balloon was steadily increased at a rate of 2.5 mm Hg/s beginning at 0 mm Hg until the abdominal musculature contracted, and was repeated until an increase of the pressure in the sensing balloon was detected. The minimal pressure at which abdominal musculature contractions were triggered was defined as the threshold response for visceral nociception in this test. A cutoff distension pressure of 60 mm Hg was used to prevent tissue damage.

On the day of an experiment, a CD balloon was inserted during light halothane anesthesia, and the rats were tested awake after recovery from the halothane anesthesia. Both the TF and CD tests were performed in each rat at the same time points, with a 2-min interval between each test. Each animal was tested on multiple days but never received the same dose of drug twice, and each recovered for 2 days between experimental tests.

After determination of the baseline values, one of the following regimens was administered by a single bolus intrathecal injection:

1.Lidocaine hydrochloride 20 µg (n = 7), 40 µg (n = 7), 60 µg (n = 8), 100 µg (n = 6)
2.CNQX 0.2 µg (n = 7),0.4 µg (n = 7), 0.6 µg (n = 8), 2.0 µg (n = 7), 4.0 µg (n = 6)
3.Combination CNQX 0.4 µg + lidocaine 20 µg
4.Isotonic sodium chloride solution (n = 7)

The above doses were determined after preliminary studies to define appropriate dose ranges. To perform isobolographic analysis, the dose ratio of the combination was fixed at CNQX to lidocaine 1:50 by adjusting the concentrations of solutions. Additional combination doses at CNQX 0.2 µg + lidocaine 10 µg (n = 6) or CNQX 0.6 µg + lidocaine 30 µg (n = 8) were used to conduct isobolographic analysis. Both drugs were dissolved in sterile saline. All drug injections were given in a volume of 10 µL, followed by 10 µL of saline to flush the catheter. Measurements of the TF latency and the CD threshold were taken 5, 10, 15, 20, 30, 60, 90, 120, and 180 min after injection. Motor function was evaluated 1, 5, 10, 15, 20, 30, 60, 90, 120, and 180 min after drug administration. At the end of an experiment, each rat was injected intrathecally with 10 µL of 2% lidocaine. Data obtained from rats that failed to show motor block after the intrathecal lidocaine injection were not included in the data analysis. TF latency and CD threshold were converted to percent maximal possible effect (%MPE) = (postdrug value - baseline value)/(cutoff value - baseline value) x 100%. %MPE is presented as mean ± SEM. Changes in %MPE after the intrathecal injection were analyzed using analysis of variance for repeated measures to assess the influence of treatment, followed by Scheffé’s test (StatView 4.5; Abacus Concepts, Inc., Berkley, CA). Differences were considered to be significant at P < 0.05.

To determine whether the antinociceptive interaction of CNQX and lidocaine is additive or synergistic, isobolographic analysis was performed using the method of Tallarida et al. (17). The 50% effective dose (ED50) values, 95% confidence intervals in the dose-effect curves in %MPEs, and the theoretical additive point were computed (Pharm/pcs 4; MicroComputer Specialists, Philadelphia, PA) (17,18). Statistical significance between theoretical additive and experimental points was evaluated according to the method of Tallarida (19).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Given intrathecally, lidocaine produced dose-dependent antinociceptive effects in both the TF and CD tests, whereas saline did not show significant changes in either test (Fig. 1, A and B). The peak effects of %MPE in both tests were observed 5–10 min after drug administration. Lidocaine 40 µg significantly increased %MPE in the TF test (30 min) but showed no significant change in the CD test (Fig. 1B). The significant increases in %MPEs in the TF test lasted longer than those in the CD test.



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  		Figure 1. Time course effects on percent maximal possible effect (%MPE) in the tail flick (TF) test (A and C) and colorectal distension (CD) test (B and D) after the intrathecal injection of saline (SAL); lidocaine (Lid) 20, 40, 60, and 100 µg; or CNQX 0.4, 0.6, 2, and 4 µg. Data are presented as mean ± SEM. *P < 0.05 compared with SAL.

 
Intrathecally administered CNQX (0.6–4.0 µg) significantly increased %MPE in the TF test in a dose- and time-dependent manner (Fig. 1C). The peak effects of %MPE in both tests were observed 5 min after drug administration. CNQX 2.0 µg produced a slight increase in %MPE in the CD test with no statistical significance (Fig. 1D). CNQX 4.0 µg increased %MPEs in the TF and CD tests. The duration of the antinociceptive effects was longer in the TF test than in the CD test.

The combination of CNQX 0.4 µg + lidocaine 20 µg, which produced no significant changes in %MPEs in the TF and CD tests by itself, significantly increased the %MPE for 30 min in the TF test (Fig. 2A) and for 10 min in the CD test (Fig. 2B) compared with CNQX or lidocaine alone. Figure 3 shows the isobologram in the TF test at 20 min. The experimental ED50 was below the theoretical additive line, and the CIs of the theoretical additive point and those of the experimental point did not overlap each other. This indicates a synergistic interaction between CNQX and lidocaine.



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  		Figure 2. Time course effects on percent maximal possible effect (%MPE) in the tail flick (TF) test (A) and colorectal distension (CD) test (B) after the intrathecal combination of CNQX and lidocaine (Lid). Data for Lid alone and CNQX alone are transferred from Figure 1. Data are presented as mean ± SEM. *P < 0.05 compared with the same dose of Lid alone and CNQX alone at individual time points.

 


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  		Figure 3. Isobologram of antinociceptive 50% effective dose (ED50) values and 95% confidence intervals for CNQX ({blacksquare} on the horizontal axis), lidocaine ({blacksquare} on the vertical axis), or the CNQX-lidocaine combination (•) 20 min after the intrathecal injection in the tail flick test. The heavy lines on the axes represent the confidence intervals for the single drugs. The dashed diagonal line connecting the CNQX and lidocaine ED50 values ({blacksquare}s) is the theoretical additive line, and the point on this line ({blacktriangleup}) is the theoretical additive point. The fact that the experimental points are below the theoretical additive points indicates that the antinociceptive interaction is synergistic.

 
The intrathecal administration of <60 µg of lidocaine or <2.0 µg of CNQX did not affect motor function. One of six rats or three of six rats demonstrated motor impairment in the lower limbs after the administration of lidocaine 100 µg or CNQX 4.0 µg, respectively (Table 1). Motor impairment was only observed 5 min after drug administration. The combination of CNQX and lidocaine did not produce any motor impairment (Table 1) .


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  		Table 1. Motor Impairment After Drug Administration
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our study clearly demonstrated that the intrathecal administration of CNQX produced antinociceptive effects on somatic and visceral noxious stimuli. The combination of CNQX and lidocaine enhanced their own antinociceptive effects. The isobolographic analysis in the TF test confirmed that the antinociceptive interaction between CNQX and lidocaine was synergistic. In the CD test, we could not perform the isobolographic analysis because the peak effects of CD threshold increased to 50%MPE and because it was difficult to increase the dose because of motor impairment caused by CNQX. However, the visceral antinociceptive effects in the CD test were significantly increased after the combination of CNQX and lidocaine, neither of which showed antinociceptive effects alone. This result supports the probability that CNQX combined with lidocaine similarly produces synergistic antinociception on visceral stimuli.

Although large doses of CNQX produced antinociceptive effects, those doses simultaneously caused motor impairment. The motor impairment may restrict the possible use of non-NMDA glutamate receptor antagonists. However, our results showing that the combination of CNQX with lidocaine produced antinociceptive effects with no motor impairment suggest an advantage of that combination. Furthermore, the combination may reduce the adverse effects of non-NMDA glutamate receptor antagonists or local anesthetics due to the reduced requirement of each drug. These findings support the possible clinical use of non-NMDA glutamate receptor antagonists in humans (7), especially in combination with local anesthetics. However, further studies regarding adverse effects, including neurotoxicity of those combinations in different animal species, should be performed before clinical use.

The results of previous studies regarding the antinociceptive effects of non-NMDA glutamate receptor antagonists are controversial. Some studies demonstrated that CNQX did not have antinociceptive effects in formalin test in rats (20) and in the TF test in mice (21). In contrast, non-NMDA glutamate receptor antagonists NBQX, CNQX, or DNQX produced antinociceptive effects in the TF test, formalin test, or hotplate test in mice (4,5), as shown in our results. Although the reasons for the difference in the results is not clear, the study setting, the nociceptive test used, dose of drug administered, route of administration of drugs, or species of animals might be responsible for the differential actions of non-NMDA glutamate receptor antagonists. CNQX suppressed the membrane depolarization and decreased the action potentials in high-threshold mechanoreceptive neurons (22). CNQX also reduced nociceptive activity stimulated by peripheral application of capsaicin in a rat isolated spinal cord-tail preparation (23). These observations support the antinociceptive effects of CNQX at the spinal level.

Recently, Zahn et al. (6) investigated the antinociceptive effects of intrathecal NBQX or DNQX in a rat model of postoperative pain, in which the withdrawal threshold to von Frey filaments significantly decreased after surgery. They demonstrated that NBQX and DNQX increased the withdrawal thresholds in this model, which indicates that those agents inhibit the hyperalgesic state induced by the surgery. Brennan et al. (24) have shown that bupivacaine significantly increased the withdrawal threshold to von Frey filaments on the day of surgery in the same model and that it inhibited the hyperalgesic state induced by surgery. Our results suggest that the combination of non-NMDA glutamate receptor antagonists and local anesthetics may have an advantage in the treatment of postoperative pain and hyperalgesia.

Most reports regarding the role of non-NMDA glutamate receptor on spinal sensory processing have focused on the modulation of somatic, rather than visceral, information (5,9), although the visceral pain is of major concern in the clinical setting. The activation of spinal non-NMDA glutamate receptors enhanced the sensitivity of visceral hyperalgesia to mechanical stimuli in the CD test, and the enhancement was inhibited by the intrathecal administration of DNQX (8). The results suggest the antinociceptive effect on visceral stimulus of a non-NMDA glutamate receptor antagonist. In fact, the large dose of CNQX showed visceral antinociception in this study. Furthermore, the combination of CNQX and lidocaine strongly enhanced the antinociceptive effects on visceral stimuli. These results suggest that the combination of CNQX and lidocaine is useful in controlling visceral pain.

In conclusion, intrathecally administered CNQX produced both somatic and visceral antinociception. The combination of CNQX and lidocaine produced synergistic antinociceptive effects at the spinal level, which suggests the clinical relevance of a combination of non-NMDA glutamate receptors and local anesthetics for pain management.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Skilling SR, Smullin DH, Beitz AJ, Larson AA. Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation. Neurochem 1988;51:127–32.
  2. Aanonsen LM, Wilcox GL. Nociceptive action of excitatory amino acids in the mouse: effects of spinally administered opioids, phencyclidine and sigma agonists. J Pharmacol Exp Ther 1987;243:9–19.[Abstract/Free Full Text]
  3. Raigorodsky G, Urca G. Spinal antinociceptive effects of excitatory amino acid antagonists: quisqualate modulates the action of N-methyl-D-aspartate. Eur J Pharmacol 1990;182:37–47.[Web of Science][Medline]
  4. Näsström J, Karlsson U, Post C. Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice. Eur J Pharmacol 1992;212:21–9.[Web of Science][Medline]
  5. Lutfy K, Cai SX, Woodward RM, Weber E. Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice. Pain 1997;70:31–40.[Web of Science][Medline]
  6. Zahn PK, Umali E, Brennan TJ. Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. Pain 1998;74:213–23.[Web of Science][Medline]
  7. Sang CN, Hostetter MP, Gracely RH. AMPA/Kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology 1998;89:1060–7.[Web of Science][Medline]
  8. Coutinho SV, Meller ST, Gebhart GF. Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors. Brain Res 1996;736:7–15.[Web of Science][Medline]
  9. Ren K, Williams GM, Hylden JLK, et al. The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats. Eur J Pharmacol 1992;219:235–43.[Web of Science][Medline]
  10. Rose CR, Ransom BR. Mechanisms of H+ and Na+ changes induced by glutamate, kainate, and D-aspartate in rat hippocampal astrocytes. J Neurosci 1996;16:5393–404.[Abstract/Free Full Text]
  11. Lohr C, Deitmer JW. Intracellular Ca2+ release mediated by metabotrophic glutamate receptor activation in the leech giant glial cell. J Exp Biol 1997;200:2565–73.[Abstract]
  12. Butterworth JF, Strichartz GR. Molecular mechanisms of local anesthesia. Anesthesiology 1990;72:711–34.[Web of Science][Medline]
  13. Olschewski A, Hempelmann G, Vogel W, Safronov BV. Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord. Anesthesiology 1998;88:172–9.[Web of Science][Medline]
  14. Bonica JJ. General conditions of abdominal pain. Philadelphia:Lea & Febiger, 1990.
  15. Kaneko M, Yoji S, Kirihara Y, et al. Synergistic antinociceptive interaction after epidural coadministration of morphine and lidocaine in rats. Anesthesiology 1994;80:137–50.[Web of Science][Medline]
  16. Maves TJ, Gebhart GF. Antinociceptive synergy between intrathecal morphine and lidocaine during visceral and somatic nociception in the rat. Anesthesiology 1992;76:91–9.[Web of Science][Medline]
  17. Tallarida RJ, Porreca F, Cowan A. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci 1989;45:947–61.[Web of Science][Medline]
  18. Tallarida RJ, Murray RB. Manual of pharmacologic calculations with computer programs. 2nd ed. New York:Springer-Verlag, 1987:26–31.
  19. Tallarida RJ. Statistical analysis of drug combinations for synergism. Pain 1992;49:93–7.[Web of Science][Medline]
  20. Coderre TJ, Empel IV. The utility of excitatory amino acid (EAA) antagonists as analgesic agents. II. Comparison of the antinociceptive activity of various classes of EAA antagonists in mechanical, thermal and chemical nociceptive tests. Pain 1994;59:345–52.[Web of Science][Medline]
  21. Suh HW, Song DK, Choi YS, Kim YH. Multiplicative interaction between intrathecally and intracerebroventricularly administered morphine for antinociception in the mouse: involvement of supraspinal NMDA but not non-NMDA receptors. Life Sci 1995;56:181–5.
  22. Schneider SP, Perl ER. Synaptic mediation from cutaneous mechanical nociceptors. Neurophysiol 1994;72:612–21.[Abstract/Free Full Text]
  23. Ault B, Hildebrand LM. Effects of excitatory amino acid receptor antagonists on a capsaicin-evoked nociceptive reflex: a comparison with morphine, clonidine and baclofen. Pain 1993;52:341–9.[Web of Science][Medline]
  24. Brennan TJ, Umail EF, Zahn PK. Comparison of pre- versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model of postoperative pain. Anesthesiology 1997;87:1517–28.[Web of Science][Medline]
Accepted for publication April 7, 1999.




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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 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press