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Anesth Analg 2001;92:134-139
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Anesthetic Interaction Between Adenosine Triphosphate and N-methyl-D-Aspartate Receptor Antagonists in the Rat

Eiji Masaki, MD, PhD*,{dagger}, Koji Yamazaki, MD{ddagger}, Yuji Ohno, MD*, Haruhisa Nishi, PhD*, Yasunori Matsumoto, DDS*, and Masahiro Kawamura, MD*

Departments of *Pharmacology (I), {dagger}Anesthesiology, and {ddagger}Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan

Address correspondence and reprint requests to Eiji Masaki, Department of Pharmacology (I), Jikei University School of Medicine, 3–25-8, Nishishinbashi Minato-ku, Tokyo 105-8461, Japan. Address e-mail to jkyakuri{at}sepia.ocn.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Modulation of synaptic neurotransmission through the ligand-gated ion channel is probably involved in the mechanisms of analgesic and anesthetic actions. In the central nervous system, adenosine triphosphate and glutamate are fast excitatory neurotransmitters through their effects on P2X and N-methyl-D-aspartate (NMDA) receptors respectively. To examine the anesthetic interaction between adenosine triphosphate and NMDA receptor antagonists, we studied the effect of intracerebroventricular administration of P2 and/or NMDA antagonists on the minimum alveolar concentration (MAC) of sevoflurane in rats. Intracerebro- ventricular administration of phosphonopentanoic acid azophenyl-2',4'-disulfonate and D (-)-2-anino-5-phophonopentanoic acid, P2 and NMDA antagonists, significantly reduced the MAC of sevoflurane. The reduction of the MAC by both phosphonopentanoic acid azophenyl-2',4'-disulfonate and D (-)-2-anino-5-phophonopentanoic acid was dose-dependent. The effect of coadministration of both antagonists was additive in the reduction of sevoflurane minimum alveolar concentration. These results suggest that P2 and NMDA receptors mediate nociceptive/anesthetic processing as inhibition of these receptors resulted in analgesic and anesthetic effects. However the pathway mediated through each receptor may be different postsynaptically and/or one of these presynaptic receptors may modulate the neurotransmitter release of the other.

Implications: Because P2X and N-methyl-D-aspartate receptors mediate a fast neurotransmission, we examined the anesthetic interaction between antagonists of these receptors. P2 and N-methyl-D-aspartate receptor antagonists showed additive anesthetic interaction.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Although, historically, volatile anesthetics (VA) are thought to suppress the activity of the central nervous system in a nonspecific manner, these anesthetics can be selective in their actions. For example, synaptic transmission mediated by ligand-gated ion channel receptors, such as N-methyl-D-aspartate (NMDA) (1) and {gamma}-aminobutyric acidA (GABAA) (2) are sensitive to clinically relevant concentrations of VA.

The present study demonstrates the anesthetic interaction between P2 and NMDA receptor antagonists. In central nervous system, adenosine triphosphate (ATP) and glutamate function as fast neurotransmitters via P2X and NMDA receptors, respectively. These receptors are members of postsynaptic ligand-gated cation channels (3,4). Antagonism of P2 (5) and NMDA (6) receptors is also involved in anesthetic action.

We examined the effect of coadministration of both P2 and NMDA receptor antagonists on the depth of anesthesia and the type of interaction between these two antagonists. Therefore we investigated the effects of intracerebroventricular (ICV) administration of pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and D (-)-2-amino-5-phosphonopentanoic acid (D-AP5), antagonists of P2 and NMDA receptors, on the minimum alveolar concentration (MAC) of sevoflurane.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by our institutional committee on animal research. Male Sprague-Dawley rats (7w, 200–250 g), which were allowed free access to food and water until the time of experiment, were randomly divided into four groups (I-IV) according to agents used for ICV administration as follows: I, saline (control); II, PPADS; III, D-AP5; and IV, coadministered both antagonists. We determined the MAC of sevoflurane in each group.

At 24 h before measuring MAC, the rats were anesthetized with intraperitoneal thiopental (50 mg/kg) and placed in a stereotactic apparatus (SR-6N; Narishige, Tokyo, Japan). After skin incision, a hole was drilled 2 mm caudal and lateral to bregma. A fine, stainless, L-shaped tube was implanted into the right lateral ventricle and secured to the skull with strong adhesive. A silicone tube, 0.3 mm in inner diameter, was connected to one end of this stainless pipe, tunneled through the cervical subcutaneous region and fixed. Correct placement of the tip of the L-shaped tube in the ventricular space was determined by injection of lissamine green dye after measurement of the MAC.

MAC of sevoflurane was measured according to the methods of Eger et al. (7). Each rat was placed in an individual plastic chamber (30 cm long and 5 cm in diameter) and was given sevoflurane in oxygen (4 L/min total gas flow). Expired gas, which was drawn from the outflow tube, was continuously sampled and anesthetic concentration was monitored with an infrared analyzer (Datex Ultima, Helsinki, Finland). Rectal temperature was measured and maintained between 36.5 and 37.5°C with an electronic heating mat. After initial equilibration (2.5% sevoflurane for 40 min), a tail clamp was applied for 1 min by using a long hemostat and movement in response to the stimulation was observed. The concentration of VA was increased or decreased by 0.2–0.3% steps with 20 min equilibration time allowed after changes in concentration. The response to a noxious stimulus was tested at each concentration. The mean of the smallest concentration without stimulus-evoked movement and the largest concentration with movement was taken as MAC. After measurement of baseline MAC (before the ICV administration), ICV administration was conducted by using a volume of 25 µL. The MAC was measured again at 30 min after the ICV injection. Absence of hypoxia, hypercapnia, and acidosis was confirmed with blood gas analysis by sampling of arterial blood from the abdominal aorta after the second measurement of MAC.

Sevoflurane was purchased from Dinabot Japan (Osaka, Japan). D-AP5 and PPADS were obtained from Tocris Cookson Ltd. (Bristol, UK) and RBI (Natick, MA) respectively.

ED50 values for D-AP5 and PPADS were calculated by using nonlinear regression with PrismTM (version 2.0; GraphPad, San Diego, CA) according to the following equation. Go


where X is the logarithm of antagonist amount and Y is the sevoflurane MAC. Bottom is the Y value at the bottom plateau; Top is the Y value at the top plateau.

The data were analyzed by analysis of variance with subsequent intragroup comparisons by using the Scheffé F test. A value of P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The ICV administration of PPADS (75 µg/rat) and D-AP5 (125 µg/rat) significantly reduced the MAC of sevoflurane. The coadministration of both antagonists produced a deeper anesthetic level (Figure 1a). When the smaller doses of PPADS (37.5 µg/rat) and D-AP5 (62.5 µg/rat) were administered, only D-AP5 significantly inhibited the MAC of sevoflurane and the coadministration of both antagonists failed to show further reduction of the MAC (Figure 1b). Before the ICV administration, the baseline MAC for sevoflurane was not different among the four groups. Additionally, there was no significant difference in arterial blood gas data among groups. No rats exhibited hypoxia, hypercapnia, and acidosis (Table 1). The reduction of MAC of sevoflurane by D-AP5 was dose-dependent and PPADS potentiated the effect of D-AP5. The enhancement of PPADS was uniform at all concentrations of D-AP5 (Figure 2). Log ED50 values for D-AP5 in the absence and presence of PPADS were nearly identical (2.09 ± 0.12 and 2.07 ± 0.12 µg/rat, with and without D-AP5 respectively, mean ± SE, n = 10). PPADS also inhibited the MAC of sevoflurane in a dose-dependent manner and D-AP5 potentiated the inhibitory effect of PPADS. The potentiation of D-AP5 was to the same extent at all concentrations of PPADS (Figure 3). Log ED50 values for PPADS in the absence and presence of D-AP5 (1.62 ± 0.30 and 1.37 ± 0.55 µg/rat, respectively, mean ± SE, n = 10) were not significantly different.



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  		Figure 1. Anesthetic interaction between intracerebroventricular (ICV) administration of pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and D (-)-2-amino-5-phosphonopentanoic acid (D-AP5) (a: large-dose, b: small dose). After measurement of baseline minimum alveolar concentration (MAC) (before ICV administration), the ICV administration was conducted with the indicated amount of the antagonists in a volume of 25 µL. Data are expressed as mean ± SD. In each group, an n = 10 experiment was performed. *P < 0.05 vs saline, P < 0.05 vs D-AP5, P < 0.01 vs PPADS, §P < 0.05 vs PPADS.

 

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  		Table 1. Blood Gas Analysis
 


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  		Figure 2. Dose-response curve of D (-)-2-amino-5-phosphonopentanoic acid (D-AP5) with and without pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) on sevoflurane minimum alveolar concentration (MAC). After intracerebroventricular administration of the indicated amount of the antagonists in a volume of 25 µL, the MAC was measured. Data are expressed as mean ± SD. At each concentration of antagonist, an n = 10 experiment was performed. *P < 0.05 vs without PPADS, P < 0.05 vs 0 µg, P < 0.01 vs 0 g, §§P < 0.01 vs 62.5 µg.

 


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  		Figure 3. Dose-response curve of pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) with and without D (-)-2-amino-5-phosphonopentanoic acid (D-AP5) on sevoflurane minimum alveolar concentration (MAC). After intracerebroventricular administration of the indicated amount of the antagonists in a volume of 25 µL, the MAC was measured. Data are expressed as mean ± SD. At each concentration of antagonist, an n = 10 experiment was performed. **P < 0.01 vs without D-AP5, P < 0.05 vs 0 µg, §P < 0.05 vs 18.8 µg.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study shows that PPADS and D-AP5 reduced the MAC of sevoflurane and the coadministration of both antagonists produced further reduction of MAC. The mode of interaction between both antagonists seems to be additive because a) each antagonist has a uniform inhibitory effect over a wide range concentration of the other (Figure 2, 3), b) Log ED50 values for one antagonist in the absence and presence of the other were not different (Figure 2 and 3), and c) the smaller dose of PPADS could not enhance the effect of D-AP5 (Figure 1b). These results suggest that P2 and NMDA receptors mediate nociceptive processing; however, the postsynaptic processes of these two receptors may not be linked with one another and/or one of these presynaptic receptors regulate the release of the neurotransmitter of the other.

The additive and synergistic interaction are defined in the following equations (8). Additive: C = A + B, Supra-additive (Synergictic): C > A + B where A is the effect of drug a, B is the effect of drug b, and C is the effect of combination of drug a and b. Although these terms have very limited usefulness, the anesthetic interaction in the present study was found to be additive by applying this equation. In Figure 1a, PPADS and D-AP5 reduced the MAC by 0.53 ± 0.26% and 0.75 ± 0.29% (mean ± SD), respectively, and the combination of both antagonists decreased the MAC by 1.23 ± 0.26% (mean ± SD).

The modulation of synaptic transmission mediated by ligand-gated ion channel receptors is one of the mechanisms and sites of action of VA. The antagonists or agonists of ligand-gated ion channel receptors exhibit anesthetic effects, and VA at clinically relevant concentrations affects the function of those receptors. The MAC of VA was reduced by antagonists of NMDA (6), {alpha}-amino-3-hyroxy-5-methyl-4-isoxazole propionic acid (AMPA) (9) receptors and P2 purinoceptor (5). NMDA-gated single channel activity in hippocampal neurons and ATP-induced inward current in locus ceruleus neurons were inhibited by isoflurane (1) and sevoflurane (10), respectively. The agonist of an inhibitory neurotransmiter was found to exert a similar effect. The GABA analog, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol was found to produce analgesia, sedation, and loss of righting reflex in rats and mice (11), and halothane and enflurane enhanced GABA and glycine-induced chloride currents in neurons dissociated from the nucleus tractus solitarius (12). We demonstrate another association between anesthetic action and ligand-gated ion channel receptors and showed an anesthetic interaction between P2 and NMDA receptor antagonists.

Nonadditive interaction between NMDA and AMPA receptor antagonists during halothane anesthesia was demonstrated in rats (13). These two receptors are physiologically linked postsynaptically (14). Stimulation of the AMPA receptor causes fast excitation resulting in depolarization. This depolarization allows alleviation of the Mg2+ blockade in the NMDA ionophore and accelerates the activation of NMDA receptor. The activation of the P2X receptor can also cause fast excitation (15), which can lead to opening the NMDA ionophore. If P2X and NMDA receptors exist in the same neuron, these two receptors should display a nonadditive interaction similar to that of AMPA and NMDA receptors. Because P2 and NMDA receptor antagonists showed additive interaction, we suggest that P2X and NMDA receptors may not seem to co-localize in the same neuron, and may conduct the nociceptive responses by different pathways postsynaptically.

In rat spinal cord, an additive interaction, inhibitory to nociceptive responses, was demonstrated between A1 adenosine and {alpha}2-adrenergic receptors, even though these receptors are not ligand-gated ion channel receptors (16). A1 adenosine and {alpha}2-adrenergic receptors are coupled with G protein and modulate the level of the intracellular concentration of adenosine 3' 5'-cyclic monophosphate (17). Intrathecal administration of adenosine and clonidine, A1 and {alpha}2 receptor agonists, reduced hypersensitivity that occurs after ligation of the spinal nerve root. When both agonists were coadministered, they interacted in an additive manner. Because the antihypersensitive effects of intrathecal adenosine were blocked by the specific {alpha}2-adrenergic antagonist and adenosine agonist induced the norepinephrine release in rat spinal cord slices in vitro, the authors suggested that spinally administered adenosine may act to reduce hypersensitivity by activation of spinal noradrenergic terminals to release norepinephrine. Gu and MacDermott (18) suggested that P2X purinoceptors are expressed on presynaptic terminals of dorsal root ganglion (DRG) neurons and their activation enhances glutamate release. In this study, some of the antagonists (PPADS and D-AP5) that were administered ICV could have spread to the cord through the cerebrospinal fluid and affected their respective receptors. In addition, one study indicated that the spinal cord is a principal site of action for VA with respect to MAC measurements (19). In our study, PPADS decreased the release of glutamate by binding to presynaptic P2X on DRG neurons and the D-AP5 inhibited the action of glutamate on the postsynaptic NMDA receptor, resulting in an additive effect on sevoflurane MAC.

Shehnaz et al. (20) suggested that PPADS exerts other effects than those on P2 purinoceptors. PPADS inhibited arachidonic acid release stimulated by various compounds including nucleotides in Madin-Darby canine kidney cells. These results imply that the effect of PPADS is not involved in the inhibition of a specific receptor. Suramin, another P2 purinoceptor antagonist, also affects not only P2 purinoceptor but other sites. Glutamete-evoked AMPA current (21), NMDA-induced inward current (22), and GABA-evoked whole cell current (23) are all inhibited by suramin. There are no specific P2 purioceptor antagonists. But some kind of P2 purinoceptor antagonists were used in each experiment. In our previous study (5), the MAC of sevoflurane and isoflurane were measured after ICV administration of PPADS and suramin. Both antagonists had similar effects on the MAC, thus suggesting that the PPADS in the present study, at least in part, exert its effect through P2 purinoceptor.

When an agonist for P2 purinoceptor was injected ICV, the MAC of sevoflurane was not changed in our preliminary experiment performed in our laboratory (data not shown). {alpha},ß-methylene ATP, a putative P2X purinoceptor agonist, failed to increase the MAC of sevoflurane, when administered alone at doses up to 75 µg/rat. In human study, the MAC of sevoflurane was also not potentiated by IV administration of ATP (24). If P2 purinoceptor antagonists reduced the MAC of sevoflurane, the agonists of this receptor, {alpha},ß-methylene ATP and ATP, would be expected to increase it. In the case of our preliminary experiment, the failure would result from the desensitization of P2 purinoceptor by {alpha},ß-methylene ATP, which are resistant to adenosinetriphosphatase. ATP injected IV degraded rapidly into adenosine in the human study (25). Adenosine decreases the MAC of VA (26,27). A similar observation has been made in NMDA receptors. Putative antagonists of the polyamine site in NMDA receptors increased the anesthetic potency of ethanol, but an inverse agonist was inactive (28). This study suggests that the stimulatory polyamine site is probably tonically activated, in vivo, and that the further addition of an inverse agonist active at this site would not be expected to alter anesthetic potency.

Näsström et al. (29) demonstrated that systemic or ICV injection of NMDA receptor antagonists attenuates the antinociceptive activity of intrathecally administered NMDA receptor antagonists, as measured by hot plate test. These results indicate that supraspinal systems can limit the spinal antinociceptive effect of NMDA receptor antagonists, and would disagree with our results. In contrast to the results of Näsström et al. (29), systemically administered NMDA receptor antagonists are reported to reduced the MAC of VA (6,13,30). Although the exact reason for this discrepancy among studies is not apparent, the different results may arise from different assessments of nociceptive responses. During the determination of MAC, several neuronal functions other than mediating nociception, such as motor and cognition, are also influenced by anesthetics and these influences can alter the response for noxious stimulus. Consequently, the NMDA receptor antagonists may yield different results between the MAC measurements and hot plate experiments. Alternatively, it is possible that thermal and mechanical nociceptive responses cannot be mediated through the same pathway.

The MAC value of sevoflurane never approached zero, even when large doses of both antagonists were coadministered. Other receptors are likely to be involved in the mechanisms of VA anesthetic action besides the P2 and NMDA receptors. Fast excitatory neurotransmission is mediated by five major ligand-gated ion channel receptors, i.e., NMDA, AMPA, neuronal nicotinic acetylcholine, 5-hydoxytryptamine 3, and P2X, in mammalians. These receptors are widely distributed throughout the central nervous system and are modulated by general anesthetics (1,10,31–33). Although MAC is believed to predominantly reflect nociception at the spinal cord level, descending modulatory pathways exist and may influence anesthetic action on the cord (34). Therefore, inhibition of these five receptors in the brain and spinal cord could be the mechanism of action of VA. Although P2 and NMDA receptors exhibited additive anesthetic interaction, the other combinations of these receptors might show different types of interactions that are involved in mediating anesthetic effects.

In conclusion, the ATP and NMDA receptor antagonists reduced the MAC of sevoflurane, and coadministration of both antagonists resulted in a deeper level of anesthesia. Although many other receptors and complicated mechanisms are involved in anesthetic action, the interaction between ATP and NMDA receptors presented in this study could be one of the mechanisms of VA’s mode of action.


   Acknowledgments
 
This work was supported in part by Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture of Japan, and the Japan Health Science Foundation. The authors thank Dr. Salim Hayek (Case Western Reserve University, Cleveland, OH) for his help with manuscript preparation.


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 Introduction
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Accepted for publication September 1, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press