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Anesth Analg 2000;90:928-932
© 2000 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

N-Methyl-D-Aspartate Receptor Channel Block by Meperidine Is Dependent on Extracellular pH

Tomohiro Yamakura, MD*, Kenji Sakimura, PhD{dagger}, and Koki Shimoji, MD*

*Department of Anesthesiology, Niigata University School of Medicine; and {dagger}Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

Address correspondence and reprint requests to Tomohiro Yamakura, MD, Department of Anesthesiology, Niigata University School of Medicine, 1–757 Asahimachi, Niigata 951-8510, Japan. Address e-mail to yamakura{at}med.niigata-u.ac.jp


   Abstract
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 Abstract
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 Methods
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 Discussion
 References
 
Large concentrations of meperidine inhibit N-methyl-D-aspartate-(NMDA) receptor channels by channel block mechanisms. Extracellular pH regulates the activity and drug sensitivity of NMDA-receptor channels. We examined the influence of extracellular pH on sensitivity to meperidine of {epsilon}/{zeta} heteromeric NMDA-receptor channels expressed in Xenopus oocytes. Inhibition of {epsilon}1/{zeta}1, {epsilon}2/{zeta}1, {epsilon}3/{zeta}1, and {epsilon}4/{zeta}1 channels by meperidine was dependent on pH, with more inhibition at acidic pH and less inhibition at alkaline pH. The degree of voltage-dependence of meperidine block was only slightly affected by changes in pH, whereas affinity for meperidine was greatly reduced at alkaline pH. Furthermore, interaction of meperidine with Mg2+ block was reduced at alkaline pH. Because the percentage of the protonated form of meperidine is only slightly affected by pH, changes in properties of the meperidine binding site may be involved in mechanisms of alteration of meperidine potency by pH.

Implications: At acidic pH the potency of meperidine for N-methyl-D-aspartate-receptor channels was increased. Any antinociceptive and neuroprotective benefit from the N-methyl-D-aspartate-receptor antagonist property of meperidine may be pH dependent.


   Introduction
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 Introduction
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In large concentrations, opioid receptor agonists and antagonists protect neurons against central nervous system (CNS) ischemia and neurotoxicity of exogenously applied N-methyl-D-aspartate (NMDA) (1–3). More recent electrophysiological and receptor binding studies have found that some opioid receptor agonists, such as meperidine, methadone, ketobemidone, and dextropropoxyphene, reduce NMDA-induced depolarization in brain slice preparations and inhibit dizocilpine ([3H]MK-801) binding in brain membranes (4–7). Large concentrations of meperidine, morphine, fentanyl, codeine, and naloxone inhibit NMDA-receptor channels by channel block mechanisms at the site which partially overlaps with those of Mg2+ and ketamine (8). Because very large concentrations of meperidine are observed in the cerebrospinal fluid after epidural/intrathecal administration (9,10), we suggest that the NMDA-receptor antagonist property of meperidine is clinically significant in the spinal cord after local administration.

NMDA-receptor channels are inhibited by protons, with an inhibitor concentration for half-control response (IC50) value of pH 7.2–7.4, indicating that NMDA-receptor channels are tonically inhibited at physiological pH (11). Because it is well documented that pH in the CNS changes under both physiological and pathological conditions (12,13), regulation of NMDA-receptor channels by pH has received increased attention. Furthermore, pH affects not only the activity of NMDA-receptor channels, but also drug sensitivity of NMDA-receptor channels. The sensitivity of NMDA-receptor channels to ketamine is altered by extracellular pH changes, with ketamine block being greater at more acidic pH (14). On the other hand, block of NMDA-receptor channels by Mg2+ and dizocilpine is reported to be independent of pH (15,16). We examined the influence of extracellular pH on meperidine sensitivity of heteromeric NMDA-receptor channels expressed in Xenopus oocytes.


   Methods
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 Abstract
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 Methods
Results
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 References
 
This study was approved by the committee for the guidelines on animal experimentation of Niigata University. Subunit-specific mRNAs were synthesized in vitro with SP6 RNA polymerase in the presence of cap dinucleotides 7mGpppG. The {epsilon}1, {epsilon}2, {epsilon}3, {epsilon}4, and {zeta}1 subunit-specific mRNAs were synthesized by using pSPGR{epsilon}1, pSPGR{epsilon}2, pSPGR{epsilon}3, pSPGR{epsilon}4, and pSPGR{zeta}1, respectively (17). X. laevis oocytes were injected with {epsilon} and {zeta} subunit-specific mRNAs at a molar ratio of 1:1; the total amount of mRNAs injected per oocyte was approximately 0.6 ng for {epsilon}1/{zeta}1 and {epsilon}2/{zeta}1 channels, and approximately 14 ng for {epsilon}3/{zeta}1 and {epsilon}4/{zeta}1 channels.

After incubation at approximately 19°C for 2–3 days, whole-cell currents evoked by bath application of agonists for approximately 15 s were recorded at -70 mV membrane potential with a conventional 2-micropipette voltage clamp. The current responses of {epsilon}/{zeta} channels were evoked by 10 µM L-glutamate plus 10 µM glycine in Ba2+-Ringer’s solution to minimize the effects of secondarily activated Ca2+-dependent Cl- currents. For measurement of effects of meperidine on NMDA-receptor channels, agonists were successively applied three times during continuous perfusion of meperidine, and the effects on the third applications of agonists were evaluated. The second and third current responses during perfusion of meperidine were of similar magnitude, indicating that the effects of meperidine were fully established in the recording system. Ba2+-Ringer’s solution contained 115 mM NaCl, 2.5 mM KCl, 1.8 mM BaCl2, and 10 mM HEPES-NaOH. The solution was adjusted to the desired pH (pH 6.0–9.0).

The IC50 and Hill coefficient values for meperidine of the {epsilon}/{zeta} channel were calculated according to the equation Rmep = 1/[1 + (M/IC50)n], where Rmep represents the relative response, M, the concentration of meperidine, and n the Hill coefficient. For quantitative estimates of the voltage-dependence of block by meperidine, data were analyzed by using the Woodhull model (18) by fitting the data to the equation Rmep = 1/[1 + (M/Kd(0)exp{z{delta}FE/RT})], where Rmep represents the relative response, M, the concentration of meperidine; Kd(0), the equilibrium dissociation constant of meperidine at a membrane potential of 0 mV; z, the charge of meperidine; {delta}, the portion of the membrane electric field sensed at the blocking site; E, the membrane potential, F, the Faraday constant; R, the gas constant; and T, the absolute temperature. Data were represented as mean ± SEM. The results obtained were statistically analyzed by Student’s t-tests or one-way analysis of variance (ANOVA) followed by Scheffe’s multiple comparison tests. P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The effects of extracellular pH on sensitivities of {epsilon}/{zeta} NMDA-receptor channels to meperidine were examined by measuring current responses to agonists during continuous perfusion of meperidine at different extracellular pH. Current responses of the NMDA-receptor channel were larger at higher pH as described previously (19). Meperidine (300 µM) effectively inhibited the current responses of the {epsilon}1/{zeta}1 channel at pH 7.0 in a fully reversible manner (Fig. 1A). In contrast, meperidine only slightly inhibited the channel at pH 8.0. The dose-inhibition relationships for meperidine of the {epsilon}1/{zeta}1 channel were examined at various extracellular pH. The sensitivity to meperidine was dependent on pH, being less sensitive at more alkaline pH (Fig. 1B). The IC50 values of the {epsilon}1/{zeta}1 channel for meperidine at pH 7.0 were 254 ± 10 µM, whereas those at pH 8.5 were 1241 ± 168 µM. Similarly, inhibition of NMDA-receptor channel by morphine was dependent on extracellular pH (data not shown).



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  		Figure 1. The pH-dependent inhibition of N-methyl-D-aspartate-receptor channels by meperidine. A, Representative tracings of inhibition of the {epsilon}1/{zeta}1 channel by 300 µM meperidine at pH 7.0 and 8.0. Inward current is downward. The duration of bath application of 10 µM L-glutamate plus 10 µM glycine is indicated by bars without taking into account the dead space time in the perfusion system (approximately 2 s). Sensitivity to meperidine was examined by measuring current responses during continuous perfusion of meperidine (indicated by hatched column). B, The dose-inhibition relationships for meperidine of the {epsilon}1/{zeta}1 channel. IG/G is the control response to L-glutamate plus glycine and IG/G + mep is the response to L-glutamate plus glycine measured in the presence of meperidine. Each point represents the mean ± SEM of measurements on 6–8 oocytes; SEM are indicated by bars when larger than the symbols. The IC50 values at pH 7.0, 7.5, 8.0, and 8.5 were 254 ± 10, 442 ± 21, 904 ± 60, and 1241 ± 168 µM, respectively, and the Hill coefficient values of those were 0.99 ± 0.05, 1.02 ± 0.05, 1.22 ± 0.06, and 1.19 ± 0.07, respectively.

 
The proton sensitivity is shown to be different between {epsilon}/{zeta} channels. The {epsilon}1/{zeta}1, {epsilon}2/{zeta}1, and {epsilon}4/{zeta}1 channels exhibit IC50 values of pH 7.2–7.3, whereas the {epsilon}3/{zeta}1 channel has the IC50 value of pH 6.2 (20). To examine whether pH-dependence of meperidine inhibition is different between {epsilon}/{zeta} channels, the extent of meperidine inhibition at various pH values was measured for four kinds of {epsilon}/{zeta} channels. The current responses of the {epsilon}2/{zeta}1 channel at pH 8.0 were 2.8 ± 0.2 times as large as those at pH 7.0, whereas the currents of the {epsilon}3/{zeta}1 channel at pH 8.0 were only 1.2 ± 0.1 times as large as those at pH 7.0 (Fig. 2A), indicating that pH sensitivity is distinct between {epsilon}2/{zeta}1 and {epsilon}3/{zeta}1 channels. However, inhibition of both {epsilon}2/{zeta}1 and {epsilon}3/{zeta}1 channels by 300 µM meperidine was dependent on extracellular pH. Fig. 2B shows that inhibition of {epsilon}1/{zeta}1, {epsilon}2/{zeta}1, {epsilon}3/{zeta}1, and {epsilon}4/{zeta}1 channels by 300 µM meperidine at various pH values. The inhibition of four {epsilon}/{zeta} channels was similarly dependent on extracellular pH, with more inhibition at acidic pH and less inhibition at alkaline pH (ANOVA, P < 0.001).



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  		Figure 2. Effects of extracellular pH on meperidine inhibition of four {epsilon}/{zeta} channels. A, The normalized current responses of {epsilon}2/{zeta}1 and {epsilon}3/{zeta}1 channels at various pH in the absence (control) or presence of 300 µM meperidine. The measured current responses were normalized to the current responses at pH 7.0 in the absence of meperidine (n = 6–7). IG/G (pH 7.0) is the control response at pH 7.0 and IG/G is the response measured at various pH. Note that values of normalized responses are different between {epsilon}2/{zeta}1 and {epsilon}3/{zeta}1 channels, indicating that pH sensitivity is distinct between channels. B, Inhibition of {epsilon}1/{zeta}1, {epsilon}2/{zeta}1, {epsilon}3/{zeta}1, and {epsilon}4/{zeta}1 channels by 300 µM meperidine at various pH (n = 5–7). IG/G is the control response and IG/G + mep is the response measured in the presence of meperidine.

 
The meperidine inhibition of NMDA-receptor channels was shown to exhibit voltage-dependence and to be effective at negative membrane potential (8). To examine whether extracellular pH affects the degree of voltage dependence or affinity of binding, meperidine inhibition of the {epsilon}2/{zeta}1 channel at various membrane potential was measured at different extracellular pH values (Fig. 3). Analyses using the Woodhull model (18) showed that Kd(0) values (the affinity of binding) for meperidine at pH 7.0, 8.0, and 8.5 were significantly different (3 ± 1, 25 ± 9 and 149 ± 55 mM, respectively; ANOVA, P < 0.001), whereas the z{delta} values (the degree of voltage-dependence of block) for those varied only slightly (0.9 ± 0.1, 1.0 ± 0.1 and 1.2 ± 0.1, respectively; ANOVA, P < 0.05).



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  		Figure 3. Effects of extracellular pH on voltage dependence of the {epsilon}2/{zeta}1 channel block by 300 µM meperidine. IG/G is the control response and IG/G + mep is the response measured in the presence of meperidine. The Kd(0) values for meperidine at pH 7.0, 8.0, and 8.5 were 3 ± 1, 25 ± 9, and 149 ± 55 mM, respectively, and the z{delta} values for those were 0.9 ± 0.1, 1.0 ± 0.1 and 1.2 ± 0.1, respectively (n = 5–6).

 
We have previously shown that meperidine reduces the sensitivity of NMDA-receptor channel to Mg2+ block, suggesting that the binding site of meperidine partially overlaps with the Mg2+ block site (8). To test whether the interaction between meperidine and Mg2+ is affected by changes in extracellular pH, the extent of Mg2+ block of the {epsilon}2/{zeta}1 channel in the absence and presence of meperidine was compared with various extracellular pH (Fig. 4). At pH 7.0 the extent of block by 30 µM Mg2+ (61% ± 1%) was significantly reduced to 48% ± 2% during perfusion of 300 µM meperidine (Student’s t-test, P < 0.001). At pH 8.0 there still was a significant, however reduced, difference in the Mg2+ block extent in the absence and presence of meperidine (Student’s t-test, P < 0.02). On the other hand, at pH 9.0 the Mg2+ block extent during meperidine perfusion was not significantly different from that in the absence of meperidine (59% ± 1% and 60% ± 1%, respectively; Student’s t-test, P > 0.26).



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  		Figure 4. Inhibition of the {epsilon}2/{zeta}1 channel by 30 µM Mg2+ in the absence (control) and presence of 300 µM meperidine at various extracellular pH values (n = 7–8). IG/G is the control response and IG/G + Mg is the response measured in the presence of Mg2+. *P < 0.02 between control and meperidine at pH 8.0. **P < 0.001 between control and meperidine at pH 7.0.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We demonstrated that inhibition of the NMDA-receptor channel by meperidine is dependent on extracellular pH, with more inhibition at acidic pH and less inhibition at alkaline pH. Furthermore, the affinity for meperidine and its interaction with Mg2+ block are reduced by an alkaline pH. These results suggest that mechanisms of pH dependence of meperidine block of NMDA-receptor channels involve the change in binding of meperidine to the channel pore site. The potency of ketamine for NMDA-receptor channels is also altered by extracellular pH changes, with ketamine block being more intense at a more acidic pH (14). However, because the pKa value of ketamine is 7.5, the percentage of the charged form changes from 9% to 91% as the pH is reduced from 8.5 to 6.5, making the interpretation of potency changes of ketamine at different pH values potentially complicated. In contrast, meperidine has a pKa value of 9.6 (21), indicating that the percentage of the fully protonated form changes only from 93% to 99% over the pH range from 8.5 to 6.5. Thus, alteration of meperidine potency by pH is likely to result from the change in properties of the meperidine binding site of NMDA-receptor channels rather than the protonation state of meperidine. In this study, we have shown that pH-dependence of meperidine inhibition is similar between four {epsilon}/{zeta} channels, although pH sensitivity itself is distinct between {epsilon}/{zeta} channels. These results may support the hypothesis that changes in properties of the meperidine binding site by pH is caused by local changes in the charge of amino acid residues composing the meperidine binding site rather than the entire conformational transition of NMDA-receptor channels caused by pH changes.

Meperidine inhibited NMDA-receptor channels in a voltage-dependent manner, which is a specific and essential property of Mg2+ block (22). Furthermore, the Mg2+ block was reduced by meperidine at pH 7.0–8.0 (Fig. 4). These results suggest that the binding site of meperidine overlaps with the Mg2+ block site. However, the block by meperidine was dependent on extracellular pH, whereas Mg2+ block did not show any pH-dependence (Fig. 4). Thus, the binding sites of meperidine and Mg2+ may not be exactly the same. We have previously shown (8) that the conserved asparagine residue in the channel-lining segment M2 of the {zeta}1 subunit, not that of the {epsilon} subunit, constitutes the meperidine binding site. On the other hand, the asparagine residues in segment M2 of the {epsilon} (NR2) subunit are reported to dominantly form a site for Mg2+ block (23). Thus, differences in pH-dependence between meperidine and Mg2+ may be related to differences in the contribution of {zeta} and {epsilon} subunits to their binding sites.

Although plasma concentrations obtained after systemic administration of meperidine are, at most, 1–3 µM (24), meperidine concentrations in the cerebrospinal fluid after epidural and intrathecal injection, reach 100–300 and 300-1000 µM, respectively (9,10). Thus, the NMDA-receptor antagonist property of meperidine may be clinically significant in the spinal cord after epidural or intrathecal administration. We found that the potency of meperidine for inhibition of NMDA-receptor channels is higher at more acidic pH. Because NMDA-receptor channels are involved in mechanisms of ischemic neuronal injury and pH reduction in the CNS during ischemia is extensively documented (13,25), the increased potency of meperidine for NMDA-receptor channels at acidic pH is considered to be a favorable property of neuroprotective drugs. Furthermore, meperidine has been clinically used as an analgesic for many years, and its safety is accepted (9). Thus, epidural meperidine may have the advantage of producing both analgesic and spinal cord protective effects without serious side effects.


   Acknowledgments
 
Supported by a grant from the Japanese Ministry of Education, Science and Culture, Tokyo, Japan.


   References
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 Abstract
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 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 14, 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 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press