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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, and Koki Shimoji, MD^*

*Department of Anesthesiology, Niigata University School of Medicine; and 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

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 / heteromeric NMDA-receptor channels expressed in Xenopus oocytes. Inhibition of 1/1, 2/1, 3/1, and 4/1 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.

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