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Local anaesthetics have different mechanisms and sites of action at the recombinant N‐methyl‐D‐aspartate (NMDA) receptors
Author(s) -
Sugimoto Masahiro,
Uchida Ichiro,
Mashimo Takashi
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705107
Subject(s) - procaine , nmda receptor , tetracaine , pharmacology , chemistry , receptor , homomeric , anesthesia , lidocaine , biochemistry , protein subunit , biology , medicine , gene
Although the principal pharmacological targets of local anaesthetics (LAs) are voltage‐gated Na + channels, other targets have also been suggested. Here we examined the effects of LAs on the N‐methyl‐D‐aspartate (NMDA) receptor, a receptor involved in the process of nociception. LAs (bupivacaine, lidocaine, procaine, and tetracaine) reversibly and concentration‐dependently inhibited recombinant ε1/ζ1 and ε2/ζ1 NMDA receptors expressed in Xenopus oocytes (IC 50 s for bupivacaine, lidocaine, procaine, and tetracaine were 1032.0, 1174.1, 642.1 and 653.8 μ M at the ε1/ζ1 receptor; and 1090.8, 1821.3, 683.0 and 662.5 μ M respectively (at the ε2/ζ1 receptor). Bupivacaine and procaine were non‐competitive antagonists; bupivacaine possesses non‐competitive and competitive actions when interacting with glycine, whereas procaine has only non‐competitive action. Mutation of asparagine residue at position 598 (Asp 598 ) in the ζ1 subunit, a residue associated with the blockade site for Mg 2+ and ketamine, to glutamine or arginine reduced the sensitivity to procaine but not to bupivacaine. Thus, procaine may interact with sites of action that are closely related to those of Mg 2+ and ketamine blockade. These results suggest that LAs inhibit the NMDA receptor by various mechanisms.British Journal of Pharmacology (2003) 138 , 876–882. doi: 10.1038/sj.bjp.0705107