Local anaesthetics have different mechanisms and sites of action at the recombinant N‐methyl‐D‐aspartate (NMDA) receptors

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Abstract
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 (IC50s for bupivacaine, lidocaine, procaine, and tetracaine were 1032.0, 1174.1, 642.1 and 653.8 μM at the ε1/ζ1 receptor; and 1090.8, 1821.3, 683.0 and 662.5 μM 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 (Asp598) in the ζ1 subunit, a residue associated with the blockade site for Mg2+ 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 Mg2+ 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