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

(1) 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. (2) LAs (bupivacaine, lidocaine, procaine, and tetracaine) reversibly and concentration-dependently inhibited recombinant epsilon1/zeta1 and epsilon2/zeta1 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 micro M at the epsilon1/zeta1 receptor; and 1090.8, 1821.3, 683.0 and 662.5 micro M respectively (at the epsilon2/zeta1 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. (3) Mutation of asparagine residue at position 598 (Asp(598)) in the zeta1 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. (4) These results suggest that LAs inhibit the NMDA receptor by various mechanisms.