Inhibition of spinal N-acetylated-alpha-linked acidic dipeptidase produces an antinociceptive effect in the rat formalin test.

N-acetyl-aspartyl-glutamate is a putative neurotransmitter and acts as a weak agonist at the N-methyl-D-aspartate receptor. N-acetyl-aspartyl-glutamate also acts as an agonist at the metabotropic glutamate receptor 3. N-acetyl-aspartyl-glutamate is hydrolyzed by N-acetylated-alpha-linked acidic dipeptidase to liberate N-acetyl-aspartate and glutamate. Recently, a specific inhibitor of N-acetylated-alpha-linked acidic dipeptidase, 2-(phosphonomethyl)pentanedioic acid, has been reported. In the present study, we examined the effect of i.t. administered 2-(phosphonomethyl)pentanedioic acid in the rat formalin test (a model of inflammatory pain) and the rat hot plate test. In the formalin test, drugs were administered 10min before (pre-treatment study) or 7min after (post-treatment study) the formalin injection. The paw formalin injection induces biphasic flinching (phase 1: 0-2min; phase 2: 10-60min) of the injected paw. In the pre-treatment study, i.t. administered 2-(phosphonomethyl)pentanedioic acid depressed both phases 1 and 2 flinching behavior in a dose-dependent manner but 2-(phosphonomethyl)pentanedioic acid had no effect on the flinching behavior in the post-treatment study. In the pre-treatment study, the potency of 2-(phosphonomethyl)pentanedioic acid in depressing the phase 2 response is greater than that in depressing the phase 1 response. Intrathecal injection of 2-(phosphonomethyl)pentanedioic acid had no effect in the hot plate test. We suggest that N-acetylated-alpha-linked acidic dipeptidase plays an important role in spinal nociceptive transmission and that inhibition of spinal N-acetylated-alpha-linked acidic dipeptidase produces an antinociceptive effect during the rat formalin test but not during the hot plate test.