Intracerebroventricular administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in inflammatory pain

Abstract

Background: The peptide neurotransmitter N-Acetylaspartylglutamate (NAAG) is the third most prevalent transmitter in the mammalian central nervous system. Local, intrathecal and systemic administration of inhibitors of enzymes that inactivate NAAG decrease responses to inflammatory pain in rat models. Consistent with NAAG's activation of group II metabotropic glutamate receptors, this analgesia is blocked by a group II antagonist.

Results: This research aimed at determining if analgesia obtained following systemic administration of NAAG peptidase inhibitors is due to NAAG activation of group II mGluRs in brain circuits that mediate perception of inflammatory pain. NAAG and NAAG peptidase inhibitors, ZJ43 and 2-PMPA, were microinjected into a lateral ventricle prior to injection of formalin in the rat footpad. Each treatment reduced the early and late phases of the formalin-induced inflammatory pain response in a dose-dependent manner. The group II mGluR antagonist reversed these analgesic effects consistent with the conclusion that analgesia was mediated by increasing NAAG levels and the peptide's activation of group II receptors.

Conclusion: These data contribute to proof of the concept that NAAG peptidase inhibition is a novel therapeutic approach to inflammatory pain and that these inhibitors achieve analgesia by elevating synaptic levels of NAAG within pain processing circuits in brain.

Figure 1

Effects of intracerebroventricular (ICV) injection of 10 μg of ZJ43 (a), 2-PMPA (b) or NAAG (c) on the time course of the flinches observed after the formalin injection into the dorsal surface of the right rat hind-paw. Drugs were administered 10 min before the formalin injection. The group II mGluR antagonist LY341495 (1mg/kg, i.p.) was injected 10 min before ZJ43, 2-PMPA, NAAG or saline (d). The number of flinches/min is plotted vs time after the formalin injection. NAAG and the NAAG peptidase inhibitors ZJ43 and 2-PMPA significantly reduced both phases of the response to formalin injection (see text for statistical assessment). The effects of the peptidase inhibitors were blocked by the LY341495 as was the effect of NAAG on phase 2 of the response to formalin. Each line represents the group mean and S.E.M. of four to six rats.

Figure 2

Dose-response curves for ICV injection of ZJ43, 2-PMPA and NAAG representing the cumulative instances of formalin evoked flinches during the phase 1 (a) and the phase 2 (b). ZJ43, 2-PMPA and NAAG reduced the number of phase 1 and the phase 2 flinching behaviors in a dose dependent manner. Each point represents the group mean and S.E.M. of responses by groups of 5–6 rats. * <0.05 and ** <0.005 versus rats given saline ICV prior to formalin-induced inflammation.