Local administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats

The peptide neurotransmitter N‐acetylaspartylglutamate (NAAG) selectively activates group II metabotropic glutamate receptors (mGluRs). Systemic administration of inhibitors of the enzymes that inactivate NAAG results in decreased pain responses in rat models of inflammatory and neuropathic pain. These effects are blocked by a group II mGluR antagonist. This research tested the hypothesis that some analgesic effects of NAAG peptidase inhibition are mediated by NAAG acting on sensory neurite mGluRs at the site of inflammation. Group II mGluR agonists, SLx‐3095‐1, NAAG and APDC, or NAAG peptidase inhibitors, ZJ‐43 and 2‐PMPA, injected into the rat footpad reduced pain responses in carrageenan or formalin models. The analgesic effects of SLx‐3095‐1, APDC, ZJ‐43, 2‐PMPA and NAAG were blocked by co‐injection of LY341495, a selective group II mGluR antagonist. Injection of group II mGluR agonists, NAAG or the peptidase inhibitors into the contralateral rat footpad had no effect on pain perception in the injected paw. At 10–100 µm ZJ‐43 and 2‐PMPA demonstrated no consistent agonist activity at mGluR2 or mGluR3. Consistent with the conclusion that peripherally administered NAAG peptidase inhibitors increase the activation of mGluR3 by NAAG that is released from peripheral sensory neurites, we found that the tissue average concentration of NAAG in the unstimulated rat hind paw was about 6 µm. These data extend our understanding of the role of this peptide in sensory neurons and reveal the potential for treatment of inflammatory pain via local application of NAAG peptidase inhibitors at doses that may have little or no central nervous system effects.