Abstract
N–acetyl–aspartyl–glutamate (NAAG) is the most prevalent and widely distributed peptide transmitter in the mammalian nervous system.NAAG acts as an agonist at metabotropic glutamate receptor 3 (mGluR3). Metabotropic GluRs have been identified as significant analgesic targets. NAAG is degraded to N–acetyl–aspartate (NAA) and glutamate by extra cellular peptidase which is named NAAG peptidase (also known as glutamate carboxypeptidase II (GCPII)). Glutamate, a metabolite of NAAG, may act as a neurotransmitter and activate glutamate receptors such as NMDA receptor and other type of mGluRs. Thus, it is impossible to examine the role of NAAG itself, if NAAG was administered. As a result, we examined the role of NAAG in the nocicep tive transmission by using NAAG peptidase inhibitors. In the present article, I showed the analgesic profile of NAAG peptidase inhibitors in the rat formalin model.
NAAG peptidase inhibitor produced an analgesic effect when administered intravenously, locally, intrathecally, and intracerebroventricularly without any adverse effects. These analgesic effects were completely antagonized by intraperitoneal injection of LY341495, an mGluR3 antagonist. These data suggested that NAAG itself acts as analgesics by activating mGluR3. Next, I explored the site of action of NAAG peptidase inhibitor in the brain. Microinjection of NAAG peptidase inhibitor into the periaqueductal grey (PAG) contralateral, but not ipsilateral, to the side of formalin injection produced an analgesic effect and this effect was completely antagonized by LY341495. Microinjection of NAAG peptidase inhibitor into the rostral ventro medial medulla (RVM) produced analgesic action and this effect was completely antagonized by LY341495. These data suggested that PAG and RVM are the sites of action of NAAG peptidase inhibitor to produce an analgesic effect in the rat formalin model. In conclusion, these data strongly suggested that NAAG peptidase inhibitors are a target of new class analgesics.
