Other Glutamate Mechanisms

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Metabotrophic Glutamate Receptor (mGluR) Modulators - Metabotropic glutamate receptors consist of eight different subunits of G protein coupled receptors that are classified into three groups [group I receptors (mGluR 1,5), group II (mGluR 2,3) and group III (mGluR 4,6,7,8)] based on sequence homology, coupling to intracellular messengers and pharmacologic profile (24,25). Recently, the mGluR5 selective compound 6 (MPEP) was identified and shown to reverse mechanical hypersensitivity in the Freund's complete adjuvant (FCA) inflammatory pain model without modifying the magnitude of edema at p.o. doses between 10 and 30 mg/kg (26). However, a higher dose _

of 100 mg/kg p.o. failed to reduce mechanical ff\ _

hypersensitivity in a neuropathic pain model (26). While \ / == these data suggest the potential for Group 1 antagonists 6

in inflammatory pain, their weak effects for reversing established allodynia in neuropathic pain models suggest that they might have limited potential as clinical pharmacotherapies (27,28). Recently described mGluRI and mGluR2 ligands might provide additional insight into their clinical utility (25).

NAALADase Inhibitors - Glutamate carboxypeptidase II (GCP II; also termed N-acetylated-a-linked-acidic dipeptidase or NAALADase) is a membrane bound enzyme that hydrolyses N-acetyl-L-aspartyl-L-glutamate (NAAG) to form N-acetyl-aspartate and glutamate (29). In this regard, GCP II terminates the agonist activity of NAAG at mGluR3 and liberates glutamate. Importantly, the release of NAAG and hydrolysis to glutamate appears to increase under conditions of neuronal excitability observed in some neurological diseases. Selective GCP II inhibitors, such as 2-PMPA (7), have been shown to have antiallodynic and antihyperalgesic effects in a number of pain models following i.t. or i.v. administration (30). Another GCPII

inhibitor, GPI-5232 (8} partially blocked the development of thermal hypersensitivity following daily dosing i.p. in a genetic model of insulin-dependent Type I diabetes (31). Other compounds such as thiol 9 were recently synthesized and inhibit GCP II activity (32,33).

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