Group II metabotropic glutamate receptors (mGluRs) couple to the inhibitory G-protein Gi. The group II mGluRs\r\ninclude two subtypes, mGlu2 and mGlu3, and their pharmacological activation produces analgesic effects in\r\ninflammatory and neuropathic pain states. However, the specific contribution of each one of the two subtypes has\r\nnot been clarified due to the lack of selective orthosteric ligands that can discriminate between mGlu2 and mGlu3\r\nsubtypes.\r\nIn this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the\r\nendogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3\r\nreceptor agonists.\r\nOur results showed that mGlu2-/- mice display a significantly greater pain response compared to their wild type\r\nlittermates. Interestingly the increased pain sensitivity in mGlu2-/- mice occurred only in the second phase of the\r\nformalin test. No differences were observed in the first phase. In contrast, mGlu3-/- mice did not significantly differ\r\nfrom their wild type littermates in either phase of the formalin test.\r\nWhen systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a\r\nsignificant reduction of both phases in wild-type mice and in mGlu3-/- but not in mGlu2-/- mice. However tolerance\r\nto the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-/- mice developed following 5 consecutive days of\r\ninjection.\r\nTaken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors\r\nin the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely\r\nmediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of\r\nmGlu2/3 agonists develops despite the lack of mGlu3 receptors.
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