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mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists

DOI: 10.1186/1744-8069-7-6

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In this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the endogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3 receptor agonists.Our results showed that mGlu2-/- mice display a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2-/- mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3-/- mice did not significantly differ from their wild type littermates in either phase of the formalin test.When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3-/- but not in mGlu2-/- mice. However tolerance to the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-/- mice developed following 5 consecutive days of injection.Taken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely mediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of mGlu2/3 agonists develops despite the lack of mGlu3 receptors.Metabotropic glutamate (mGlu) receptors are considered promising targets in the treatment of chronic pain. All mGlu receptor subtypes (mGlu1-8), except mGlu6, are widely distributed along the pain neuraxis, and modulate cellular mechanisms of nociceptive sensitization that underlie the development of chronic pain [1-3]. We and others have focused on the role of group-II mGlu receptors (mGlu2 and mGlu3), which are coupled to Gi proteins and depress pain transmission at synapses between primary afferent fibers and second order sensory neurons in the dorsal horn of the spinal cord [4,5]. mG

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