Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain

Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10 mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20 mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3 mg/kg; i.p.) potentiated the effects of a single morphine injection (20 mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3 mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20 mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.