The influence of AMN082, metabotropic glutamate receptor 7 (mGlu7) allosteric agonist on the acute and chronic antinociceptive effects of morphine in the tail-immersion test in mice: Comparison with mGlu5 and mGlu2/3 ligands

摘要

Abstract Preclinical data indicated that the metabotropic glutamate receptors 5 (mGlu5) and glutamate receptors 2/3 (mGlu2/3) are involved in modulating morphine antinociception. However, little is known about the role of metabotropic glutamate receptors 7 (mGlu7) in this phenomenon. We compared the effects of AMN082 (0.1, 1 or 5mg/kg, ip), a selective mGlu7 allosteric agonist, LY354740 (0.1, 1 or 5mg/kg, ip), an mGlu2/3 agonist and MTEP (0.1, 1 or 5mg/kg, ip), a selective mGlu5 antagonist, on the acute antinociceptive effect of morphine (5mg/kg, sc) and also on the development and expression of tolerance to morphine analgesia in the tail-immersion test in mice. To determine the role of mGlu7 in morphine tolerance, and the association of the mGlu7 effect with the N -methyl- d -aspartate (NMDA) receptors regulation, we used MMPIP (10mg/kg, ip), a selective mGlu7 antagonist and MK-801, a NMDA antagonist. Herein, the acute administration of AMN082, MTEP or LY354740 alone failed to evoked antinociception, and did not affect morphine (5mg/kg, sc) antinociception. However, these ligands inhibited the development of morphine tolerance, and we indicated that MMPIP reversed the inhibitory effect of AMN082. When given together, the non-effective doses of AMN082 and MK-801 did not alter the tolerance to morphine. Thus, mGlu7, similarly to mGlu2/3 and mGlu5, are involved in the development of tolerance to the antinociceptive effects of morphine, but not in the acute morphine antinociception. Furthermore, while mGlu7 are engaged in the development of morphine tolerance, no interaction exists between mGlu7 and NMDA receptors in this phenomenon. Highlights ? We studied the effects of AMN082, a mGlu7 agonist, on morphine nociception in mice. ? AMN082 inhibits morphine tolerance without effects on acute morphine antinociception. ? The effect of AMN082 was comparable to mGlu5 antagonist and mGlu2/3 agonist. ? The effect of AMN082 on morphine tolerance was mGlu7-dependent. ? No interactions exist between AMN082 and MK801 in morphine tolerance.