Effect of metabotropic glutamate 5 receptor antagonists on morphine efficacy and tolerance in rats with neuropathic pain.

The metabotropic glutamate 5 (mGlu5) receptor is involved in both pain processing and modulation of µ-opioid induced antinociception and antihyperalgesia. Systemic mGlu5 receptor antagonists 2-methyl-6-phenylethynylpyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine (MTEP) provide antihyperalgesic effects in various pain models, but few studies have shown their interaction with morphine in neuropathic pain models. The aim of this study is to compare the effects of systemic and intrathecal MPEP/MTEP on morphine efficacy and tolerance in rats with chronic neuropathic pain. L5-6 spinal nerve ligation (SNL) was used to establish neuropathic pain model in rats. The Von Frey test and the hot water tail flick test were employed as behavior tests. Low, medium and high doses of MPEP/MTEP were tested for their effect on both acute morphine efficacy and chronic morphine tolerance. SNL provides sustained neuropathic pain on the ipsilateral hind paw of rats. Both systemic and intrathecal MPEP/MTEP had antiallodynia effects and boosted morphine's efficacy in a dose-dependent manner in the Von Frey tests but not in the tail flick tests. In fact, high doses of MTEP and MPEP attenuated morphine's antinociceptive effect in the latter test. After intrathecal chronic co-administration with morphine, low-doses of MTEP/MPEP attenuated morphine tolerance in both tests. Systemically, only MTEP attenuated morphine tolerance, and only in the Von Frey tests, not in the tail flick tests, whereas MPEP had no effect on morphine tolerance in either tests. The therapeutic use of mGlu5 receptor antagonists may have distinct effects in different pain models.