ABSTRACT
N-methyl-D-aspartate receptor (NMDAR) and Group I metabotropic glutamate receptors (mGluRs) are involved in the process of morphine tolerance. Previous studies have shown that Group I mGluRs can modulate NMDAR functions in the central nervous system. The aim of the present study was to examine the influence of Group I mGluRs antagonists on the expression of NMDA receptor NR1 subunit (NR1) in the rat spinal cord. Morphine tolerance was induced in rats by repeated administration of 10 microg morphine (intrathecal, i.t.) twice a day for 7 consecutive days. Tail flick test was used to assess the effect of Group I mGluRs antagonist, AIDA ((RS)-1-Aminoindan-1,5 dicarboxylic acid) or mGluR5 antagonist, MPEP (2-methyl-6-(phenylethynyl)pyridine) on morphine antinociceptive tolerance. The expression of NR1 was measured by immunofluorescence and Western blot. Behavioral tests revealed that both AIDA and MPEP attenuated the development of morphine tolerance. The expression of NR1 was upregulated in the dorsal horn of spinal cord after chronic morphine treatment. AIDA or MPEP co-administered with morphine attenuated morphine induced upregulation of NR1. These findings suggest that the development of morphine tolerance partly prevented by Group I mGluRs antagonists may due to its inhibitory effect on the expression of NR1 subunit.
Subject(s)
Analgesics, Opioid/administration & dosage , Drug Tolerance/physiology , Morphine/administration & dosage , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Spinal Cord/drug effects , Animals , Excitatory Amino Acid Antagonists/administration & dosage , Indans/administration & dosage , Male , Pain Threshold/drug effects , Posterior Horn Cells/drug effects , Posterior Horn Cells/physiology , Pyridines/administration & dosage , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Spinal Cord/physiology , Up-Regulation/drug effectsABSTRACT
OBJECTIVE: To investigate the expression of metabotropic glutamate receptor 5 (mGluRS) in spinal cord of morphine tolerant rats and understand the influence of mGluR5 antagonist MPEP upon the expression of mGluRS. METHODS: Male Sprague-Dawley rats were randomly divided into four groups with 8 rats each:control group (NS), morphine group, morphine plus MPEP group and MPEP group. A morphine tolerance model of rat was established by repeated administration of 10 microg morphine intrathecally twice daily for 7 days. The effects of morphine co-administrated with MPEP upon the thermal pain threshold were examined by tail flick test. Tail flick latency (TFL) was measured at 30 min pre- and postdosing. MPE% (percentage of maximal possible effect) was calculated by the equation: MPE (%) = [(test response time-basal response time)/(cut-off time-basal response time)] x 100%. The rats were sacrificed and L4-5 spinal cord tissue was removed. The expression of mGluR5 in every group was examined by immunofluorescence and Western blot. RESULTS: MPE% of morphine group decreased gradually after chronic administration of morphine intrathecally. There was no significant difference between morphine group and control group at Day 7 (P > 0.05). Morphine plus MPEP group had significant analgesic effect as compared with morphine group at Day 7 (P < 0.05). The expression of mGluR5 was up-regulated in the dorsal horn of spinal cord in morphine tolerant rats. The protein level of mGluRS in morphine plus MPEP group was lower than that in morphine group (P < 0.05), but higher than control group (P < 0.05). CONCLUSION: The mGluR5 antagonist MPEP can prevent the development of morphine tolerance. The expression of mGluR5 protein increases in the spinal cord of morphine tolerant rats. MPEP plays its role in morphine tolerance by partly inhibiting the expression of mGluRS.
