Metabotropic glutamate receptor 5 signalling induced NMDA receptor subunits alterations during the development of morphine-induced antinociceptive tolerance in mouse cortex - 06/01/19
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Graphical abstract |
Highlights |
• | Morphine tolerance leads to increased mGluR5 levels and phosphorylation of NR2B. |
• | Loss of mGluR5 prevents the development of tolerance and thermal hyperalgesia. |
• | Disruption of NMDA receptor and mGluR5 connection by mutation of shank3 doesn’t prevent the development of morphine-induced tolerance. |
Abstract |
Background and purpose |
The aim of this study was to investigate the interactions between mGluR5 and NMDAR during the development of tolerance to the analgesic effect of chronic morphine following disruption of the link between mGluR5 and NMDAR.
Methods |
For these experiments, mGluR5 knockout (KO) mice, Shank3 ΔC mutant mice and their littermate controls were used. Repeated morphine treatment through intrathecal injections (i.t. 10 μg/10 μl twice daily for 5 days) was used to induce antinociceptive tolerance and thermal hyperalgesia, which was determined by tail-flick latency and calculated as a percentage of the maximum possible effect (%MPE). Expression of NMDAR subunits (NR1, NR2A and NR2B) and phosphorylation of NR2B in cortex were evaluated by Western blot.
Results |
Chronic morphine treatment increased the total expression of mGluR5 and NR2A but not NR1 and NR2B in the cortex and enhanced the phosphorylation of NR2B in wild-type mice after tolerance developed. mGluR5 KOs had attenuated morphine-induced tolerance and thermal hyperalgesia and reduced chronic morphine-induced phosphorylation of NR2B but not total NR2A expression. Shank3 ΔC mice were used to imitate the loss of the physiological connection between mGluR5 and NMDAR, and the mice showed a similar analgesic effect to morphine as their littermate controls, and there were no differential effects on NMDAR subunits compared with controls during the development of morphine-induced tolerance.
Conclusions |
It may be mGluR5-mediated PKC signalling that plays the most significant role in the mechanisms underlying morphine-induced antinociceptive tolerance rather than the physiological connection between mGluR5 and NMDAR.
Le texte complet de cet article est disponible en PDF.Abbreviations : NMDAR, PKC, %MPE, mGluR5, CNS, PSD, PLC, DAG, IP3, PSD-95, GKAP, TBS, TBST
Keywords : Morphine, Tolerance, mGluR5, NMDA receptor, Shank3, Hyperalgesia
Plan
Vol 110
P. 717-726 - février 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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