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Neuropharmacology. 2009 Mar;56(4):768-78. doi: 10.1016/j.neuropharm.2008.12.010.

Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the micro-opioid receptor.

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Dept of Pharmacology and Toxicology, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.


Recent evidence suggests that opioid analgesia and tolerance can be modulated by metabotropic glutamate receptors. Therefore, we studied the functional coupling and desensitization of the micro-opioid receptor (MOR) in human embryonic kidney (HEK) 293 cells which co-express metabotropic glutamate receptor 5 (mGluR5). As demonstrated by the D-Ala2,N-MePhe4,Gl-ol5-enkephalin (DAMGO)-induced inhibition of intracellular cAMP level and by binding studies, the co-expression of mGluR5 had no substantial effect on the agonist binding sites and functional coupling of the MOR. However, in MOR/ mGluR5 co-expressing cells, the non-competitive mGluR5 antagonist MPEP (2-methyl-6-(phenyl-ethynyl)-pyridine) decreases the DAMGO-induced MOR phosphorylation, internalization, and desensitization, whereas non-selective competitive mGluR antagonists or agonists had no effects. These findings indicate that an allosteric modulation of mGluR5 can affect the agonist-induced MOR signalling and regulation. As a mechanistic basis for the observed effects we suggested an interaction/heterodimerization of MOR and mGluR5, which is supported by the DAMGO-induced co-internalization of MOR and mGluR5 and by the increase of MPEP binding sites (Bmax) and a change of the binding affinity (K(D)) of mGluR5 receptors after the co-expression of MOR. In addition, co-immunoprecipitation experiments revealed evidence for an interaction between MOR and mGluR5 which is facilitated by MPEP treatment.

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