The Mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control
Résumé
The capacity of opioids to alleviate inflammatory pain is negatively regulated by the glutamate-binding N-methyl-D-aspartate receptor (NMDAR). Increased activity of this receptor complicates the clinical use of opioids to treat persistent neuropathic pain. Immunohistochemical and ultrastructural studies have demonstrated the co-existence of both receptors within single neurons of the central nervous system, including those in the mesencephalic periaqueductal grey (PAG), a region that is implicated in the opioid control of nociception. We now report that mu-opioid receptors (MOR) and NMDAR NR1 subunits associate in postsynaptic structures of PAG neurons. Morphine disrupts this complex by protein kinase C (PKC)-mediated phosphorylation of the NR1 C1 segment and potentiates the NMDAR-calcium and calmodulin dependent kinase II (CaMKII), pathway that is implicated in morphine tolerance. Inhibition of PKC, but not protein kinase A (PKA) or G-protein receptor kinase 2 (GRK2), restored the MOR-NR1 association and rescued the analgesic effect of morphine as well. The administration of N-methyl-D-aspartic acid separated the MOR-NR1 complex, increased MOR serine phosphorylation, reduced the association of the MOR with G proteins, and diminished the antinociceptive capacity of morphine. Inhibition of PKA, but not PKC, CaMKII or GRK2, blocked these effects and preserved morphine antinociception. Thus, the opposing activities of the MOR and NMDAR in pain control affect their relation within neurons of structures such as the PAG. This finding could be exploited developing bifunctional drugs that would act exclusively on those NMDARs associated with MORs.
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