title: The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control.
abstract: 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 coexistence of both receptors within single neurons of the CNS, including those in the mesencephalic periaqueductal gray (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 the 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-CaMKII, pathway that is implicated in morphine tolerance. Inhibition of PKC, but not PKA or 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 Ser 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 in developing bifunctional drugs that would act exclusively on those NMDARs associated with MORs.
authors.affiliation: CIBER of Mental Health (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: Ana
authors.initials: A
authors.lastname: Vicente-Sánchez
authors.forename: Esther
authors.initials: E
authors.lastname: Berrocoso
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000503:physiopathology* / Q000517:prevention & control; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011940:Receptor Aggregation / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D016202:N-Methylaspartate; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2