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.

Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms

“…A decrease in KAT II activity has indeed been associated with increased cerebral glutamate levels and thus NMDA activation (37). In addition, the increased NMDA activation could interfere with opioid receptor function (38). Anatomical studies, ultrastructural analyses, and electrophysiological data have indeed suggested interactions between opioid receptors and NMDA receptors.…”

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

“…On the other hand, activation of N-methyl-D-aspartate (NMDA) receptors within the PAG might antagonize the effects of endogenous opioid peptides and produce hyperalgesia. 25 Interestingly, under normal conditions, there is a high degree of colocalization of NMDA receptors and MORs within the PAG. 26 Molecular interaction of both of these receptors when activated within neuronal compartments has been mapped, showing that NMDA receptor activation along with MORs contribute to morphine tolerance.…”

Hepatic encephalopathy induces site-specific changes in gene expression of GluN1 subunit of NMDA receptor in rat brain

“…In addition, NMDA receptor pathway has been shown to be involved in modulation of cholestasisinduced antinociception in rats (Hasanein et al 2007). According to previous researches, NMDA receptors play a key role not only in pain signal transmission in the spinal cord but also in pain perception at higher brain centers (Piovesan et al 2008;Rodriguez-Munoz et al 2012;Zhou et al 2011). Therefore, we propose possible changes in NMDA receptor system may account for, at least partly, alteration in nociception threshold in the BDL model of HE.…”