Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter

  title={Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter},
  author={Javier Garz{\'o}n and Mar{\'i}a F Rodr{\'i}guez-Mu{\~n}oz and Pilar S{\'a}nchez-Bl{\'a}zquez},

The Mu-Opioid Receptor and the NMDA Receptor Associate in PAG Neurons: Implications in Pain Control

It is reported that mu-opioid receptors (MOR) and NMDAR NR1 subunits associate in the postsynaptic structures of PAG neurons, a finding that could be exploited in developing bifunctional drugs that would act exclusively on those N MDARs associated with MORs.

RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States

It is demonstrated that RGS9-2 positively regulates the rewarding effects of oxycodone in pain-free states, and in a model of neuropathic pain, which provides new information on the signal-transduction mechanisms that modulate the rewarding and analgesic actions of oxy codone.

Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS

The role played by RGS proteins in the intensity and duration of the effects of mu-opioid receptor agonists, and how they influence the delayed tolerance that develops in response to specific doses of opioids are reviewed.

Morphine induces endocytosis of neuronal μ-opioid receptors through the sustained transfer of Gα subunits to RGSZ2 proteins

In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs, and recycled MORs recover the control on these Gα subunits and opioid tolerance develops slowly.

Direct association of Mu-opioid and NMDA glutamate receptors supports their cross-regulation: molecular implications for opioid tolerance.

This work proposes a model that incorporates the most relevant signaling components implicated in opioid tolerance in which, certain signals originating from the activated MOR are perceived by the associated NMDAR, which in turn exerts a negative feedback effect on MOR signaling.

Mu-Opioid Receptors Transiently Activate the Akt-nNOS Pathway to Produce Sustained Potentiation of PKC-Mediated NMDAR-CaMKII Signaling

The Akt-nNOS pathway acts as a primer for morphine-triggered events which leads to the sustained potentiation of the NMDAR-CaMKII pathway and MOR inhibition, ultimately leading to morphine tolerance.

The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation

It is found that the MOR-associated histidine triad nucleotide-binding protein 1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR and may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms independent of N MDAR.

Regulators of G-Protein Signaling (RGS) Proteins Promote Receptor Coupling to G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels

The studies indicate that RGS proteins have multiple mechanisms of modulating GPCR signaling that produce negative and positive regulation of signaling depending on the effector, and this coupling is critical for opioid- and baclofen-mediated spinal antinociception.



RGS9 proteins facilitate acute tolerance to mu‐opioid effects

It is reported that regulators of G‐protein signalling (RGS) proteins modulate the timing and amplitude of opioid signals by a push–pull mechanism, and in mice with impaired RGS9, the potency and, in particular, the duration of opioid antinociception increased.

RGSZ1 and GAIP Regulate μ- but Not δ-Opioid Receptors in Mouse CNS: Role in Tachyphylaxis and Acute Tolerance

The results indicate that μ but not δ receptors are linked to Rz regulation, and the μ receptor-mediated activation of Gz proteins is effective at recruiting the adaptive mechanisms leading to the development of opioid desensitization.

Essential role for RGS9 in opiate action

These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in R GS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration.

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

Members of the R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11) are found in the mouse CNS. The expression of these proteins was effectively reduced in

delta Opioid receptor subtypes activate inositol-signaling pathways in the production of antinociception.

The results suggest the existence of different molecular forms of the delta opioid receptor, and the involvement of inositol-signaling pathways in the supraspinal antinociceptive effects of delta agonists.

In vivo injection of antisense oligodeoxynucleotides to G alpha subunits and supraspinal analgesia evoked by mu and delta opioid agonists.

The in vivo antisense strategy and the use of specific antibodies to G alpha subunits gave comparable results, indicating that in the neural tissue the mRNAs and the Galpha subunits can be accessed by the corresponding ODNs and IgGs.

Prolonged Morphine Treatment Targets δ Opioid Receptors to Neuronal Plasma Membranes and Enhances δ-Mediated Antinociception

Results demonstrate that prolonged stimulation of neurons with morphine markedly increases recruitment of intracellular δORs to the cell surface, both in vitro and in vivo, and propose that this type of receptor subtype cross-mobilization may widen the transduction repertoire of G-protein-coupled receptors and offer new therapeutic strategies.

Antibodies to the cloned mu-opioid receptor detect various molecular weight forms in areas of mouse brain.

The results confirm the existence of several molecular forms of the cloned rat mu-opioid receptor due to glycosylation.