scholarly journals Opioid receptor heteromers in analgesia

2012 ◽  
Vol 14 ◽  
Author(s):  
Cristina M. Costantino ◽  
Ivone Gomes ◽  
Steven D. Stockton ◽  
Maribel P. Lim ◽  
Lakshmi A. Devi
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Therapeutic Targets ◽  
Endogenous Opioid ◽  
Chronic Morphine ◽  
Receptor Complexes ◽  
Receptor Signalling ◽  
Receptor Heteromers ◽  
The Usa ◽  
Abused Drugs

Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.

scholarly journals Immunoprecipitation of opioid receptor-Go-protein complexes using specific GTP-binding-protein antisera

1995 ◽  
Vol 306 (1) ◽  
pp. 71-75 ◽  
Author(s):  
Z Georgoussi ◽  
G Milligan ◽  
C Zioudrou
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Protein Complexes ◽  
Binding Protein ◽  
Guanine Nucleotide ◽  
Guanine Nucleotide Binding Protein ◽  
Receptor Complexes ◽  
Delta Opioid Receptors ◽  
Guanine Nucleotide Binding ◽  
Cortical Membranes

Solubilization of opioid receptors from rat cortical membranes that retained high-affinity guanine nucleotide-sensitive agonist binding was achieved using 10 mM CHAPS. We report the nature of the interactions of mu and delta opioid receptors with the guanine nucleotide-binding protein G(o) by immunoprecipitation of CHAPS extracts with selective G(o)alpha-subunit protein antisera. Antiserum IM1 raised against amino acids 22-35 of G(o)alpha selectively co-immunoprecipitated G(o)alpha-mu and G(o)alpha-delta opioid receptor complexes detected in the immunoprecipitates by specific [3H][D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin and [3H][D-Ser2,Leu5,Thr6]enkephalin binding respectively. By contrast, antisera directed against the C-terminal decapeptide (OC2) and the N-terminal hexadecapeptide (ON1) of isoforms of G(o)alpha were unable to immunoprecipitate solubilized opioid receptor-G(o) complexes, although both were able to immunoprecipitate solubilized G(o)alpha and have been shown to reduce the affinity of [D-Ala2,D-Leu5]enkephalin for opioid receptors in rat cortical membranes [Georgoussi, Carr and Milligan (1993) Mol. Pharmacol. 44, 62-69]. These findings demonstrate that CHAPS-solubilized mu and delta opioid receptors from rat cortical membranes form stable complexes with one or more variants of G(o).

scholarly journals Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?

2018 ◽  
Vol 2 (2) ◽  
Author(s):  
Sarah J. Bailey ◽  
Stephen M. Husbands
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Stress Responses ◽  
Therapeutic Potential ◽  
Fine Tuning ◽  
Endogenous Opioid ◽  
Alternative Approach ◽  
Opioid Receptor Antagonists ◽  
Clinical Potential ◽  
G Protein Coupled

The opioid receptors are a family of G-protein coupled receptors (GPCRs) with close structural homology. The opioid receptors are activated by a variety of endogenous opioid neuropeptides, principally β-endorphin, dynorphins, leu- and met-enkephalins. The clinical potential of targeting opioid receptors has largely focused on the development of analgesics. However, more recent attention has turned to the role of central opioid receptors in the regulation of stress responses, anhedonia and mood. Activation of the κ opioid receptor (KOP) subtype has been shown in both human and rodent studies to produce dysphoric and pro-depressive like effects. This has led to the idea that selective KOP antagonists might have therapeutic potential as antidepressants. Here we review data showing that mixed μ opioid (MOP) and KOP antagonists have antidepressant-like effects in rodent behavioural paradigms and highlight comparable studies in treatment-resistant depressed patients. We propose that developing multifunctional ligands which target multiple opioid receptors open up the potential for fine-tuning hedonic responses mediated by opioids. This alternative approach towards targeting multiple opioid receptors may lead to more effective treatments for depression.

scholarly journals Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats

2021 ◽  
Author(s):  
Lukas Dehe ◽  
Mohammed Shaqura ◽  
Michael Nordine ◽  
Helmut Habazettl ◽  
Petra von Kwiatkowski ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Wistar Rats ◽  
Volume Overload ◽  
Left Ventricular ◽  
Endogenous Opioid ◽  
Kappa Opioid ◽  
Receptor Mrna ◽  
Naltrexone Treatment

Abstract Purpose Myocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation–contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure. Methods Volume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls. Results In ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls. Conclusion Opioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload.

scholarly journals On the G-Protein-Coupled Receptor Heteromers and Their Allosteric Receptor-Receptor Interactions in the Central Nervous System: Focus on Their Role in Pain Modulation

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Wilber Romero-Fernandez ◽  
Alicia Rivera ◽  
Kathleen Van Craenenbroeck ◽  
Alexander O. Tarakanov ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
G Protein ◽  
Opioid Receptor ◽  
Pain Modulation ◽  
Chronic Morphine ◽  
Receptor Heteromers ◽  
Receptor Interactions ◽  
The Central Nervous System

The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating viaβ-arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia.

scholarly journals Enhancement of Spinal N -Methyl-d-aspartate Receptor Function by Remifentanil Action at δ-Opioid Receptors as a Mechanism for Acute Opioid-induced Hyperalgesia or Tolerance

2008 ◽  
Vol 109 (2) ◽  
pp. 308-317 ◽  
Author(s):  
Min Zhao ◽  
Daisy T. Joo
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Activation ◽  
Delta Opioid Receptor ◽  
Receptor Subtype ◽  
Chronic Morphine ◽  
Nmda Current ◽  
Opioid Induced Hyperalgesia ◽  
Response Increase ◽  
Deltorphin Ii

Background Intraoperative remifentanil infusions have been associated with postoperative opioid-induced hyperalgesia and tolerance. Using a previously identified subpopulation of spinal neurons that displays an augmentation in N-methyl-D-aspartate (NMDA) receptor current after chronic morphine, investigations were undertaken to determine whether remifentanil induces acute increases in NMDA responses that are concentration dependent and receptor subtype dependent. Methods Electrophysiologic recordings of NMDA current were made from cultured rat dorsal horn neurons treated with remifentanil at various concentrations for 60 min. Selective mu- or delta-opioid receptor inhibitors and agonists were used to determine the site of action of remifentanil. Results Remifentanil at 4, 6, and 8 nM, but not higher or lower concentrations, caused significant mean increases in NMDA peak current amplitude of 37.30% (P < 0.001), 30.19% (P < 0.001), and 23.52% (P = 0.025), respectively, over control conditions. This occurred by 36 min of remifentanil perfusion and persisted throughout its washout. Inhibition by 100 nM naloxone or 1 nM naltrindole attenuated the remifentanil-induced NMDA response increase. Selective delta-opioid agonists [D-Pen(2), D-Pen(5)]enkephalin and deltorphin II displayed a similar bell-shaped concentration-response relation for the enhancement of NMDA responses, and 10 nM deltorphin II occluded the effects of 4 nM remifentanil on NMDA responses. Conclusions Clinically relevant concentrations of remifentanil induce rapid, persistent increases in NMDA responses that mirror the development of remifentanil-induced hyperalgesia and tolerance. NMDA enhancement by remifentanil is dependent on the activation of both mu- and delta-opioid receptors and is inducible solely by delta-opioid receptor activation. Therefore, selective delta-opioid inhibition may attenuate acute paradoxical increases in pain and tolerance to opioids.

Cardiac enkephalins interrupt vagal bradycardia via δ2-opioid receptors in sinoatrial node

2003 ◽  
Vol 284 (5) ◽  
pp. H1693-H1701 ◽  
Author(s):  
Martin Farias ◽  
Keith E. Jackson ◽  
Darice Yoshishige ◽  
James L. Caffrey
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Sinoatrial Node ◽  
Opiate Receptor ◽  
Positive Control ◽  
Receptor Subtype ◽  
Endogenous Opioid ◽  
Opioid Receptor Antagonists ◽  
Vagal Bradycardia ◽  
Deltorphin Ii

Local cardiac opioids appear to be important in determining the quality of vagal control of heart rate. Introduction of the endogenous opioid methionine-enkephalin-arginine-phenylalanine (MEAP) into the interstitium of the canine sinoatrial node by microdialysis attenuates vagally mediated bradycardia through a δ-opioid receptor mechanism. The following studies were conducted to test the hypothesis that a δ2-opiate receptor subtype mediates the interruption of vagal transmission. Twenty mongrel dogs were anesthetized and instrumented with microdialysis probes inserted into the sinoatrial node. Vagal frequency responses were performed at 1, 2, and 3 Hz during vehicle infusion and during treatment with the native agonist MEAP, the δ1-opioids 2-methyl-4aa-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino[2,3,3- g]isoquinoline (TAN-67) and [d-pen2,5]-enkephalin (DPDPE), and the δ2opioid deltorphin II. The vagolytic effects of intranodal MEAP and deltorphin were then challenged with the δ1- and δ2-opioid receptor antagonists 7-benzylidenenaltrexone (BNTX) and naltriben, respectively. Although the positive control deltorphin II was clearly vagolytic in each experimental group, TAN-67 and DPDPE were vagolytically ineffective in the same animals. In contrast, TAN-67 improved vagal bradycardia by 30–35%. Naltriben completely reversed the vagolytic effects of MEAP and deltorphin. BNTX was ineffective in this regard but did reverse the vagal improvement observed with TAN-67. These data support the hypothesis that the vagolytic effect of the endogenous opioid MEAP was mediated by δ2-opioid receptors located in the sinoatrial node. These data also support the existence of vagotonic δ1-opioid receptors also in the sinoatrial node.

scholarly journals Increased Abundance of Opioid Receptor Heteromers After Chronic Morphine Administration

2010 ◽  
Vol 3 (131) ◽  
pp. ra54-ra54 ◽  
Author(s):  
A. Gupta ◽  
J. Mulder ◽  
I. Gomes ◽  
R. Rozenfeld ◽  
I. Bushlin ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Chronic Morphine ◽  
Morphine Administration ◽  
Receptor Heteromers
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