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.

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.

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders

2020 ◽  
Vol 60 (1) ◽  
pp. 615-636 ◽  
Author(s):  
Moriah L. Jacobson ◽  
Caroline A. Browne ◽  
Irwin Lucki
Keyword(s):  
Opioid Receptor ◽  
Therapeutic Potential ◽  
Kappa Opioid Receptor ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
Antagonist Activity ◽  
Kappa Opioid ◽  
Opioid Receptor Antagonists ◽  
Emergent Literature ◽  
Potential Therapeutics

Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.

Interleukin-6 is differently modulated by central opioid receptor subtypes

1997 ◽  
Vol 273 (3) ◽  
pp. R956-R959 ◽  
Author(s):  
M. Bertolucci ◽  
C. Perego ◽  
M. G. De Simoni
Keyword(s):  
Opioid Receptor ◽  
Fine Tuning ◽  
Opioid System ◽  
Receptor Subtypes ◽  
Receptor Blockade ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
General Role ◽  
Opioid Receptor Subtypes ◽  
Mu Antagonist

The central endogenous opioid system is involved in the modulation of interleukin (IL)-6, an inflammatory cytokine that plays a major role in the acute phase response. The present study evaluates whether specific opioid receptor subtypes are selectively involved in this immunomodulatory action. IL-1 beta was administered either intracerebroventricularly or intraperitoneally at the dose of 400 ng to rats pretreated with the mu-antagonist beta-funaltrexamine, the delta-antagonist naltrindole, or the kappa-antagonist nor-binaltorphimine, each at the doses of 1, 10, and 100 micrograms/rat intracerebroventricularly. Serum IL-6 levels were measured 2 h later. The results show that mu-receptor blockade increases, whereas delta-receptor blockade decreases IL-6 induction, suggesting that the fine tuning exerted by opioids on the immune system may be achieved through a balance of opposing effects. Moreover the three antagonists affect IL-6 induction by central and peripheral IL-1 beta with a similar pattern, indicating that the brain endogenous opioid system plays a general role in the regulation of this cytokine.

Morphine initiates migrating myoelectric complexes by acting on peripheral opioid receptors

1985 ◽  
Vol 249 (5) ◽  
pp. G557-G562 ◽  
Author(s):  
G. L. Telford ◽  
M. Hoshmonai ◽  
A. J. Moses ◽  
J. H. Szurszewski
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Silver Chloride ◽  
Phase Iii ◽  
Opioid Receptor Antagonists ◽  
Peripheral Opioid Receptors ◽  
Silver Silver ◽  
Silver Silver Chloride ◽  
Higher Doses

The role of peripheral and central opioid receptors in morphine-induced migrating myoelectric complexes (MMECs) was studied in conscious dogs implanted with silver-silver chloride electrodes. In normal fasted dogs morphine (100-200 micrograms/kg iv) initiated phase III of the MMEC in the duodenum. Once initiated the MMEC propagated distally. This effect of morphine was blocked by the opioid receptor antagonists naloxone (2 mg/kg iv) and N,N-diallylnormorphinium bromide (4 mg/kg iv). Higher doses of morphine (300-600 micrograms/kg iv) initiated phase III activity in fed dogs as early as 20 min after feeding, while lower doses (150 micrograms/kg iv) initiated phase III activity routinely when administered 100 min after feeding. In dogs with bilateral vagotomies and bilateral thoracolumbar sympathetic chain ganglionectomies, morphine (150 micrograms/kg iv) initiated phase III activity in the duodenum, which then migrated distally. This study demonstrates that morphine initiates phase III of the MMEC by acting through peripheral opioid receptors.

Compartment-specific opioid receptor signaling is selectively modulated by Dynorphin subtypes

2020 ◽  
Author(s):  
Jennifer M. Kunselman ◽  
Achla Gupta ◽  
Ivone Gomes ◽  
Lakshmi A. Devi ◽  
Manoj A. Puthenveedu
Keyword(s):  
Opioid Receptor ◽  
Opioid Peptides ◽  
Kappa Opioid Receptor ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Spatial Profile ◽  
Downstream Signaling ◽  
G Protein Coupled ◽  
Fine Tune ◽  
Signal Transduction Systems

AbstractMany signal transduction systems have an apparent redundancy built into them, where multiple physiological agonists activate the same receptors. Whether this is true redundancy, or whether this provides as-yet unrecognized specificity in downstream signaling, is not well understood. We address this question using the kappa opioid receptor (KOR), a physiologically relevant G protein-coupled receptor (GPCR) that is activated by multiple members of the Dynorphin family of opioid peptides. We show that, although highly related Dynorphins bind and activate KOR to similar extents on the cell surface, they localize KOR to distinct subcellular compartments, dictate different post-endocytic fates of the receptor, and differentially induce KOR signaling from the degradative pathway. Our results show that seemingly redundant endogenous opioid peptides that are often co-released can in fact fine-tune signaling by differentially regulating the subcellular spatial profile of GPCR localization and signaling.

scholarly journals Regular Exercise Reverses Sensory Hypersensitivity in a Rat Neuropathic Pain Model

2011 ◽  
Vol 114 (4) ◽  
pp. 940-948 ◽  
Author(s):  
Nicola J. Stagg ◽  
Heriberto P. Mata ◽  
Mohab M. Ibrahim ◽  
Erik J. Henriksen ◽  
Frank Porreca ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Opioid Receptor ◽  
Endogenous Opioids ◽  
Receptor Antagonists ◽  
Endogenous Opioid ◽  
Sensory Hypersensitivity ◽  
Opioid Receptor Antagonists

Background Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems. Methods After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry. Results Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area. Conclusions Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.

scholarly journals Molecular cloning of a rat κ opioid receptor reveals sequence similarities to the μ and δ opioid receptors

1993 ◽  
Vol 295 (3) ◽  
pp. 625-628 ◽  
Author(s):  
Y Chen ◽  
A Mestek ◽  
J Liu ◽  
L Yu
Keyword(s):  
Adenylate Cyclase ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Brain Cdna Library ◽  
Inhibitory Coupling ◽  
Receptor Cdna ◽  
G Protein Coupled ◽  
Sequence Similarities

By screening a rat brain cDNA library using a cloned mu opioid receptor cDNA as probe, a clone was identified that is very similar to both the mu and delta opioid receptor sequences. Transient expression of this clone in COS-7 cells showed that it encodes a kappa opioid receptor, designated KOR-1, which is capable of high-affinity binding to kappa-selective ligands. Treatment of transfected cell membranes with bremazocine, a kappa-selective agonist, resulted in a 53% decrease in adenylate cyclase activity, indicating that this kappa opioid receptor displays inhibitory coupling to adenylate cyclase. Thus, one member from each of the three opioid receptor types, mu, kappa and delta, has been molecularly cloned. Analysis of sequence similarities among these opioid receptors, as well as between opioid receptors and other G-protein-coupled receptors, revealed regions of sequence conservation that may underlie the ligand-binding and functional specificities of opioid receptors.

scholarly journals Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

2020 ◽  
Author(s):  
Elyssa B. Margolis ◽  
Tanya L. Wallace ◽  
Lori Jean Van Orden ◽  
William J. Martin
Keyword(s):  
Opioid Receptor ◽  
Therapeutic Potential ◽  
Outward Current ◽  
Complete Recovery ◽  
Kappa Opioid Receptor ◽  
Dopamine Neurons ◽  
Kappa Opioid ◽  
Opioid Receptor Antagonists ◽  
Neurobehavioral Disorders ◽  
Circuit Function

AbstractActivation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively). JNJ-67953964 showed an IC50 of 0.3 ± 1.3 nM. PF-04455242 (IC50 = 19.6 ± 16 nM) exhibited partial antagonist activity (∼60% maximal blockade). In 50% of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within disorder-relevant circuits implicated in neurobehavioral disorders.

scholarly journals Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

2011 ◽  
Vol 115 (6) ◽  
pp. 1363-1381 ◽  
Author(s):  
Ream Al-Hasani ◽  
Michael R. Bruchas
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Receptor Subtypes ◽  
Receptor Signaling ◽  
Molecular Pharmacology ◽  
And Behavior ◽  
G Protein Coupled

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.

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