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 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 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.

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.

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.

Functional localization of specific receptors mediating gastrointestinal motor correlates of vomiting

1989 ◽  
Vol 256 (1) ◽  
pp. G92-G99 ◽  
Author(s):  
I. M. Lang ◽  
J. Marvig
Keyword(s):  
Small Intestine ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Agonist ◽  
Sch 23390 ◽  
Receptor Antagonists ◽  
Motor Responses ◽  
Opioid Receptor Agonist ◽  
Opioid Receptor Antagonists ◽  
Gastrointestinal Motor

The gastrointestinal motor correlates of vomiting consist of two contractile events, 1) a giant retrogradely propagated contraction of the upper small intestine, the retrograde giant contraction (RGC) and 2) a series of post-RGC phasic contractions that occur primarily in the lower small intestine. The effects of cholinergic, dopaminergic, serotonergic, and opioid receptor antagonists and an opioid receptor agonist on vomiting and its gastrointestinal motor correlates initiated by apomorphine (APO), CuSO4, or cholecystokinin octapeptide (CCK-8) were determined in awake dogs. Atropine blocked the retrograde giant contraction only, and hexamethonium blocked all jejunoileal motor responses activated by APO, CuSO4, or CCK-8. Domperidone blocked all effects of APO only, whereas haloperidol, methysergide, 1-(1-naphthyl) piperazine, and fentanyl blocked or inhibited responses to both APO and CuSO4. None of the dopaminergic, serotonergic, or opioid receptor antagonists or the opioid receptor agonist affected the gastrointestinal motor responses to CCK-8. Cinanserin or Sch 23390 had no effect on any of the responses activated by APO, CuSO4, or CCK-8. These results suggested that D2 dopaminergic and 5-HT2 serotonergic receptors of the emetic central pattern generator mediate vomiting and its gastrointestinal motor correlates, whereas opioid receptors may mediate tonic inhibition of these responses. In addition, peripheral muscarinic or nicotinic cholinergic receptors but not peripheral 5-HT2, dopaminergic, or opioid receptors mediate the gastrointestinal motor correlates of vomiting.

Repeated δ1-opioid receptor stimulation reduces δ2-opioid receptor responses in the SA node

2006 ◽  
Vol 291 (5) ◽  
pp. H2246-H2254 ◽  
Author(s):  
S. H. Deo ◽  
S. Johnson-Davis ◽  
M. A. Barlow ◽  
D. Yoshishige ◽  
J. L. Caffrey
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Independent Effect ◽  
Receptor Stimulation ◽  
Sa Node ◽  
Time Control ◽  
Before And After ◽  
Vagolytic Effect ◽  
Higher Doses ◽  
Deltorphin Ii

Ultra-low-dose methionine-enkephalin-arginine-phenylalanine improves vagal transmission (vagotonic) and decreases heart rate via δ1-opioid receptors within the sinoatrial (SA) node. Higher doses activate δ2-opioid receptors, interrupt vagal transmission (vagolytic), and reduce the bradycardia. Preconditioning-like occlusion of the nodal artery produced a vagotonic response that was reversed by the δ1-antagonist 7-benzylidenaltrexone (BNTX). The following study tested the hypothesis that extended δ1-opioid receptor stimulation reduces subsequent δ2-receptor responses. The δ2-agonist deltorphin II was introduced in the SA node by microdialysis to evaluate δ2 responses before and after infusion of the δ1-agonist TAN-67. TAN-67 reduced the vagolytic effect of deltorphin by two-thirds. When the δ1-antagonist BNTX was combined with TAN-67, the deltorphin response was preserved, suggesting that attrition of the prior response was mediated by δ1 activity. When TAN-67 was omitted in time control studies, some loss of δ2 responses was apparent in the absence of the δ1 treatment. This loss was also eliminated by BNTX, suggesting that the attenuation of the response after deltorphin alone was also the result of δ1 activity. Additional studies tested TAN-67 alone in the absence of prior deltorphin. When time controls were conducted without the initial deltorphin treatment, a robust vagolytic response was observed. When TAN-67 preceded the delayed deltorphin, the vagolytic response was eroded, indicating an independent effect of TAN-67. BNTX infused afterward was unable to restore the δ2 response. These data support the conclusion that the loss of the δ2 response resulted from reduced δ2 activity mediated by continued δ1-receptor stimulation and not the arithmetic consequence of increased competition from that same δ1 receptor.

scholarly journals The Contribution of δ1- and δ2-Opioid Receptors to Hypoxia-Induced Pial Artery Dilation in the Newborn Pig

1995 ◽  
Vol 15 (3) ◽  
pp. 539-546 ◽  
Author(s):  
W. M. Armstead
Keyword(s):  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Activation ◽  
Severe Hypoxia ◽  
Moderate Hypoxia ◽  
Cranial Window ◽  
Pial Artery ◽  
Opioid Receptor Antagonist ◽  
Deltorphin Ii

Previously, it has been observed that μ-opioid receptors contribute to while κ-opioid receptors oppose pial artery dilation in response to hypoxia. The present study was designed to investigate the contribution of δ1- and δ2-opioid receptor activation to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial artery diameter and collect cortical periarachnoid CSF for assay of opioids. Hypoxia increased CSF leucine enkephalin (a δ-agonist) from 36 ± 6 to 113 ± 17 pg/ml (n = 5). Hypoxiainduced pial artery vasodilation was attenuated during moderate hypoxia (Pao2 ≈ 35 mm Hg), while this response was blunted during severe hypoxia (Pao2 ≈ 25 mm Hg), by the δ1-opioid receptor antagonist 7-benzylidenenaltrexone (BNTX; 10−8 M) (23 ± 2 vs. 13 ± 2 and 34 ± 6 vs. 10 ± 3% for moderate and severe hypoxia in the absence and presence of BNTX, respectively; n = 5). In contrast, the δ2-opioid receptor antagonist naltrindole (10−9 M) blunted pial vasodilation during moderate hypoxia, but only attenuated the vasodilator response during severe hypoxia (22 ± 2 vs. 8 ± 2 and 33 ± 4 vs. 23 ± 4% for moderate and severe hypoxia in the absence and presence of naltrindole, respectively; n = 5). Receptor selectivity experiments show that BNTX blocked responses to the δ1-agonist DPDPE, whereas responses to the δ2-agonist deltorphin II were unchanged (12 ± 3 vs. 2 ± 1% and 14 ± 4 vs. 14 ± 3% for DPDPE at 10−6 M and deltorphin II at 10−6 M in the absence and presence of BNTX; n = 5). Similarly, naltrindole blocked responses to deltorphin II, but responses to DPDPE were unchanged. These data indicate that δ1-receptor activation contributes to both moderate and severe hypoxia-induced vasodilation, but the δ1-receptors appear to be more important during severe hypoxia relative to δ2-receptors. Additionally, these data show that δ2-receptors primarily contribute to dilation during moderate hypoxia.

scholarly journals Peripherally Acting μ-Opioid Receptor Antagonists for the Treatment of Opioid-Related Side Effects: Mechanism of Action and Clinical Implications

2017 ◽  
Vol 31 (6) ◽  
pp. 658-669 ◽  
Author(s):  
John M. Streicher ◽  
Edward J. Bilsky
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Mechanism Of Action ◽  
Bowel Dysfunction ◽  
Cardiac Risk ◽  
Common Side Effect ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonists ◽  
Opioid Administration

Opioid receptors are distributed throughout the central and peripheral nervous systems and on many nonneuronal cells. Therefore, opioid administration induces effects beyond analgesia. In the enteric nervous system (ENS), stimulation of µ-opioid receptors triggers several inhibitory responses that can culminate in opioid-induced bowel dysfunction (OBD) and its most common side effect, opioid-induced constipation (OIC). OIC negatively affects patients’ quality of life (QOL), ability to work, and pain management. Although laxatives are a common first-line OIC therapy, most have limited efficacy and do not directly antagonize opioid effects on the ENS. Peripherally acting µ-opioid receptor antagonists (PAMORAs) with limited ability to cross the blood-brain barrier have been developed. The PAMORAs approved by the U S Food and Drug Administration for OIC are subcutaneous and oral methylnaltrexone, oral naloxegol, and oral naldemedine. Although questions of cost-effectiveness and relative efficacy versus laxatives remain, PAMORAs can mitigate OIC and improve patient QOL. PAMORAS may also have applications beyond OIC, including reducing the increased cardiac risk or potential tumorigenic effects of opioids. This review discusses the burden of OIC and OBD, reviews the mechanism of action of new OIC therapies, and highlights other potential opioid-related side effects mediated by peripheral opioid receptors in the context of new OIC therapies.

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.

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