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.

Relationship between vasopressin and opioids in hypoxia induced pial artery vasodilation

1996 ◽  
Vol 271 (2) ◽  
pp. H521-H527 ◽  
Author(s):  
M. I. Rossberg ◽  
W. M. Armstead
Keyword(s):  
Receptor Antagonist ◽  
Severe Hypoxia ◽  
Vasopressin Receptor ◽  
Fetal Sheep ◽  
Moderate Hypoxia ◽  
Cranial Window ◽  
Pial Artery ◽  
Window Technique ◽  
Vasopressin Receptor Antagonist ◽  
And Control

It has been observed that a vasopressin receptor antagonist attenuates hypoxic hyperemia in fetal sheep, whereas methionine enkephalin (Met) and leucine enkephalin (Leu) contribute to hypoxia-induced pial artery dilation in newborn pigs. This study was designed to investigate the relationship between vasopressin and opioids in hypoxia-induced pial artery dilation in the newborn pig by use of the closed cranial window technique. Hypoxia-induced pial artery dilation was attenuated during moderate [arterial Po2 (PaO2) approximately 35 mmHg] and severe hypoxia (PaO2 approximately 25 mmHg) by the vasopressin receptor antagonist, [beta-mercapto-beta beta-cyclopentamethylenepropionyl, 2-O-Me-Tyr2, Arg8]vasopressin (MeAVP, 5 micrograms/kg i.v.; 29 +/- 1 vs. 14 +/- 2 and 37 +/- 2 vs. 18 +/- 2% for moderate and severe hypoxia in absence vs. presence of MeAVP, respectively, n = 7). Hypoxia-induced dilation was accompanied by increased cerebrospinal fluid (CSF) vasopressin concentration (26 +/- 1 vs. 67 +/- 4 and 26 +/- 1 vs. 99 +/- 4 pg/ml for control vs. moderate and control vs. severe hypoxia, n = 5). Vasopressin increased CSF Met (895 +/- 28, 1,147 +/- 63, 1,327 +/- 48, and 1,600 +/- 75 pg/ml for control and 40, 400, and 4,000 pg/ml vasopressin, respectively, n = 7). CSF Leu concentration was similarly increased by vasopressin. Furthermore, MeAVP attenuated the release of Met during moderate hypoxia (910 +/- 38 and 2,682 +/- 49 vs. 911 +/- 38 and 2,110 +/- 84 pg/ml for control and moderate hypoxia in absence and presence of MeAVP, respectively, n = 5). MeAVP had similar effects on hypoxia-induced Leu release. These data show that vasopressin contributes to hypoxia-induced pial artery dilation and that vasopressin increases CSF Met and Leu concentrations. These data also suggest that elevated CSF vasopressin concentrations that occur during hypoxemia result in opioid release, which subsequently contributes to hypoxic pial artery dilation.

kappa-Opioid antagonist improves cellular bioenergetics and recovery after traumatic brain injury

1991 ◽  
Vol 261 (6) ◽  
pp. R1527-R1532 ◽  
Author(s):  
R. Vink ◽  
P. S. Portoghese ◽  
A. I. Faden
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Neurological Outcome ◽  
Kappa Opioid Receptors ◽  
Kappa Opioid ◽  
Opioid Receptor Antagonist ◽  
Cellular Bioenergetics

Treatment with opioid receptor antagonists improves outcome after experimental brain trauma, although the mechanisms underlying the protective actions of these compounds remain speculative. We have proposed that endogenous opioids contribute to the pathophysiology of traumatic brain injury through actions at kappa-opioid receptors, possibly by affecting cellular bioenergetic state. In the present study, the effects of the kappa-selective opioid-receptor antagonist nor-binaltorphimine (nor-BNI) were examined after fluid percussion brain injury in rats. Metabolic changes were evaluated by 31P magnetic resonance spectroscopy; the same animals were subsequently followed over 2 wk to evaluate neurological recovery. Nor-BNI, administered intravenously as a 10 or 20 mg/kg bolus at 30 min after injury, significantly improved neurological outcome at 2 wk posttrauma compared with controls. Animals treated with nor-BNI showed significantly greater recovery of intracellular free magnesium concentrations and cytosolic phosphorylation potentials during the first 4 h after injury compared with saline-treated controls. The improvement in cytosolic phosphorylation potential was significantly correlated to neurological outcome. These data support the hypothesis that kappa-opioid receptors mediate pathophysiological changes after traumatic brain injury and that the beneficial effects of opioid-receptor antagonist may result from improvement of posttraumatic cellular bioenergetics.

Protection of cardiac myocytes via δ1-opioid receptors, protein kinase C, and mitochondrial KATP channels

2001 ◽  
Vol 280 (1) ◽  
pp. H377-H383 ◽  
Author(s):  
Joon Huh ◽  
Garrett J. Gross ◽  
Hiroshi Nagase ◽  
Bruce T. Liang
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Receptor Antagonist ◽  
Cardiac Myocytes ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Inhibitory Effect ◽  
Cardioprotective Effect ◽  
Opioid Receptor Antagonist ◽  
Kinase C

The objective of the present study was to investigate the role of δ1-opioid receptors in mediating cardioprotection in isolated chick cardiac myocytes and to investigate whether protein kinase C and mitochondrial ATP-sensitive K+(KATP) channels act downstream of the δ1-opioid receptor in mediating this beneficial effect. A 5-min preexposure to the selective δ1-opioid receptor agonist (−)-TAN-67 (1 μM) resulted in less myocyte injury during the subsequent prolonged ischemia compared with untreated myocytes. 7-Benzylidenenaltrexone, a selective δ1-opioid receptor antagonist, completely blocked the cardioprotective effect of (−)-TAN-67. Naltriben methanesulfonate, a selective δ2-opioid receptor antagonist, had only a slight inhibitory effect on (−)-TAN-67-mediated cardioprotection. Nor-binaltorphimine dihydrochloride, a κ-opioid receptor antagonist, did not affect (−)-TAN-67-mediated cardioprotection. The protein kinase C inhibitor chelerythrine and the KATP channel inhibitors glibenclamide, a nonselective KATP antagonist, and 5-hydroxydecanoic acid, a mitochondrial selective KATPantagonist, reversed the cardioprotective effect of (−)-TAN-67. These results suggest that the δ1-opioid receptor is present on cardiac myocytes and mediates a potent cardioprotective effect via protein kinase C and the mitochondrial KATP channel.

Synaptic Actions of Neuropeptide FF in the Rat Parabrachial Nucleus: Interactions With Opioid Receptors

2000 ◽  
Vol 84 (2) ◽  
pp. 744-751 ◽  
Author(s):  
Xihua Chen ◽  
Jeffrey A. Zidichouski ◽  
Kim H. Harris ◽  
Jack H. Jhamandas
Keyword(s):  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Distribution Curve ◽  
Parabrachial Nucleus ◽  
Synaptic Currents ◽  
Opioid Receptor Antagonist ◽  
Neuropeptide Ff ◽  
Δ Opioid Receptor ◽  
Synaptic Effects

The pontine parabrachial nucleus (PBN) receives both opioid and Neuropeptide FF (NPFF) projections from the lower brain stem and/or the spinal cord. Because of this anatomical convergence and previous evidence that NPFF displays both pro- and anti-opioid activities, this study examined the synaptic effects of NPFF in the PBN and the mechanisms underlying these effects using an in vitro brain slice preparation and the nystatin-perforated patch-clamp recording technique. Under voltage-clamp conditions, NPFF reversibly reduced the evoked excitatory postsynaptic currents (EPSCs) in a dose-dependent fashion. This effect was not accompanied by apparent changes in the holding current, the current-voltage relationship or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–induced inward currents in the PBN cells. When a paired-pulse protocol was used, NPFF increased the ratio of these synaptic currents. Analysis of miniature EPSCs showed that NPFF caused a rightward shift in the frequency-distribution curve, whereas the amplitude-distribution curve remained unchanged. Collectively, these experiments indicate that NPFF reduces the evoked EPSCs through a presynaptic mechanism of action. The synaptic effects induced by NPFF (5 μM) could not be blocked by the specific μ-opioid receptor antagonist,d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2(1 μM), but application of δ-opioid receptor antagonist Tyr-Tic-Phe-Phe (5 μM) almost completely prevented effects of NPFF. Moreover, the δ-opioid receptor agonist, Deltorphin (1 μM), mimicked the effects as NPFF and also occluded NPFF's actions on synaptic currents. These results indicate that NPFF modulates excitatory synaptic transmission in the PBN through an interaction with presynaptic δ-opioid receptors. These observations provide a cellular basis for NPFF enhancement of the antinociceptive effects consequent to central activation of δ-opioid receptors.

scholarly journals Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on δ-opioid receptor stimulation

2010 ◽  
Vol 299 (5) ◽  
pp. H1604-H1609 ◽  
Author(s):  
Mathivadhani Panneerselvam ◽  
Yasuo M. Tsutsumi ◽  
Jacqueline A. Bonds ◽  
Yousuke T. Horikawa ◽  
Michelle Saldana ◽  
...  
Keyword(s):  
Infarct Size ◽  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Low Dose ◽  
Ischemia Reperfusion ◽  
Receptor Activation ◽  
Cardiac Protection ◽  
Receptor Stimulation ◽  
Opioid Receptor Antagonist ◽  
Δ Opioid Receptor

Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH2-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to produce cardiac protection from ischemia-reperfusion injury.

scholarly journals Activation of δ-Opioid Receptors Reduces Excitatory Input to Putative Gustatory Cells Within the Nucleus of the Solitary Tract

2009 ◽  
Vol 101 (1) ◽  
pp. 258-268 ◽  
Author(s):  
Mingyan Zhu ◽  
Young K. Cho ◽  
Cheng-Shu Li
Keyword(s):  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Polymerase Chain Reaction Analysis ◽  
Excitatory Input ◽  
Solitary Tract ◽  
Opioid Receptor Antagonist ◽  
Naltrexone Hydrochloride ◽  
Parabrachial Nuclei ◽  
Δ Opioid Receptor

The rostral nucleus of the solitary tract (NST) is the first central relay in the gustatory pathway and plays a key role in processing and modulation of gustatory information. Here, we investigated the effects of opioid receptor agonists and antagonists on synaptic responses of the gustatory parabrachial nuclei (PbN)-projecting neurons in the rostral NST to electrical stimulation of the solitary tract (ST) using whole cell recordings in the hamster brain stem slices. ST-evoked excitatory postsynaptic currents (EPSCs) were significantly reduced by met-enkephalin (MetE) in a concentration-dependent fashion and this effect was eliminated by naltrexone hydrochloride, a nonselective opioid receptor antagonist. Bath application of naltrindole hydrochloride, a selective δ-opioid receptor antagonist, eliminated MetE-induced reduction of EPSCs, whereas CTOP, a selective μ-opioid receptor antagonist had no effect, indicating that δ-opioid receptors are involved in the reduction of ST-evoked EPSCs induced by MetE. SNC80, a selective δ-opioid receptor agonist, mimicked the effect of MetE. The SNC80-induced reduction of ST-evoked EPSCs was eliminated by 7-benzylidenenaltrexone, a selective δ1-opioid receptor antagonist but not by naltriben mesylate, a selective δ2-opioid receptor antagonist, indicating that δ1-opioid receptors mediate the reduction of ST-evoked EPSCs induced by SNC80. Single-cell reverse transcriptase–polymerase chain reaction analysis revealed the presence of δ1-opioid receptor mRNA in cells that responded to SNC80 with a reduction in ST-evoked EPSCs. Moreover, Western blot analysis demonstrated the presence of 40-kDa δ-opioid receptor proteins in the rostral NST tissue. These results suggest that postsynaptic δ1-opioid receptors are involved in opioid-induced reduction of ST-evoked EPSCs of PbN-projecting rostral NST cells.

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.

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