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.

scholarly journals Behavioral Consequences of Delta-Opioid Receptor Activation in the Periaqueductal Gray of Morphine Tolerant Rats

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Michael M. Morgan ◽  
Michelle D. Ashley ◽  
Susan L. Ingram ◽  
MacDonald J. Christie
Keyword(s):  
Plasma Membrane ◽  
Morphine Tolerance ◽  
Receptor Activation ◽  
Delta Opioid Receptor ◽  
Morphine Injection ◽  
Chronic Morphine ◽  
Delta Opioid Receptors ◽  
Morphine Administration ◽  
Consistent Manner ◽  
Deltorphin Ii

Chronic morphine administration shifts delta-opioid receptors (DORs) from the cytoplasm to the plasma membrane. Given that microinjection of morphine into the PAG produces antinociception, it is hypothesized that the movement of DORs to the membrane will allow antinociception to the DOR agonist deltorphin II as a way to compensate for morphine tolerance. Tolerance was induced by twice daily injections of morphine (5, 10, or 20 mg/kg, subcutaneous) for 3.5 days. Microinjection of deltorphin into the vPAG 6 hours after the last morphine injection produced a mild antinociception that did not vary in a consistent manner across morphine pretreatment doses or nociceptive tests. In contrast, deltorphin caused a decrease in activity in morphine tolerant rats that was associated with lying in the cage. The decrease in activity and change in behavior indicate that chronic morphine administration alters DORs in the vPAG. However, activation of these receptors does not appear to compensate for the decrease in antinociception caused by morphine tolerance.

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.

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.

The K+-evoked release of [3H]acetylcholine from slices of rat globus pallidus: modulation by δ-opioid receptors

1991 ◽  
Vol 69 (3) ◽  
pp. 414-418 ◽  
Author(s):  
Bianca B. Ruzicka ◽  
Khem Jhamandas
Keyword(s):  
Globus Pallidus ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Cholinergic Neurons ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Release Of Acetylcholine ◽  
Δ Opioid Receptor ◽  
Tritium Release

Previous investigations have shown that the activation of δ-opioid receptors depresses the release of acetylcholine (ACh) in the rat caudate putamen. This finding raised the possibility that the release of ACh is similarly modulated in the globus pallidus, a region containing a distinct population of cholinergic neurons and enriched in enkephalinergic nerve terminals. In the present study the pallidal release of ACh was characterized and the effects of δ-opioid receptor activation on this release were examined. The results show that this release is stimulated by high K+ in a concentration- and Ca2+-dependent manner. D-Pen2,L-Pen5-enkephalin (0.1 – 10 μM), a selective δ-opioid receptor agonist, produced a dose-related inhibition of the 25 mM K+-evoked tritium release. The maximal inhibitory effect, representing a 34% decrease in the K+-induced tritium release, was observed at a concentration of 1 μM. This opioid effect was attenuated by the selective δ-opioid receptor antagonist, ICI 174864 (1 μM). These findings support the role of a δ-opioid receptor in the modulation of ACh release in the rat globus pallidus.Key words: globus pallidus, acetylcholine, enkephalin, release.

scholarly journals TAN-67, a δ1-opioid receptor agonist, reduces infarct size via activation of Gi/oproteins and KATPchannels

1998 ◽  
Vol 274 (3) ◽  
pp. H909-H914 ◽  
Author(s):  
Jo El J. Schultz ◽  
Anna K. Hsu ◽  
Hiroshi Nagase ◽  
Garrett J. Gross
Keyword(s):  
Infarct Size ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Coronary Artery Occlusion ◽  
Receptor Activation ◽  
Artery Occlusion ◽  
Cardioprotective Effect ◽  
Area At Risk ◽  
Opioid Receptor Agonist ◽  
Δ Opioid Receptor

We have previously shown that delta (δ)-opioid receptors, most notably δ1, are involved in the cardioprotective effect of ischemic preconditioning (PC) in rats; however, the mechanism by which δ-opioid receptor-induced cardioprotection is mediated remains unknown. Therefore, we hypothesized that several of the known mediators of ischemic PC such as the ATP-sensitive potassium (KATP) channel and Gi/oproteins are involved in the cardioprotective effect produced by δ1-opioid receptor activation. To address these possibilities, anesthetized, open-chest Wistar rats were randomly assigned to five groups. Control animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. To demonstrate that stimulating δ1-opioid receptors produces cardioprotection, TAN-67, a new selective δ1-agonist, was infused for 15 min before the long occlusion and reperfusion periods. In addition, one group received 7-benzylidenenaltrexone (BNTX), a selective δ1-antagonist, before TAN-67. To study the involvement of KATPchannels or Gi/oproteins in δ1-opioid receptor-induced cardioprotection, glibenclamide (Glib), a KATPchannel antagonist, or pertussis toxin (PTX), an inhibitor of Gi/oproteins, was administered before TAN-67. Infarct size (IS) as a percentage of the area at risk (IS/AAR) was determined by tetrazolium stain. TAN-67 significantly reduced IS/AAR as compared with control (56 ± 2 to 27 ± 5%, n = 5, P < 0.05). The cardioprotective effect of TAN-67 was completely abolished by BNTX, Glib, and PTX (51 ± 3, 53 ± 5, and 61 ± 4%, n = 6 for each group, respectively). These results are the first to suggest that stimulating the δ1-opioid receptor elicits a cardioprotective effect that is mediated via Gi/oproteins and KATPchannels in the intact rat heart.

Sign in / Sign up

Export Citation Format

Share Document