scholarly journals Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists

2019 ◽  
Vol 5 (11) ◽  
pp. eaax9115 ◽  
Author(s):  
Tobias Claff ◽  
Jing Yu ◽  
Véronique Blais ◽  
Nilkanth Patel ◽  
Charlotte Martin ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Opioid Receptor ◽  
Small Molecule ◽  
Pain Treatment ◽  
Receptor Activation ◽  
Atomic Scale ◽  
Site Directed Mutagenesis ◽  
Opioid Agonist ◽  
Activated State ◽  
Δ Opioid Receptor

Selective activation of the δ-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to μ-opioid receptor (MOP) agonists that are in the spotlight of the current “opioid crisis.” Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.

Inhibitory and excitatory effects of μ-, δ-, and κ-opioid receptor activation on breathing in awake turtles, Trachemys scripta

2008 ◽  
Vol 295 (5) ◽  
pp. R1599-R1612 ◽  
Author(s):  
Stephen M. Johnson ◽  
Matthew E. Kinney ◽  
Liana M. Wiegel
Keyword(s):  
Respiratory Depression ◽  
Opioid Receptor ◽  
Receptor Activation ◽  
Trachemys Scripta ◽  
Receptor Subtype ◽  
Breathing Frequency ◽  
Opioid Agonist ◽  
Acetate Salt ◽  
Before And After ◽  
Δ Opioid Receptor

For ectothermic vertebrates, such as reptiles, the effects of opioid receptor subtype activation on breathing are poorly understood. On the basis of previous studies on mammals and lampreys, we hypothesized that μ- and δ-opioid receptor (MOR and DOR, respectively) activation would cause respiratory depression, whereas κ-opioid receptor (KOR) activation would have no effect. To address this question, we measured respiration in awake, freely swimming adult red-eared slider turtles ( Trachemys scripta) before and after injection with agonists for specific opioid receptors. Injection of the MOR agonist [d-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin acetate salt (DAMGO, 1.5 or 6.5 mg/kg) decreased ventilation (V̇e) by 72 ± 9% and 95 ± 3%, respectively, 4.0 h after injection as a result of decreased breathing frequency and no change in tidal volume (Vt). DOR agonists, such as [d-Pen2,5]-enkephalin hydrate (DPDPE, 5.0 mg/kg) and [d-Ala2,d-Leu5]-enkephalin acetate salt (DADLE, 6.3 mg/kg), decreased V̇e by 44 ± 10% and 89 ± 4%, respectively, 4.0 h after injection as a result of decreased breathing frequency and no change in Vt. DADLE also increased breath duration by a maximum of 25 ± 9% at 6.0 h after injection. The KOR agonist U-50488 (6.2 mg/kg) increased Vt by a maximum of 52 ± 30% at 5.0 h after injection, with variable nonsignificant changes in V̇e and breathing frequency. Naloxone injections (0.25–0.5 mg/kg) 1.0 h before opioid agonist injections blocked all DAMGO-dependent effects, DPDPE-dependent frequency depression, and DADLE-dependent breath duration augmentation for 2.0 h after agonist injections. These results show that MOR and DOR activation causes respiratory depression as a result of decreased breathing frequency, whereas Vt is increased after KOR activation.

Role of δ-opioid receptor agonists on infarct size reduction in swine

2002 ◽  
Vol 282 (6) ◽  
pp. H1953-H1960 ◽  
Author(s):  
Daniel C. Sigg ◽  
James A. Coles ◽  
Peter R. Oeltgen ◽  
Paul A. Iaizzo
Keyword(s):  
Infarct Size ◽  
Opioid Receptor ◽  
Ischemic Preconditioning ◽  
Myocardial Function ◽  
Receptor Activation ◽  
Area At Risk ◽  
Opioid Agonist ◽  
Important Species ◽  
Δ Opioid Receptor

Opioids are involved in cardiac ischemic preconditioning. Important species differences in cellular signaling mechanisms, antiarrhythmic, and antistunning effects have been described. The role of the δ-opioid receptor activation in swine remains unknown. Forty minutes before a 45-min occlusion and 180-min reperfusion of the left anterior descending coronary artery, open-chest, pentobarbital-anesthetized swine received either 1) saline (controls); 2) [d-Ala2,d-Leu5]enkephalin (DADLE); 3) [d-Pen2,5]enkephalin (DPDPE); 4) deltorphin-D, a novel δ2-opioid agonist; or 5) ischemic preconditioning (IP). Assessed were 1) infarct size to area at risk (IS, triphenyltetrazolium staining), 2) regional and global myocardial function (sonomicrometry, ventricular pressure catheters), and 3) arrhythmias (electrocardiogram analyses). It was found that DPDPE and deltorphin-D pretreatment reduced IS from 64.7 ± 5 to 36.5 ± 6% and 27.4 ± 11% ( P < 0.01), respectively, whereas DADLE had no effect (66.8 ± 3%). Both IP and DADLE had a proarrhythmic effect ( P < 0.01). However, no differences in global or regional myocardial function or arrhythmia scores were observed between groups. This suggests that δ-receptor-specific opioids provide cardioprotection in swine.

scholarly journals Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5406
Author(s):  
Charlène Gadais ◽  
Justyna Piekielna-Ciesielska ◽  
Jolien De Neve ◽  
Charlotte Martin ◽  
Anna Janecka ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pain Treatment ◽  
Binding Assays ◽  
Opioid Agonist ◽  
Opioid Binding ◽  
Μ Opioid Receptor ◽  
Multiple Ligands ◽  
Neurokinin 1 ◽  
Covalently Linked ◽  
Δ Opioid Receptor

Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.

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.

δ-Opioid receptor activation reduces α-synuclein overexpression and oligomer formation induced by MPP+ and/or hypoxia

2014 ◽  
Vol 255 ◽  
pp. 127-136 ◽  
Author(s):  
Tao Chen ◽  
Jessica Li ◽  
Dongman Chao ◽  
Harleen K. Sandhu ◽  
Xiaoping Liao ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Activation ◽  
Oligomer Formation ◽  
Δ Opioid Receptor

scholarly journals Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia

2013 ◽  
Vol 14 (8) ◽  
pp. 15959-15976 ◽  
Author(s):  
Xuesong Tian ◽  
Fei Hua ◽  
Harleen Sandhu ◽  
Dongman Chao ◽  
Gianfranco Balboni ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Activation ◽  
Mouse Cortex ◽  
Tnf Α ◽  
Δ Opioid Receptor

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.

Sign in / Sign up

Export Citation Format

Share Document