scholarly journals Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors

Neuron ◽  
2015 ◽  
Vol 88 (6) ◽  
pp. 1227-1239 ◽  
Author(s):  
Matthew Ryan Banghart ◽  
Shay Quentin Neufeld ◽  
Nicole Christine Wong ◽  
Bernardo Luis Sabatini
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Delta Opioid Receptors

scholarly journals Heteromerization of Endogenous Mu and Delta Opioid Receptors Induces Ligand-Selective Co-Targeting to Lysosomes

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4493 ◽  
Author(s):  
Lyes Derouiche ◽  
Florian Pierre ◽  
Stéphane Doridot ◽  
Stéphane Ory ◽  
Dominique Massotte
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Acid Ethyl Ester ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Therapeutic Drugs ◽  
Delta Opioid Receptors ◽  
The Impact ◽  
Fine Tune ◽  
Intracellular Fate

Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures. We established ligand selective mu–delta co-internalization upon activation by 1-[[4-(acetylamino)phenyl]methyl]-4-(2-phenylethyl)-4-piperidinecarboxylic acid, ethyl ester (CYM51010), [d-Ala2, NMe-Phe4, Gly-ol5]enkephalin (DAMGO), and deltorphin II, but not (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), morphine, or methadone. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors, and led to sorting to the lysosomal compartment. Altogether, our data indicate that mu–delta co-expression, likely through heteromerization, alters the intracellular fate of the mu opioid receptor, which provides a way to fine-tune mu opioid receptor signaling. It also represents an interesting emerging concept for the development of novel therapeutic drugs and strategies.

scholarly journals Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking

2018 ◽  
Author(s):  
Lyes Derouiche ◽  
Muzeyyen Ugur ◽  
Florian Pierre ◽  
Anika Mann ◽  
Stéphane Doridot ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Mu Opioid Receptor ◽  
Endogenous Opioid ◽  
Endogenous Opioid Peptide ◽  
Mu Opioid ◽  
Nociceptive Transmission ◽  
Delta Opioid Receptors ◽  
The Impact

AbstractIncreasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures and in vivo. We established ligand selective mu-delta co-internalization upon activation by exogenous ligands and provide evidence for mu-delta co-internalization by the endogenous opioid peptide met-enkephalin, but not β-endorphin. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors and led to sorting to the lysosomal compartment. This alteration in the mu opioid receptor intracellular fate was accompanied by sustained ERK1/2 phosphorylation. In addition, increased mu-delta neuronal co-localization in the rostral ventromedial medulla in a chronic neuropathic state suggests that mu-delta heteromers are involved in the regulation of nociceptive transmission

Opioid receptors in the accessory optic system of the rat: Effects of monocular enucleation

1990 ◽  
Vol 5 (5) ◽  
pp. 497-506 ◽  
Author(s):  
R.A. Giolli ◽  
R.H.I. Blanks ◽  
Y. Torigoe ◽  
R.J. Clarke ◽  
J.H. Fallon ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Binding ◽  
Mu Opioid Receptor ◽  
Mu Opioid Receptors ◽  
Mu Opioid ◽  
Mu Receptor ◽  
Monocular Enucleation ◽  
Mu Receptors ◽  
Opioid Receptor Binding

AbstractThe presence and concentrations of each of the three subtypes of opioid receptors (mu, kappa, and delta) has been studied in the accessory optic nuclei (dorsal, lateral, and medial terminal nuclei and the interstitial nucleus of the superior fasciculus, posterior fibers: DTN, LTN, MTN, and inSFp) in normal young rats with radioligands directed towards each opioid receptor subtype. The changes in mu opioid receptors have also been investigated in monocularly enucleated rats in which one eye was removed and the rats sacrificed at postoperative day (PO) 2, 3, 5, 7, 14, and 30. As the MTN is the only accessory optic nucleus of the rat large enough for semiquantitative evaluation, the mu receptor population of the MTN has been subjected to optical microdensitometric analysis.All four of the accessory optic nuclei (AOS nuclei) are found to contain exceedingly high levels of mu opioid receptor binding with the selective radioligand [3H]-[D-Ala, MePhe4, Gly-ol5] (DAGO), low levels of kappa opioid receptor binding using the radioligand [3H]-[ethylketocyclazocine] (EKC) together with the competing agents [D-Pro4]-morphiceptin and [D-Ser2, Thr6]-Leu-enkephalin, and an absence of delta opioid receptor binding with the radioligand [3H]-[D-A1a2, D-Leu5]-enkephalin (DADLE) combined with the competing agent [D-Pro4]-morphiceptin. Monocular enucleation, as studied on the mu opioid receptor population with this experimental approach, results in virtually a complete loss of mu opioid receptors throughout all four of the contralaterally located AOS nuclei, including both dorsal and ventral subdivisions of the medial terminal nucleus (MTNd, v). Kappa and delta receptors are very few (kappa receptors) or are lacking (delta receptors) in the AOS nuclei, and for this reason, the effects of monocular enucleation on these two opioid receptor subtypes have not been investigated. Monocular enucleation also produces a significant lowering in mu receptor binding in other primary optic nuclei (the lateral geniculate nuclei, nucleus of the optic tract, and superficial layers of the superior colliculus) and in the pars principalis of the medial geniculate nucleus (description of changes in mu receptors in non-accessory optic primary optic nuclei will be considered elsewhere).Microdensitometric study of the MTNd, v shows that the decreased binding of mu receptors in this nucleus is barely detectable (about 6%) at PO2 and rises to 6–15% at PO3. At PO5 receptor loss reaches approximately 62%, whereas at PO7 it is about 81% complete. At PO14 and PO30, the mu receptor loss is nearly complete at around 93%. Mu receptor loss involves all of the AOS nuclei contralateral, but none ipsilateral, to ocular enucleation, an observation entirely consistent with the overwhelmingly crossed (about 97%) nature of the retinofugal projection to the rat accessory optic nuclei. These opioid receptors represent a prominent feature in the AOS and other primary optic nuclei of the rat. Their role in visuomotor control remains uncertain but probably involves the fine-tuning of information concerned with compensatory eye movements.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

scholarly journals Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5677
Author(s):  
Mariana Spetea ◽  
Helmut Schmidhammer
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Analgesics ◽  
Chronic Administration ◽  
Mu Opioid Receptor ◽  
Receptor Subtype ◽  
Design Strategies ◽  
Mu Opioid ◽  
Multifunctional Ligands

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.

scholarly journals 131 A Marionettist Pulling My Strings: A Case of Buprenorphine-induced Chorea

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 282-283
Author(s):  
Dev Patel ◽  
Ishandeep Gandhi ◽  
Faisal Malek ◽  
Camille Olechowski ◽  
Alan R. Hirsch
Keyword(s):  
Basal Ganglia ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Activation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Mu Opioid ◽  
Palmar Erythema ◽  
History Of

Abstract:Introduction:Choreaform movements provoked by opiates is an infrequent adverse event. Buprenorphine induction of chorea has not heretofore been described. Such a case is presented.METHOD:Case Study: A 38-year-old female presented with a decade long history of alcohol, cocaine, benzodiazepine, and heroin abuse. The patient was insufflating 1.5 grams of heroin daily. On presentation, she was actively withdrawing, scoring 17 on the Clinical Opioid Withdrawal Scale. Urine toxicology screening was positive for opiates, cocaine, and cannabinoids. Buprenorphine 4 mg sublingual was initiated. Within one hour, she observed, “My legs were moving uncontrollably as if I was a marionette.” These dance-like movements were isolated to both legs and gradually resolved after discontinuation of buprenorphine: most of the movements manifested in the first 8 hours, and dissipated over the next 2 days. She did have similar movements after treatment with quetiapine during a previous hospitalization, years earlier.RESULTS:Abnormalities in physical examination: General: goiter, bilateral palmar erythema. Neurological examination: Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 2 (anosmia). Motor Examination: Drift testing: mild right pronator drift. Reflexes: 3+ bilateral lower extremities. Neuropsychiatric Examination: Clock Drawing Test: 3 (abnormal). Animal Fluency Test: 18 (normal). Go-No-Go Test 6/6 (normal).DISCUSSION:Buprenorphine induced chorea could be a result of partial mu-opioid agonism, or kappa and delta receptor antagonism (Burke, 2018; Cowan, 1977). Mu-opioid receptor activation causes increased dopamine turnover in the nigrostriatum, which is responsible for locomotor sensitization (Campos-Jurado, 2017). With the addition of mu-opioid receptor modulation of dopamine release, kappa-opioid receptor alters various neurotransmitters in the basal ganglia, potentiating hyperkinetic movements. Buprenorphine’s choreiformogenic action may be due to kappa-opioid receptors ability to augment neurotransmission in the striatum (Escobar, 2017; Bonnet, 1998). The combination of simultaneous activity of these three opioid receptors may cause chorea, since they act to modulate dopamine, glutamate, and GABA in the direct and indirect pathways within the basal ganglia (Abin, 1989; Cui, 2013; Allouche, 2014; Trifilieff, 2013). This patient’s history of heroin and cocaine use may have caused supersensitization of dopamine receptors (Memo, 1981), provoking hyperkinesia. Involvement of substance-induced sensitization with concurrent kappa-opioid receptor neurotransmitter augmentation in direct and indirect pathways in the basal ganglia may have primed our patient to the development of chorea after buprenorphine administration. Further investigation for the presence of extrapyramidal movements in those undergoing buprenorphine treatment is warranted.

scholarly journals Wet cupping therapy improves mu opioid receptor expression and pain threshold in animal models of inflammation

2020 ◽  
Author(s):  
Imam Subadi ◽  
Martha Kurnia Kusumawardani ◽  
Mohammad Fathul Qorib ◽  
Imam Susilo ◽  
Hanik Badriyah Hidayati
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Pain Threshold ◽  
Threshold Value ◽  
Mu Opioid Receptor ◽  
Cupping Therapy ◽  
Receptor Expression ◽  
Control Group ◽  
Mu Opioid Receptors ◽  
Mu Opioid

Background & Objectives: Treatment of chronic pain using NSAIDs, steroids, opioids, and herbs has been associated with many complications with the long-term use. Wet cupping therapy (WCT) has been used to reduce pain, by triggering mu opioid receptor expression. We conducted this study to compare the effectiveness between WCT with oral opioids for pain management. Methodology: It was an experimental study with randomized control group post-test only design. Thirty two male white rats of strain Wistar were divided into four groups: (1) Group-NC; mice in this group were given nothing as a negative control group, (2) Group-CFA; group that was given Complete Freund’s Adjuvant (CFA) only as a positive control group, (3) Group-WCT; mice were given CFA and WCT, and (4) Group-O was given CFA and oral opioids. The measured variables were pain threshold value and mu opioid receptors. Statistical analysis was done us(ing SPSS software (version 22.0, Chicago, IL). Results: The results showed no significant differences in the expression of mu opioid receptors between Group-NC and Group-CFA (p = 0.061). There were significant differences in the expression of opioid receptors between Group-CFA and Group-WCT (p < 0.001), and also between WCT group and Group-O (p = 0.002). The differences of pain threshold value were only significant between Group-NC (p = 0,006) and Group-CFA (p = 0,013) with Group-O. Conclusion: Wet cupping therapy triggers the expression of mu opioid receptors. Wet cupping therapy as effective in relieving pain as opioids. Citation: Subadi I, Kusumawardani MK, Qorib MF, Susilo I, Hidayati HB. Wet cupping therapy improves mu opioid receptor expression and pain threshold in animal models of inflammation. Anaesth pain & intensive care 2019;23(4):__   Received: 6 February 2019; Reviewed: 16 February 2019, 2 August 2019; Revised: 9 September 2019; Accepted: 15 September 2019

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