Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900	Submit
Journal of Clinical Medicine jcm	3.0	5.7	2012	16 Days	CHF 2600	Submit
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700	Submit
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900	Submit
Pharmaceutics pharmaceutics	4.9	7.9	2009	15.5 Days	CHF 2900	Submit
Chemistry chemistry	2.4	3.2	2019	17.2 Days	CHF 1800	Submit

17 pages, 2760 KiB

Open AccessArticle

Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine

by Anna Rita Galambos, Nariman Essmat, Péter P. Lakatos, Edina Szücs, Imre Boldizsár, Jr., Sarah Kadhim Abbood, Dávid Á. Karádi, Judit Mária Kirchlechner-Farkas, Kornél Király, Sándor Benyhe, Pál Riba, Tamás Tábi, Laszlo G. Harsing, Jr., Ferenc Zádor and Mahmoud Al-Khrasani

Int. J. Mol. Sci. 2024, 25(20), 11136; https://doi.org/10.3390/ijms252011136 - 17 Oct 2024

Viewed by 1646

Abstract

Opioid analgesic tolerance (OAT), among other central side effects, limits opioids’ indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement [...] Read more.

Opioid analgesic tolerance (OAT), among other central side effects, limits opioids’ indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine–NFPS combination, NFPS alone, or vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine–NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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34 pages, 6343 KiB

Open AccessReview

Opioid-Based Haptens: Development of Immunotherapy

by Sándor Hosztafi, Anna Rita Galambos, István Köteles, Dávid Á Karádi, Susanna Fürst and Mahmoud Al-Khrasani

Int. J. Mol. Sci. 2024, 25(14), 7781; https://doi.org/10.3390/ijms25147781 - 16 Jul 2024

Cited by 4 | Viewed by 2520

Abstract

Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated [...] Read more.

Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated as haptens to a carrier protein will elicit the production of antibodies capable of reacting specifically with the unconjugated hapten or its parent compound. The position of the attachment in opioid haptens to the carrier protein will influence the specificity of the antiserum produced in immunized animals with the hapten–carrier conjugate. Immunoassays for the determination of opioid drugs are based on the ability of drugs to inhibit the reaction between drug-specific antibodies and the corresponding drug–carrier conjugate or the corresponding labelled hapten. Pharmacological studies of the hapten–carrier conjugates resulted in the development of vaccines for treating opioid use disorders (OUDs). Immunotherapy for opioid addiction includes the induction of anti-drug vaccines which are composed of a hapten, a carrier protein, and adjuvants. In this review we survey the design of opioid haptens, the development of the opioid radioimmunoassay, and the results of immunotherapy for OUDs. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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13 pages, 2051 KiB

Open AccessArticle

A Bicyclic Analog of the Linear Peptide Arodyn Is a Potent and Selective Kappa Opioid Receptor Antagonist

by Solomon A. Gisemba, Michael J. Ferracane, Thomas F. Murray and Jane V. Aldrich

Molecules 2024, 29(13), 3109; https://doi.org/10.3390/molecules29133109 - 29 Jun 2024

Cited by 1 | Viewed by 1409

Abstract

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe^1,2,3,Arg⁴,D-Ala⁸]dynorphin A-(1–11)-NH₂) exhibits potent and selective kappa opioid receptor [...] Read more.

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe^1,2,3,Arg⁴,D-Ala⁸]dynorphin A-(1–11)-NH₂) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure–activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide’s affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [³⁵S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (K_i = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [³⁵S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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17 pages, 1907 KiB

Open AccessArticle

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

by Nadine Hochrainer, Pawel Serafin, Sara D’Ingiullo, Adriano Mollica, Sebastian Granica, Marek Brytan, Patrycja Kleczkowska and Mariana Spetea

Int. J. Mol. Sci. 2024, 25(7), 4007; https://doi.org/10.3390/ijms25074007 - 3 Apr 2024

Cited by 2 | Viewed by 1680

Abstract

Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We [...] Read more.

Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [³⁵S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01’s properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 3518 KiB

Open AccessArticle

SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis

by Takashi Iwai, Rei Mishima, Shigeto Hirayama, Honoka Nakajima, Misa Oyama, Shun Watanabe, Hideaki Fujii and Mitsuo Tanabe

J. Clin. Med. 2024, 13(2), 608; https://doi.org/10.3390/jcm13020608 - 21 Jan 2024

Cited by 1 | Viewed by 1653

Abstract

The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse [...] Read more.

The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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31 pages, 7792 KiB

Open AccessArticle

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

by Madhurima Das, George W. Ward, Agnieszka Sulima, Dan Luo, Thomas Edward Prisinzano, Gregory H. Imler, Andrew T. Kerr, Arthur E. Jacobson and Kenner C. Rice

Molecules 2023, 28(23), 7709; https://doi.org/10.3390/molecules28237709 - 22 Nov 2023

Cited by 1 | Viewed by 1726

Abstract

(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5 [...] Read more.

(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC₅₀ = 12 nM), and was fully efficacious (%E_max = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (−)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 3479 KiB

Open AccessArticle

Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide

by Yangmei Li, Shainnel O. Eans, Michelle Ganno-Sherwood, Abbe Eliasof, Richard A. Houghten and Jay P. McLaughlin

Molecules 2023, 28(22), 7548; https://doi.org/10.3390/molecules28227548 - 11 Nov 2023

Cited by 5 | Viewed by 1871

Abstract

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples [...] Read more.

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED₅₀ (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED₅₀ value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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48 pages, 15800 KiB

Open AccessReview

From Plant to Chemistry: Sources of Active Opioid Antinociceptive Principles for Medicinal Chemistry and Drug Design

by Rita Turnaturi, Silvia Piana, Salvatore Spoto, Giuliana Costanzo, Lorena Reina, Lorella Pasquinucci and Carmela Parenti

Molecules 2023, 28(20), 7089; https://doi.org/10.3390/molecules28207089 - 14 Oct 2023

Cited by 7 | Viewed by 5598

Abstract

Pain continues to be an enormous global health challenge, with millions of new untreated or inadequately treated patients reported annually. With respect to current clinical applications, opioids remain the mainstay for the treatment of pain, although they are often associated with serious side [...] Read more.

Pain continues to be an enormous global health challenge, with millions of new untreated or inadequately treated patients reported annually. With respect to current clinical applications, opioids remain the mainstay for the treatment of pain, although they are often associated with serious side effects. To optimize their tolerability profiles, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery, and they hold potential for pain management. Traditional medicine has had a long history in clinical practice due to the fact that nature provides a rich source of active principles. For instance, opium had been used for pain management until the 19th century when its individual components, such as morphine, were purified and identified. In this review article, we conducted a literature survey aimed at identifying natural products interacting either directly with opioid receptors or indirectly through other mechanisms controlling opioid receptor signaling, whose structures could be interesting from a drug design perspective. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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19 pages, 2431 KiB

Open AccessArticle

Discovery of 7-Azanorbornane-Based Dual Agonists for the Delta and Kappa Opioid Receptors through an In Situ Screening Protocol

by Fumika Karaki, Taro Takamori, Koumei Kawakami, Sae Sakurai, Kyoko Hidaka, Kei Ishii, Tomoya Oki, Noriko Sato, Nao Atsumi, Karin Ashizawa, Ai Taguchi, Asuka Ura, Toko Naruse, Shigeto Hirayama, Miki Nonaka, Kanako Miyano, Yasuhito Uezono and Hideaki Fujii

Molecules 2023, 28(19), 6925; https://doi.org/10.3390/molecules28196925 - 3 Oct 2023

Cited by 3 | Viewed by 1694

Abstract

In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method [...] Read more.

In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method for transmembrane proteins has not been validated due to the incompatibility with copper catalysts. To address this point, we performed ligand screening for the µ, δ, and κ opioid receptors using this protocol. As we had previously reported the 7-azanorbornane skeleton as a privileged scaffold for the G protein-coupled receptors, we performed the click reactions between various 7-substituted 2-ethynyl-7-azanorbornanes and azides. Screening assays were performed without purification using the CellKey^TM system, and the putative hit compounds were re-synthesized and re-evaluated. Although the “hit” compounds for the µ and the δ receptors were totally inactive after purifications, three of the four “hits” for the κ receptor were true agonists for this receptor and also showed activities for the δ receptor. Although false positive/negative results exist as in other screening projects for soluble proteins, this in situ method is effective in identifying novel ligands for transmembrane proteins. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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22 pages, 3844 KiB

Open AccessArticle

The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors

by Ross van de Wetering, Amy Ewald, Susan Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D. McElroy, Eduardo R. Butelman, Thomas E. Prisinzano and Bronwyn M. Kivell

Molecules 2023, 28(12), 4848; https://doi.org/10.3390/molecules28124848 - 19 Jun 2023

Cited by 5 | Viewed by 2868

Abstract

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo [...] Read more.

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light–dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 10337 KiB

Open AccessArticle

Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level

by Peng-Cheng Yu, Cui-Yun Hao, Ying-Zhe Fan, Di Liu, Yi-Fan Qiao, Jia-Bao Yao, Chang-Zhu Li and Ye Yu

Pharmaceuticals 2023, 16(2), 282; https://doi.org/10.3390/ph16020282 - 13 Feb 2023

Cited by 8 | Viewed by 3282

Abstract

Morphine, one of the most efficacious analgesics, is effective in severe pain, especially in patients with concomitant painful cancers. The clinical use of morphine may be accompanied by increased immunosuppression, susceptibility to infection and postoperative tumor metastatic recurrence, and the specific mechanisms and [...] Read more.

Morphine, one of the most efficacious analgesics, is effective in severe pain, especially in patients with concomitant painful cancers. The clinical use of morphine may be accompanied by increased immunosuppression, susceptibility to infection and postoperative tumor metastatic recurrence, and the specific mechanisms and clinical strategies to alleviate this suppression remain to be investigated. Expression of CD11b is closely associated with the macrophage phagocytosis of xenobiotic particles, bacteria or tumor cells. Here, we find that morphine at 0.1–10 nM levels inhibited CD11b expression and function on macrophages via a μ-opioid receptor (MOR)-dependent mechanism, thereby reducing macrophage phagocytosis of tumor cells, a process that can be reversed by thymopentin (TP5), a commonly used immune-enhancing adjuvant in clinical practice. By knocking down or overexpressing MOR on macrophages and using naloxone, an antagonist of the MOR receptor, and LA1, a molecule that promotes macrophage CD11b activation, we suggest that morphine may regulate macrophage phagocytosis by inhibiting the surface expression and function of macrophage CD11b through the membrane expression and activation of MOR. The CD47/SIRPα axis, which is engaged in macrophage-tumor immune escape, was not significantly affected by morphine. Notably, TP5, when combined with morphine, reversed the inhibition of macrophage phagocytosis by morphine through mechanisms that promote membrane expression of CD11b and modulate its downstream signaling (e.g., NOS2, IFNG, IL1B and TNFA, as well as AGR1, PDGFB, IL6, STAT3, and MYC). Thus, altered membrane expression and function of CD11b may mediate the inhibition of macrophage phagocytosis by therapeutic doses of morphine, and the reversal of this process by TP5 may provide an effective palliative option for clinical immunosuppression by morphine. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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15 pages, 5677 KiB

Open AccessArticle

Delta Opioid Peptide Targets Brain Microvascular Endothelial Cells Reducing Apoptosis to Relieve Hypoxia-Ischemic/Reperfusion Injury

by Ran Zhang, Meixuan Chen, Zhongfang Deng, Lingchao Kong, Bing Shen and Lesha Zhang

Pharmaceutics 2023, 15(1), 46; https://doi.org/10.3390/pharmaceutics15010046 - 23 Dec 2022

Cited by 3 | Viewed by 2775

Abstract

Stroke is one of the leading causes of death. (D-ala2, D-leu5) enkephalin (DADLE) is a synthetic peptide and highly selective delta opioid receptor (δOR) agonist that has exhibited protective properties in ischemia. However, the specific target and mechanism are still unclear. The present [...] Read more.

Stroke is one of the leading causes of death. (D-ala2, D-leu5) enkephalin (DADLE) is a synthetic peptide and highly selective delta opioid receptor (δOR) agonist that has exhibited protective properties in ischemia. However, the specific target and mechanism are still unclear. The present study explores the expression of δOR on brain microvascular endothelial cells (BMECs) and whether DADLE could relieve I/R-induced injury by reducing apoptosis. A lateral ventricular injection of DADLE for pretreatment, the neurofunctional behavior score, and TTC staining, were used to evaluate the protective effect of DADLE. Immunofluorescence technology was used to label different types of cells with apoptosis-positive signals to test co-localization status. Primary cultured BMECs were separated and treated with DADLE, accompanied by OGD/R. The CCK-8 test was conducted to evaluate cell viability and TdT-mediated dUTP Nick-end Labelling (TUNEL) staining to test apoptosis levels. The levels of apoptosis-related proteins were analyzed by Western blotting. The co-localization results showed that BMECs, but not astrocytes, microglia, or neurons, presented mostly TUNEL-positive signals, especially in the Dentate gyrus (DG) area of the hippocampus. Either activation of δORs on rats’ brains or primary BMECs mainly reduce cellular apoptosis and relieve the injury. Interference with the expression δOR could block this effect. DADLE also significantly increased levels of Bcl-2 and reduced levels of Bax. δOR’s expressions can be detected on the BMECs, but not on the HEK293 cells, by Western blotting and IFC. Therefore, DADLE exerts a cytoprotective effect, primarily under hypoxia-ischemic injury/reperfusion conditions, by targeting BMECs to inhibit apoptosis. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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