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1.
Mol Pharmacol ; 98(2): 96-108, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32487735

RESUMO

In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, >20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors, proenkephalin, prodynorphin, and proopiomelanocortin, by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides binds to all three of the opioid receptor types (µ, δ, or κ), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in the brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been used to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e., to excised tissue) or in vivo (in animals), using antagonists of opioid receptors to infer endogenous peptide activity, and genetic knockout of opioid peptide precursors. Collectively, these studies add to our current understanding of the function of endogenous opioids, especially when similar results are found using different approaches. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects, including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.


Assuntos
Peptídeos Opioides/genética , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Animais , Encéfalo/metabolismo , Carboxipeptidase H/metabolismo , Encefalinas/química , Encefalinas/genética , Humanos , Pró-Opiomelanocortina/química , Pró-Opiomelanocortina/genética , Pró-Proteína Convertases/metabolismo , Precursores de Proteínas/química , Precursores de Proteínas/genética
2.
Medicine (Baltimore) ; 99(22): e20429, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481444

RESUMO

Determining the clinically optimal dose in methadone maintenance therapy (MMT) is a time-consuming procedure, which considers clinical signs and symptoms.To perform a quantitative trait locus association for identifying genetic variants for MMT dosage that underlie heroin addiction and methadone metabolism and then integrate several genotypic and phenotypic factors are potential predictors for clinically optimal MMT dose for personalized prescription.In total, 316 heroin-dependent patients undergoing MMT were recruited at the Addiction Center of the China Medical University Hospital. A multinomial logistic regression model was used to assess associations between genetic polymorphisms and MMT dosing. The data were randomly separated into training and testing sets. In order to enhance the prediction accuracy and the reliability of the prediction model, we used areas under the receiver operating characteristic curves to evaluate optimal MMT dose in both training and testing sets.Four single nucleotide polymorphisms, namely rs806368 in CNR1, s1386493 in TPH2, s16974799 in CYP2B6, and rs2229205 in OPRL1, were significantly associated with the maximum MMT dose (P < .05). The genetic risk score (GRS) was associated with maximum MMT dose, and after adjustments for age, sex, and body mass index, the GRS remained independently associated with the maximum MMT dose. The area under the receiver operating characteristic curve of the combined GRS and craving score was 0.77 for maximum MMT dose, with 75% sensitivity and 60% specificity.Integrating the GRS and craving scores may be useful in the evaluation of individual MMT dose requirements at treatment initiation. Optimal dose prediction allows clinicians to tailor MMT to each patient's needs.


Assuntos
Fissura , Dependência de Heroína/tratamento farmacológico , Dependência de Heroína/genética , Metadona/administração & dosagem , Entorpecentes/administração & dosagem , Medicina de Precisão , Adulto , Citocromo P-450 CYP2B6/genética , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Masculino , Tratamento de Substituição de Opiáceos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptor CB1 de Canabinoide/genética , Receptores Opioides/genética , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Triptofano Hidroxilase/genética
4.
Nihon Yakurigaku Zasshi ; 155(3): 145-148, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378631

RESUMO

Alcohol dependence is one of the psychiatric disorders affecting over 1 million people in Japan. Mesolimbic dopamine neuron projecting from ventral tegmental area to nucleus accumbens (Reward system) plays important roles in alcohol dependence including other dependence. Accumulating evidence indicates that the endogenous opioid system regulate this reward system. That is, alcohol stimulates the release of endogenous opioid peptides such as ß-endorphin and dynorphin in the brain. ß-endorphin activates µ-opioid receptor leading to euphoric mood and positive reinforcement, while dynorphin activates κ-opioid receptor leading to dysphoric mood and negative reinforcement. These euphoric/dysphoric mood and reinforcement effects via endogenous opioid systems are suggested to be implicated in repeated alcohol intake in patients with alcohol dependence. Nalmefene acts as an antagonist at µ- and δ-opioid receptor and a partial agonist at κ-opioid receptor. Preclinical studies have shown that nalmefene reduced the alcohol intake in alcohol preference rats. In clinical trials, as-needed use of nalmefene with psychosocial support reduced the number of heavy-drinking days and total alcohol consumption. These results suggest that nalmefene modulates the alcohol-induced euphoric/dysphoric mood via opioid system and thereby contribute to reduction in alcohol consumption in patients with alcohol dependence. Here, we summarize the implications of opioid system in alcohol dependence and pharmacological profiles of nalmefene in preclinical and clinical studies.


Assuntos
Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/agonistas , Animais , Ensaios Clínicos como Assunto , Humanos , Japão , Naltrexona/farmacologia , Ratos
5.
Proc Natl Acad Sci U S A ; 117(21): 11820-11828, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393639

RESUMO

Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The "Opioid Epidemic" has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (µ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([35S]GTPγS binding and ß-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of ß-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.


Assuntos
Peptídeos Opioides , Receptores Opioides/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Peptídeos Opioides/agonistas , Peptídeos Opioides/metabolismo , Pró-Opiomelanocortina/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley
6.
Neuron ; 106(6): 940-951.e4, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32298640

RESUMO

Itch and pain are distinct unpleasant sensations that can be triggered from the same receptive fields in the skin, raising the question of how pruriception and nociception are coded and discriminated. Here, we tested the multimodal capacity of peripheral first-order neurons, focusing on the genetically defined subpopulation of mouse C-fibers that express the chloroquine receptor MrgprA3. Using optogenetics, chemogenetics, and pharmacology, we assessed the behavioral effects of their selective stimulation in a wide variety of conditions. We show that metabotropic Gq-linked stimulation of these C-afferents, through activation of native MrgprA3 receptors or DREADDs, evokes stereotypical pruriceptive rather than nocifensive behaviors. In contrast, fast ionotropic stimulation of these same neurons through light-gated cation channels or native ATP-gated P2X3 channels predominantly evokes nocifensive rather than pruriceptive responses. We conclude that C-afferents display intrinsic multimodality, and we provide evidence that optogenetic and chemogenetic interventions on the same neuronal populations can drive distinct behavioral outputs.


Assuntos
Channelrhodopsins/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Neurônios Aferentes/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Prurido/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Trifosfato de Adenosina , Animais , Cloroquina , Gânglios Espinais/metabolismo , Peptídeo Liberador de Gastrina/metabolismo , Luz , Camundongos , Neurônios Aferentes/fisiologia , Optogenética , Receptores Opioides/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo
7.
Neuron ; 106(6): 1009-1025.e10, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32302532

RESUMO

Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOCARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOCARC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOCARC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiologia , Dieta Hiperlipídica , Comportamento Alimentar/fisiologia , Neurônios GABAérgicos/fisiologia , Hiperfagia , Obesidade , Ganho de Peso/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Neurônios GABAérgicos/metabolismo , Camundongos , Inibição Neural/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Optogenética , Pró-Opiomelanocortina/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo , Núcleos Septais/fisiologia
8.
PLoS One ; 15(3): e0229646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126112

RESUMO

Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.


Assuntos
Mitragyna/química , Plantas Medicinais/química , Alcaloides de Triptamina e Secologanina/química , Animais , Sítios de Ligação , Células HEK293 , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Ensaio Radioligante , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/metabolismo , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Alcaloides de Triptamina e Secologanina/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacologia , Relação Estrutura-Atividade
9.
PLoS One ; 15(3): e0229761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155179

RESUMO

Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system.


Assuntos
Gânglios Parassimpáticos/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Cíclicos/farmacologia , Glândulas Salivares/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Sítios de Ligação , Gânglios Parassimpáticos/metabolismo , Gânglios Parassimpáticos/fisiologia , Masculino , Camundongos , Morfina/farmacologia , Nociceptividade , Ligação Proteica , Receptores Opioides/química , Receptores Opioides/metabolismo , Saliva/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiologia
10.
J Med Chem ; 63(5): 2688-2704, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31951130

RESUMO

A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds 4, 5, and 9 with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD. Further, unlike NOP antagonists, which appear to worsen dyskinesia expression, these NOP partial agonists did not attenuate or worsen dyskinesia expression. The NOP partial agonists and their SAR reported here may be useful to develop nondopaminergic treatments for PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Indóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptores Opioides/agonistas , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Células CACO-2 , Modelos Animais de Doenças , Humanos , Indóis/química , Indóis/farmacocinética , Masculino , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
11.
J Neuroimmunol ; 340: 577145, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31945593

RESUMO

Lavandula angustifolia (LaEO) essential oil has been widely used by aromatherapy in the treatment of various clinical conditions, with evidence of its analgesic and anti-inflammatory potential. Our results demonstrate that sixty-five substances were identified in LaEO. Among the compounds found, the major ones were linalool (30.61%) and linalyl acetate (20.36%). We found that LaEO inhalation reduces mechanical hyperalgesia in conditions of chronic inflammatory and neuropathic pain. Furthermore, this effect seems to be mediated by peripheral and central opioid and cannabinoid 2 receptors. The findings of the present study suggests that the LaEO inhalation is effective on the chronic pain treatment.


Assuntos
Hiperalgesia , Óleos Voláteis/farmacologia , Receptores de Canabinoides/metabolismo , Receptores Opioides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hiperalgesia/metabolismo , Inflamação/metabolismo , Lavandula , Camundongos , Neuralgia/metabolismo , Extratos Vegetais/farmacologia
12.
J Immunol ; 204(5): 1188-1200, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31969385

RESUMO

Endogenous opioid peptides are released at sites of injury, and their cognate G protein-coupled opioid receptors (ORs) are expressed on immune cells. Although drugs of misuse appropriate ORs, conflicting reports indicate immunostimulatory and immunosuppressive activity, in that opioid users have elevated infection risk, opioids activate innate immune cells, and opioids attenuate inflammation in murine T cell-mediated autoimmunity models. The i.v. use of drugs transmits bloodborne pathogens, particularly viruses, making the study of CD8+ T cells timely. From a cohort of nonuser controls and methadone users, we demonstrate, via t-Stochastic Neighbor Embedding and k-means cluster analysis of surface marker expression, that chronic opioid use alters human CD8+ T cell subset balance, with notable decreases in T effector memory RA+ cells. Studying global CD8+ T cell populations, there were no differences in expression of OR and several markers of functionality, demonstrating the need for finer analysis. Purified CD8+ T cells from controls respond to opioids ex vivo by increasing cytoplasmic calcium, a novel finding for OR signal transduction, likely because of cell lineage. CD8+ T cells from controls exposed to µ-OR agonists ex vivo decrease expression of activation markers CD69 and CD25, although the same markers are elevated in µ-OR-treated cells from methadone users. In contrast to control cells, T cell subsets from methadone users show decreased expression of CD69 and CD25 in response to TCR stimulus. Overall, these results indicate a direct, selective role for opioids in CD8+ T cell immune regulation via their ability to modulate cell responses through the opioid receptors and TCRs.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Metadona/efeitos adversos , Receptores de Antígenos/imunologia , Receptores Opioides/imunologia , Transdução de Sinais/imunologia , Transtornos Relacionados ao Uso de Substâncias/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/imunologia , Masculino , Transtornos Relacionados ao Uso de Substâncias/patologia
13.
Proc Natl Acad Sci U S A ; 117(5): 2656-2662, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31941713

RESUMO

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Ketamina/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Animais , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo
14.
J Pharmacol Exp Ther ; 373(1): 34-43, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31937563

RESUMO

The peptide nociceptin/orphanin FQ (N/OFQ) is the natural ligand of the N/OFQ receptor (NOP), which is widely expressed in the central and peripheral nervous system. Selective NOP antagonists are worthy of testing as innovative drugs to treat depression, Parkinson disease, and drug abuse. The aim of this study was to perform a detailed in vitro characterization of BTRX-246040 (also known as LY2940094, [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol), a novel NOP antagonist that has been already studied in humans. BTRX-246040 has been tested in vitro in the following assays: calcium mobilization in cells expressing NOP and classic opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer assay measuring NOP interaction with G proteins and ß-arrestins, the label-free dynamic mass redistribution assay, and the electrically stimulated mouse vas deferens. BTRX-246040 was systematically compared with the standard NOP antagonist SB-612111. In all assays, BTRX-246040 behaves as a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3-10-fold higher potency than the standard antagonist SB-612111. BTRX-246040 is an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists in preclinical and clinical studies. SIGNIFICANCE STATEMENT: NOP antagonists may be innovative antidepressant drugs. In this research, the novel clinically viable NOP antagonist BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent, and selective NOP antagonist.


Assuntos
Piranos/farmacologia , Receptores Opioides/fisiologia , Compostos de Espiro/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos
15.
J Agric Food Chem ; 68(7): 1877-1883, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31402656

RESUMO

The antihypertensive activity of two αs1-casein-derived peptides and casein hydrolysate containing these sequences was evaluated in the presence of naloxone. The activity was abolished by this opioid antagonist at 2, 4, and 6 h post-administration. Similarly, the antihypertensive effect of the αs1-casein peptides 90RYLGY94 (-23.8 ± 2.5 mmHg) and 143AYFYPEL149 (-21.1 ± 3.2 mmHg) at 5 mg/kg of body weight was antagonized by the co-administration of naloxone. Because peptide 143AYFYPEL149 had recently shown opioid activity, a molecular dynamic simulation of this peptide with human µ-opioid receptor was performed to demonstrate its favorable structure and interaction energy, despite the presence of Ala at the N terminus. Altogether, these results revealed that the in vivo effect on systolic blood pressure of the studied αs1-casein peptides is mediated by interaction with opioid receptors and the antihypertensive activity of casein hydrolysate can be very likely ascribed to them with the possible contribution of other mechanisms.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Caseínas/administração & dosagem , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Receptores Opioides/metabolismo , Animais , Anti-Hipertensivos/química , Caseínas/química , Bovinos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Simulação de Dinâmica Molecular , Naloxona/administração & dosagem , Peptídeos/química , Ratos , Ratos Endogâmicos SHR , Receptores Opioides/química , Receptores Opioides/genética
17.
N Engl J Med ; 382(3): 222-232, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31702883

RESUMO

BACKGROUND: Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients undergoing hemodialysis who had moderate-to-severe pruritus to receive either intravenous difelikefalin (at a dose of 0.5 µg per kilogram of body weight) or placebo three times per week for 12 weeks. The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). The secondary outcomes included the change from baseline in itch-related quality-of-life measures, the percentage of patients with an improvement of at least 4 points in the WI-NRS score at week 12, and safety. RESULTS: A total of 378 patients underwent randomization. A total of 82 of 158 patients (51.9%) in the difelikefalin group had a decrease of at least 3 points in the WI-NRS score (primary outcome), as compared with 51 of 165 (30.9%) in the placebo group. The imputed percentage of patients with a decrease of at least 3 points in the WI-NRS score was 49.1% in the difelikefalin group, as compared with 27.9% in the placebo group (P<0.001). Difelikefalin also resulted in a significant improvement from baseline to week 12 in itch-related quality of life as measured by the 5-D itch scale and the Skindex-10 scale. The imputed percentage of patients with a decrease of at least 4 points in the WI-NRS score at week 12 was significantly greater in the difelikefalin group than in the placebo group (37.1% [observed data: 64 of 158 patients] vs. 17.9% [observed data: 35 of 165 patients], P<0.001). Diarrhea, dizziness, and vomiting were more common in the difelikefalin group than in the placebo group. CONCLUSIONS: Patients treated with difelikefalin had a significant reduction in itch intensity and improved itch-related quality of life as compared with those who received placebo. (Funded by Cara Therapeutics; KALM-1 ClinicalTrials.gov number, NCT03422653.).


Assuntos
Falência Renal Crônica/complicações , Piperidinas/uso terapêutico , Prurido/tratamento farmacológico , Receptores Opioides/agonistas , Diálise Renal , Uremia/complicações , Adulto , Método Duplo-Cego , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Prurido/etiologia , Qualidade de Vida , Resultado do Tratamento
18.
Curr Med Chem ; 27(9): 1562-1575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31057099

RESUMO

Morphine and related drugs that act through activating opioid receptors are the most effective analgesics for the relief of severe pain. They have been used for decades, despite the range of unwanted side effects that they produce, as no alternative has been found so far. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists and to improve the therapeutic utility of opioid drugs. In the search for safer and more potent analgesics, analogs with mixed opioid receptor profile gained a lot of interest. However, recently the concept of biased agonism, that highlights the fact that some ligands are able to differentially activate receptor downstream pathways, became a new approach in the design of novel drug candidates for clinical application. In this review, we summarize current knowledge on the development of opioid ligands of peptide and nonpeptide structure, showing how much opioid pharmacology evolved in recent years.


Assuntos
Manejo da Dor , Analgésicos , Analgésicos Opioides , Humanos , Dor , Receptores Opioides
19.
Support Care Cancer ; 28(3): 1083-1088, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31183560

RESUMO

BACKGROUND: Opioid-induced nausea and vomiting (OINV) is induced by opioid receptor stimulation of chemoreceptor trigger zones and vestibular apparatus by opioids. Naldemedine tosylate (NALD) is a peripherally acting non-selective opioid receptor antagonist, used for opioid-induced constipation (OIC). However, the effect of NALD on OINV had not yet been investigated. In this retrospective study, we investigated the secondary effects of NALD on OINV. METHOD: Patients who received sustained-release oral morphine or oxycodone preparation were enrolled in the study. Patients who used NALD (0.2 mg) within 2 days of opioid initiation were included in the analysis. The use of rescue antiemetics within 7 days from opioid initiation was defined as OINV expression. Patients who received antiemetics before opioid initiation or those who received chemotherapy around 4 days from opioid initiation were excluded from the analysis. The incidence of OINV was compared between patients who used and did not use NALD. RESULTS: In total, 982 patients were included in the study. Among them, 89 patients who received NALD and 614 patients who did not receive NALD were analyzed. The incidence of OINV in patients who used NALD was significantly lower than that of patients who did not use NALD (36.0% vs. 47.2%, p = 0.046). CONCLUSION: For patients with constipation, using NALD at an early stage of opioid initiation might have secondary benefits, such as relief from OINV, besides improvement of OIC. To confirm the effectiveness of NALD for OINV, the symptom grade and intensity during concomitant use of NALD should be observed in a future study.


Assuntos
Analgésicos Opioides/efeitos adversos , Antieméticos/uso terapêutico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Náusea/prevenção & controle , Vômito/prevenção & controle , Idoso , Analgésicos Opioides/uso terapêutico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/prevenção & controle , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Morfina/uso terapêutico , Naltrexona/uso terapêutico , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Oxicodona/efeitos adversos , Oxicodona/uso terapêutico , Receptores Opioides/efeitos dos fármacos , Estudos Retrospectivos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico
20.
J Ethnopharmacol ; 248: 112276, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31593812

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum Epling & Játiva is a Mexican plant used not only in rituals but also in traditional medicine for pain relief. One of the most known bioactive compounds is salvinorin A, which acts centrally in kappa-type opioid receptors. AIM OF THE STUDY: Despite its traditional use as a medicinal plant, there is not enough scientific investigation to reinforce its potential as analgesic. In this study, Salvia divinorum antinociceptive activity was evaluated in experimental models of nociceptive pain; the writhing test and formalin-induced licking behavior in mice. MATERIAL AND METHODS: Different Salvia divinorum extracts were prepared by maceration at room temperature in increased polarity (hexane, ethyl acetate and methanol). The ethyl acetate extract (EAEx) was chosen in order to be fractioned and to obtain a mixture of salvinorins. The antinociceptive effect of EAEx (3, 10, 30, and 100 mg/kg, i.p.) was compared with that of tramadol (a partial opioid agonist analgesic drug, 30 mg/kg, i.p.) and the mixture of salvinorins (30 mg/kg, i.p.). In addition, a participation of opioids (naloxone, NX 1 and/or 3 mg/kg, i.p.) and serotonin 5-HT1A receptors (WAY100635, 0.32 mg/kg, i.p.) was investigated as possible inhibitory neurotransmission involved. RESULTS: As a result, the EAEx produced significant and dose-dependent antinociceptive effect concerning salvinorins constituents. This effect was blocked in the presence of NX and WAY100635 in the abdominal test, but only by NX in the formalin-induced licking behavior. Whereas, the effect of salvinorins mixture involved opioids and serotonin 5-HT1A receptors. CONCLUSION: Data provide evidence of the potential of this species, where salvinorin A is in part responsible bioactive constituent involving participation of the opioids and/or 5-HT1A serotonin receptors depending on the kind of pain model explored.


Assuntos
Analgésicos/uso terapêutico , Diterpenos Clerodânicos/uso terapêutico , Dor/tratamento farmacológico , Salvia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Folhas de Planta , Receptor 5-HT1A de Serotonina/fisiologia , Receptores Opioides/fisiologia
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