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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.
Nature ; 580(7803): 376-380, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296182

RESUMO

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.


Assuntos
Ingestão de Alimentos , Retroalimentação , Neurônios/fisiologia , Animais , Encefalinas/genética , Encefalinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Trato Gastrointestinal Superior/fisiologia
4.
Gene ; 742: 144583, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184167

RESUMO

BACKGROUND: Studies showed that increased let-7b-5p microRNA during repeated electroacupuncture (EA) treatment was associated the formation of EA tolerance, which manifested as gradually decreased nociceptive threshold. Proenkephalin (PENK) is the precursor of enkephalin which is a pivot neuropeptide responsible for the decreased nociceptive threshold in EA. The aim of this study was to evaluate the relationship between let-7b-5p and PENK in EA tolerance. METHODS: The target gene of let-7b-5p microRNA was determined through the dual-luciferase reporter assay in cortical neurons. Seventy-two Sprague Dawley rats received a combination of EA and intracerebroventricular injection of microRNA (let-7b-5p agomir, antagomir or their controls). The nociceptive thresholds were assessed with radiant heat tail-flick method. PENK and let-7b-5p were measured with Western Blot and qPCR, respectively, after administration of let-7b-5p agomir, antagomir, and their controls at day 1, 4 and 7. RESULTS: Let-7b-5p targeted the 3' untranslated region of Penk1. The nociceptive thresholds in Let-7b-5p agomir + EA group were decreased (p < 0.05) compared with those in Let-7b-5p antagomir + EA group at day 1 to 7. Compared with Let-7b-5p agomir + EA group, the expression level of PENK in Let-7b-5p antagomir + EA group was increased at days 1, 4, and 7 (p < 0.05) CONCLUSION: Let-7b-5p may be a new potential target for decreasing the EA tolerance effect and facilitating the application of EA in treating chronic nociception of patients.


Assuntos
Eletroacupuntura , Encefalinas/genética , MicroRNAs/metabolismo , Dor Nociceptiva/terapia , Precursores de Proteínas/genética , Animais , Antagomirs/administração & dosagem , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Injeções Intraventriculares , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/diagnóstico , Dor Nociceptiva/genética , Dor Nociceptiva/imunologia , Limiar da Dor/efeitos dos fármacos , Ratos
5.
J Cancer Res Clin Oncol ; 146(4): 897-907, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146565

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS: The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS: Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION: Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.


Assuntos
Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Metilação de DNA , Genes Supressores de Tumor , Neoplasias Pancreáticas/genética , Proteína C-Reativa/genética , Carcinoma Ductal Pancreático/sangue , Estudos de Casos e Controles , Diferenciação Celular/genética , DNA Tumoral Circulante/sangue , Encefalinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Osteonectina/genética , Neoplasias Pancreáticas/sangue , Pancreatite Crônica/sangue , Pancreatite Crônica/genética , Regiões Promotoras Genéticas , Precursores de Proteínas/genética , Ubiquitina Tiolesterase/genética
6.
Mol Cell ; 77(3): 656-668.e5, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004469

RESUMO

Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/ultraestrutura , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/ultraestrutura , Sequência de Aminoácidos , Microscopia Crioeletrônica/métodos , Encefalinas , Humanos , Ligantes , Modelos Moleculares , Peptídeos , Precursores de Proteínas , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Acoplados a Proteínas-G/ultraestrutura , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Transdução de Sinais
7.
Clin Appl Thromb Hemost ; 26: 1076029619895318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31973568

RESUMO

OBJECTIVE: The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort. METHODS: The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures. RESULTS: After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33). CONCLUSION: Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.


Assuntos
Encefalinas/sangue , Precursores de Proteínas/sangue , Acidente Vascular Cerebral/diagnóstico , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/mortalidade , Estudos de Coortes , Humanos , Razão de Chances , Prognóstico , Análise de Regressão , Acidente Vascular Cerebral/mortalidade
8.
J Phys Chem Lett ; 11(4): 1215-1221, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31978303

RESUMO

Site-selective dissociation induced by core photoexcitation of biomolecules is of key importance for the understanding of radiation damage processes and dynamics and for its promising use as "chemical scissors" in various applications. However, identifying products of site-selective dissociation in large molecules is challenging at the carbon, nitrogen, and oxygen edges because of the high recurrence of these atoms and related chemical groups. In this paper, we present the observation of site-selective dissociation at the sulfur L-edge in the gas-phase peptide methionine enkephalin, which contains only a single sulfur atom. Near-edge X-ray absorption mass spectrometry has revealed that the resonant S 2p → σ*C-S excitation of the sulfur contained in the methionine side chain leads to site-selective dissociation, which is not the case after core ionization above the sulfur L-edge. The prospects of such results for the study of charge dynamics in biomolecular systems are discussed.


Assuntos
Gases/química , Peptídeos/química , Enxofre/química , Espectroscopia por Absorção de Raios X , Encefalinas/química , Metionina/química , Prótons , Teoria Quântica
9.
J Anal Toxicol ; 44(2): 173-179, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31287544

RESUMO

Botulinum neurotoxins (BoNTs) are a family of protein toxins consisting of seven known serotypes (BoNT/A-BoNT/G) and multiple subtypes within the serotypes, and all of which cause the disease botulism-a disease of great public health concern. Accurate detection of BoNTs in human clinical samples is therefore an important public health goal. To achieve this goal, our laboratory developed a mass spectrometry-based assay detecting the presence of BoNT via its enzymatic activity on a peptide substrate. Recently, publications reported the use of new peptide substrates to detect BoNT/A and /B with improved results over other peptide substrates. However, the authors did not provide results of their peptide substrate on multiple subtypes of BoNT. In this work, we describe the results of testing the new substrates with multiple BoNT/A and /B subtypes and find that the substrates cannot detect many subtypes of BoNT/A and /B.


Assuntos
Toxinas Botulínicas/análise , Bioensaio , Toxinas Botulínicas Tipo A , Botulismo , Encefalinas , Humanos , Limite de Detecção , Espectrometria de Massas , Peptídeos , Precursores de Proteínas
10.
Anesth Analg ; 130(1): 248-257, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166231

RESUMO

BACKGROUND: Persistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury. METHODS: In a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury. RESULTS: In the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury. CONCLUSIONS: These findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.


Assuntos
Dor Aguda/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/agonistas , Recompensa , Ferimentos Penetrantes/tratamento farmacológico , Dor Aguda/metabolismo , Dor Aguda/fisiopatologia , Dor Aguda/psicologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Encefalinas/genética , Encefalinas/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Ferimentos Penetrantes/metabolismo , Ferimentos Penetrantes/fisiopatologia , Ferimentos Penetrantes/psicologia
11.
Int J Mol Sci ; 20(20)2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635381

RESUMO

A wide variety of peptides not only interact with the cell surface, but govern complex signaling from inside the cell. This has been referred to as an "intracrine" action, and the orchestrating molecules as "intracrines". Here, we review the intracrine action of dynorphin B, a bioactive end-product of the prodynorphin gene, on nuclear opioid receptors and nuclear protein kinase C signaling to stimulate the transcription of a gene program of cardiogenesis. The ability of intracrine dynorphin B to prime the transcription of its own coding gene in isolated nuclei is discussed as a feed-forward loop of gene expression amplification and synchronization. We describe the role of hyaluronan mixed esters of butyric and retinoic acids as synthetic intracrines, controlling prodynorphin gene expression, cardiogenesis, and cardiac repair. We also discuss the increase in prodynorphin gene transcription and intracellular dynorphin B afforded by electromagnetic fields in stem cells, as a mechanism of cardiogenic signaling and enhancement in the yield of stem cell-derived cardiomyocytes. We underline the possibility of using the diffusive features of physical energies to modulate intracrinergic systems without the needs of viral vector-mediated gene transfer technologies, and prompt the exploration of this hypothesis in the near future.


Assuntos
Diferenciação Celular/genética , Encefalinas/genética , Encefalinas/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Animais , Butiratos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Peptídeos Opioides/genética , Peptídeos Opioides/metabolismo , Organogênese/genética , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo , Tretinoína/metabolismo
12.
Phys Chem Chem Phys ; 21(41): 22700-22703, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31579899

RESUMO

We use cold ion spectroscopy and quantum-chemical computations to solve the structures of opioid peptides enkephalins in the gas phase. The derived structural parameters clearly correlate with the known pharmacological efficiency of the studied drugs, suggesting that gas-phase methods, perhaps, can be used for predicting the relative potency of ligand drugs that target the hydrophobic pockets of receptors.


Assuntos
Encefalinas/química , Gases/química , Modelos Moleculares , Análise Espectral , Encefalinas/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neurotransmissores/química , Neurotransmissores/farmacologia , Relação Estrutura-Atividade
13.
Endocr Regul ; 53(3): 165-177, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517634

RESUMO

OBJECTIVE: The aim of the present study was to demonstrate the spatial relationship between the c-Fos immunoreactive cells elicited by an acute treatment with neuroleptics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI) and enkephalinergic (ENK), substance P (SP), and tyrosine hydroxylase (TH) innervation fields in the rat septum. METHODS: Male Sprague Dawley rats received a single injection of OLA (5 mg), ARI (10 mg), AMI (20 mg), QUE (15 mg/kg/b.w.). Ninety min after antipsychotics administration, the animals were transcardially perfused with a fixative and the brains cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black endproduct. Afterwards, the sections were exposed to ENK, SP, and TH antibodies and the reaction product visualized by biotin-labeled fluorescent AlexaFluor 564 dye. The data were evaluated from the sections either simultaneously illuminated with fluorescent and transmission microscope beams or after merging the separately illuminated sections in the Adobe Photoshop 7.0 software. RESULTS: ENK, SP, and TH displayed characteristic spatial images formed by a dense accumulation of immunoreactive fibers and terminals on the both sides of the septum. A dense plexus of axons formed by ENK and SP immunopositive terminals were situated predominantly in the lateral, while TH ones more medial portion of the septum. QUE and AMI activated distinct amount of c-Fos expression in cells located within the SP-immunoreactive principal innervation field. The OLA effect on the c-Fos expression was very pronounced in the ventral TH-labeled principal innervation field including the space between the ENK field ventral portion and the dorsal margin of the accumbens nucleus shell. Generally, the occurrence of c-Fos cells in the ENK-immunoreactive principal innervation field, in comparison with the surrounding septal area, was less abundant after all of the four antipsychotics treatments. CONCLUSION: The data of the present study indicate that ENK, SP, and TH innervation fields may influence separate populations of septal cells activated by AMI, OLA, QUE, and ARI and that each of these region-differently innervated cells may be associated with the functional heterogeneity of the individual lateral septal nuclei.


Assuntos
Antipsicóticos/farmacologia , Encefalinas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Septo do Cérebro/efeitos dos fármacos , Substância P/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Amissulprida/farmacologia , Animais , Aripiprazol/farmacologia , Imuno-Histoquímica , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Olanzapina/farmacologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Fumarato de Quetiapina/farmacologia , Ratos , Ratos Sprague-Dawley , Septo do Cérebro/metabolismo , Distribuição Tecidual/efeitos dos fármacos
14.
Vitam Horm ; 111: 105-129, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421697

RESUMO

After millennia of knowledge of opium, it was only recently that endogenous substances called opioids with similar properties to opium and derivatives were discovered. The first to be discovered were enkephalins. In addition to the regulation of their synthesis and expression of receptors, an important mechanism for the regulation of their functions carried out by multiple proteolytic enzymes acting at all levels of their structure is described. The action of such enzymes, known as enkephalinases, is also regulated by endogenous and exogenous factors which ultimately affect the control of the enkephalins's action. For therapeutic purposes, it is not only necessary to develop specific inhibitors but also to acquire a deep knowledge of the influence that such factors exert on their activities. This knowledge could help us to establish adapted therapeutic strategies in the treatment of pain or other processes in which enkephalinases are involved. In this chapter, some of these regulatory factors are discussed, such as regional and subcellular distribution, developmental changes, diurnal variations, hormonal influences, stress, dietary factors or interactions with other neurotransmitters.


Assuntos
Neprilisina/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/ultraestrutura , Química Encefálica/fisiologia , Ritmo Circadiano/fisiologia , Dieta , Sistema Endócrino/fisiologia , Encefalinas/fisiologia , Feminino , Homeostase , Humanos , Masculino , Neprilisina/análise , Manejo da Dor/métodos , Estresse Psicológico/enzimologia , Frações Subcelulares/química , Distribuição Tecidual
15.
Vitam Horm ; 111: 147-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421699

RESUMO

The pentapeptides methionine-enkephalin and leucine-enkephalin belong to the opioid family of peptides, and the non-opiate peptide adrenocorticotropin hormone (ACTH) to the melanocortin peptide family. Enkephalins/ACTH are derived from pro-enkephalin, pro-dynorphin or pro-opiomelanocortin precursors and, via opioid and melanocortin receptors, are responsible for many biological activities. Enkephalins exhibit the highest affinity for the δ receptor, followed by the µ and κ receptors, whereas ACTH binds to the five subtypes of melanocortin receptor, and is the only member of the melanocortin family of peptides that binds to the melanocortin-receptor 2 (ACTH receptor). Enkephalins/ACTH and their receptors exhibit a widespread anatomical distribution. Enkephalins are involved in analgesia, angiogenesis, blood pressure, embryonic development, emotional behavior, feeding, hypoxia, limbic system modulation, neuroprotection, peristalsis, and wound repair; as well as in hepatoprotective, motor, neuroendocrine and respiratory mechanisms. ACTH plays a role in acetylcholine release, aggressive behavior, blood pressure, bone maintenance, hyperalgesia, feeding, fever, grooming, learning, lipolysis, memory, nerve injury repair, neuroprotection, sexual behavior, sleep, social behavior, tissue growth and stimulates the synthesis and secretion of glucocorticoids. Enkephalins/ACTH are also involved in many pathologies. Enkephalins are implicated in alcoholism, cancer, colitis, depression, heart failure, Huntington's disease, influenza A virus infection, ischemia, multiple sclerosis, and stress. ACTH plays a role in Addison's disease, alcoholism, cancer, Cushing's disease, dermatitis, encephalitis, epilepsy, Graves' disease, Guillain-Barré syndrome, multiple sclerosis, podocytopathies, and stress. In this review, we provide an updated description of the enkephalinergic and ACTH systems.


Assuntos
Hormônio Adrenocorticotrópico/fisiologia , Encefalinas/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Hormônio Adrenocorticotrópico/análise , Hormônio Adrenocorticotrópico/genética , Sequência de Aminoácidos , Animais , Encefalinas/análise , Encefalinas/genética , Humanos , Sistema Nervoso , Precursores de Proteínas/metabolismo , Receptores da Corticotropina/fisiologia , Receptores Opioides/fisiologia , Transdução de Sinais , Distribuição Tecidual
16.
Vitam Horm ; 111: 313-337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421706

RESUMO

Endogenous opioids (enkephalins, endorphins and dynorphins) are small peptides that play a main role in pain perception and analgesia, as well as in alcohol (ethanol) reinforcement and reward. Alcohol reinforcement involves the ethanol-induced activation of the endogenous opioid system, a process that may augment the hedonic value and the reinforcing properties of the drug, which in turn increases substance consumption. Changes in opioidergic transmission may contribute to alcohol intoxication and to the neuroadaptive responses produced by the long-lasting exposure to ethanol. Opioidergic transmission may be altered by ethanol at distinct levels, including the expression of precursor mRNAs, biosynthesis and release of opioid peptides, as well as ligand binding to opioid receptors. In adult rats, ß-endorphinergic and enkephalinergic transmission, through activation of mu and delta opioid receptors, mediate ethanol reinforcement and high alcohol drinking behavior. Prenatal ethanol exposure (PEE) selectively modifies Methionine-enkephalin (Met-enk) content in several brain regions of infant and adolescent rats, particularly those of the reward circuits. In preweanling rats, Met-enk content is decreased in the ventral tegmental area but is increased in the prefrontal cortex and the nucleus accumbens and other brain areas, as a consequence of a short and moderate ethanol exposure during late gestation. PEE also increases Met-enk levels in the prefrontal cortex and other brain regions of 30-day-old adolescent rats. These findings suggest that mesocorticolimbic enkephalins are essential in ethanol reinforcement in offspring, as previously reported in adult rats.


Assuntos
Encefalinas/análise , Encefalinas/fisiologia , Etanol/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Transmissão Sináptica/efeitos dos fármacos , Consumo de Bebidas Alcoólicas , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Dopamina/fisiologia , Etanol/administração & dosagem , Etanol/efeitos adversos , Feminino , Núcleo Accumbens/metabolismo , Peptídeos Opioides/metabolismo , Córtex Pré-Frontal/metabolismo , Gravidez , Ratos , Receptores Opioides/metabolismo , Reforço Psicológico , Área Tegmentar Ventral/metabolismo
17.
Genes Brain Behav ; 18(8): e12600, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31339663

RESUMO

Persistent alterations of proopiomelanocortin (Pomc) and mu-opioid receptor (Oprm1) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome-wide deletion of neuronal Pomc enhancer1 (nPE1-/- ), had hypothalamic-specific partial reductions of beta-endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1+/+ ). We used RNA-Seq to measure steady-state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1+/+ and nPE1-/- mice after 1-day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1-/- had lower basal Pomc and Pdyn (prodynorphin) levels compared to nPE1+/+ , coupled with increased basal Oprm1 and Oprk1 (kappa-opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1+/+ in the water group, without significant effects on Oprm1 and Oprk1. In nPE1+/+ , excessive alcohol intake increased Pomc and Oprm1, with no effect on Pdyn or Oprk1. For stress genes, nPE1-/- had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1+/+ . In nPE1+/+ , excessive alcohol intake decreased Oxt and Avpi1 (AVP-induced protein1). Functionally examining the effect of pharmacological blockade of mu-opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1+/+ , but not nPE1-/- . Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.


Assuntos
Bebedeira/genética , Elementos Facilitadores Genéticos/genética , Hipotálamo/metabolismo , Pró-Opiomelanocortina/genética , Animais , Arginina Vasopressina/metabolismo , Bebedeira/metabolismo , Encefalinas/genética , Encefalinas/metabolismo , Etanol/farmacologia , Hipotálamo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/metabolismo , Pró-Opiomelanocortina/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Transcriptoma
18.
Eur J Med Chem ; 178: 571-588, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220675

RESUMO

In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 µg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.


Assuntos
Analgésicos Opioides/farmacologia , Encefalinas/farmacologia , Indóis/farmacologia , Naftalenos/farmacologia , Oxicodona/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Encefalinas/química , Indóis/química , Camundongos , Estrutura Molecular , Naftalenos/química , Oxicodona/química , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
19.
Life Sci ; 231: 116542, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176781

RESUMO

AIM: To compare the effect of 150 min vs. 300 min of weekly moderate intensity exercise training on the activation of the opioid system and apoptosis in the hearts of a diet-induced obesity model. METHODS: Male Wistar rats were fed with either control (CON) or high fat (HF) diet for 32 weeks. At the 20th week, HF group was subdivided into sedentary, low (LEV, 150 min·week-1) or high (HEV, 300 min·week-1) exercise volume. After 12 weeks of exercise, body mass gain, adiposity index, systolic blood pressure, cardiac morphometry, apoptosis biomarkers and opioid system expression were evaluated. RESULTS: Sedentary animals fed with HF presented pathological cardiac hypertrophy and higher body mass gain, systolic blood pressure and adiposity index than control group. Both exercise volumes induced physiological cardiac hypertrophy, restored systolic blood pressure and improved adiposity index, but only 300 min·week-1 reduced body mass gain. HF group exhibited lower proenkephalin, PI3K, ERK and GSK-3ß expression, and greater activated caspase-3 expression than control group. Compared to HF, no changes in the cardiac opioid system were observed in the 150 min·week-1 of exercise training, while 300 min·week-1 showed greater proenkephalin, DOR, KOR, MOR, Akt, ERK and GSK-3ß expression, and lower activated caspase-3 expression. CONCLUSION: 300 min·week-1 of exercise training triggered opioid system activation and provided greater cardioprotection against obesity than 150 min·week-1. Our findings provide translational aspect with clinical relevance about the critical dose of exercise training necessary to reduce cardiovascular risk factors caused by obesity.


Assuntos
Cardiomegalia/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores Opioides/fisiologia , Adiposidade , Animais , Apoptose/fisiologia , Pressão Sanguínea , Peso Corporal , Dieta Hiperlipídica , Encefalinas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Coração/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosfatidilinositol 3-Quinase/metabolismo , Condicionamento Físico Animal/métodos , Precursores de Proteínas/metabolismo , Ratos , Ratos Wistar
20.
J Reprod Dev ; 65(5): 397-406, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31155522

RESUMO

Increasing evidence shows that puberty onset is largely dependent on body weight rather than chronological age. To investigate the mechanism involved in the energetic control of puberty onset, the present study examined effects of chronic food restriction during the prepubertal period and the resumption of ad libitum feeding for 24 and 48 h on estrous cyclicity, Kiss1 (kisspeptin gene), Tac3 (neurokinin B gene) and Pdyn (dynorphin A gene) expression in the hypothalamus, luteinizing hormone (LH) secretion and follicular development in female rats. When animals weighed 75 g, they were subjected to a restricted feeding to retard growth to 70-80 g by 49 days of age. Then, animals were subjected to ad libitum feeding or remained food-restricted. The growth-retarded rats did not show puberty onset associated with suppression of both Kiss1 and Pdyn expression in the arcuate nucleus (ARC). 24-h ad libitum feeding increased tonic LH secretion and the number of Graafian and non-Graafian tertiary follicles with an increase in the numbers of ARC Kiss1- and Pdyn-expressing cells. 48-h ad libitum feeding induced the vaginal proestrus and a surge-like LH increase with an increase in Kiss1-expressing cells in the anteroventral periventricular nucleus (AVPV). These results suggest that the negative energy balance causes pubertal failure with suppression of ARC Kiss1 and Pdyn expression and then subsequent gonadotropin secretion and ovarian function, while the positive energetic cues trigger puberty onset via an increase in ARC Kiss1 and Pdyn expression and thus gonadotropin secretion and follicular development in female rats.


Assuntos
Ração Animal , Encefalinas/metabolismo , Kisspeptinas/metabolismo , Precursores de Proteínas/metabolismo , Maturidade Sexual , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Encéfalo/patologia , Feminino , Privação de Alimentos , Transtornos do Crescimento/fisiopatologia , Hipotálamo Anterior/metabolismo , Hormônio Luteinizante/metabolismo , Neurocinina B/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Ratos , Ratos Wistar , Útero/metabolismo
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