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1.
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
2.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484312

RESUMO

Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or ß-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies.


Assuntos
Adenilil Ciclases/metabolismo , Dependência de Morfina/metabolismo , Adenilil Ciclases/genética , Animais , Humanos , Dependência de Morfina/genética , Receptores Opioides/genética , Receptores Opioides/metabolismo , beta-Arrestinas/metabolismo
3.
Chem Biol Interact ; 311: 108790, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400342

RESUMO

Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Interferon gama/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/genética , Edema/tratamento farmacológico , Edema/patologia , Comportamento Exploratório/efeitos dos fármacos , Pé/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Interferon gama/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Testes de Toxicidade Aguda , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
J Assoc Physicians India ; 67(4): 22-25, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31309790

RESUMO

Introduction: With 1 billion tobacco users worldwide, nicotine dependence has a major impact on global health. Advances in medication development for nicotine dependence require an improved understanding of the neurobiology of this complex, relapsing brain disorder. Aims: To study association of µ Opioid Receptor polymorphism in patients of rheumatoid arthritis and its correlation with severity of disease and prevalent alleles of the OPRM1 genes. Material and Methods: This is a case control study wherein all available patients and volunteers were recruited. 142 controls subjects with no known history of disease and 85 study group cases were included. Results: Comparison of genotype frequencies showed a statistically significant difference between the studied groups (p<0.004). A statistically significant difference was found when the allelic frequencies between the two groups were compared (p<0.0001), with the 17T allele having a-1.7518 fold higher risk of having RA (risk ratio (RR)=1.7518, 95%CI of RR=1.2988-2.3627, OR =3.2914; 95%CI =1.9608-5.5251). Significant difference was also found when the allelic frequencies between the two groups were compared (p<0.0001), with the 118G allele having a 1.5-fold higher risk of developing RA (RR)=1.5801, 95%CI =1.3091-1.9071, OR=3.1357; 95%CI 2.1083-4.6638). Conclusion: The study definitely needs to be extended to larger cohort of patients and control samples and to a larger set of candidate µ opioid receptors. Extending the studies to a larger cohort will also allow genetic analyses of clinically defined endophenotypes observed in the patients of this chronic metabolic disease with attributes of autoimmune disorder and multiple symptoms in patients.


Assuntos
Artrite Reumatoide/genética , Receptores Opioides/genética , Estudos de Casos e Controles , Humanos , Polimorfismo Genético , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Índice de Gravidade de Doença
5.
Alcohol Alcohol ; 54(5): 559-565, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31206155

RESUMO

AIMS: The present study examined how variation in mu- (OPRM1), kappa- (OPRK), and delta- (OPRD) opioid receptor genes may influence the efficacy of naltrexone in the context of a smoking cessation trial. METHODS: The study's primary objective was to examine the association of the Asn40Asp OPRM1 single nucleotide polymorphism (SNP) with naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior during a double-blind, randomized clinical trial in 280 adult DSM-IV nicotine-dependent participants. The secondary goal of the study was to examine the relationship of 20 additional SNPs of OPRM1, OPRK, and OPRD with the aforementioned outcomes. RESULTS: Results indicated a null association between any opioid-receptor gene SNP and naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior in this sample of nicotine dependent participants. CONCLUSIONS: In sum, these results do not suggest that genetic variation in opioid-receptors is related to treatment responses to naltrexone in a smoking cessation trial.


Assuntos
Genótipo , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides/genética , Abandono do Hábito de Fumar/métodos , Fumar Tabaco/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Fumar Tabaco/tratamento farmacológico , Resultado do Tratamento
6.
PLoS One ; 14(6): e0217371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170174

RESUMO

Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.


Assuntos
Analgésicos Opioides , Receptores Opioides , Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Animais , Células CHO , Cricetulus , Células HEK293 , Humanos , Camundongos , Receptores Opioides/química , Receptores Opioides/genética , Receptores Opioides/metabolismo
7.
Int Immunopharmacol ; 73: 23-40, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078923

RESUMO

The incidence and mortality of type 2 diabetes mellitus (T2DM) rank among the top ten worldwide. Emerging studies indicate pathological roles for the immune system in inflammation, insulin resistance and islet ß-cell damage in subjects with T2DM. Methionine enkephalin (MENK) is present in endocrine cells of the pancreas and has been suggested to be an important mediator between the immune and neuroendocrine systems. Therefore, it may play a role in modulating insulin secretion from islet cells. Since little is known about the effect of MENK on T2DM, therefore it was the aim of this study to characterize the role and possible mechanism of action of MENK on plasma glucose and serum insulin levels in T2DM rats and INS-1 cells in vivo and in vitro. MENK significantly decreased the plasma glucose level and increased the serum insulin concentration in T2DM rats. It also increased the serum levels of the cytokines IL-5 and IL-10, while decreased TNF-α and IL-2 levels. We further confirmed that MENK regulated glucose metabolism by upregulating opioid receptor expression and modulating the IL-33/ST2 and MyD88-TRAF6-NF-κB p65 signaling pathways. Based on these results, an intraperitoneal injection of MENK represents a potentially new approach for T2DM.


Assuntos
Citocinas/imunologia , Diabetes Mellitus Tipo 2/imunologia , Encefalina Metionina/farmacologia , Receptores de Interleucina-1/imunologia , Animais , Glicemia/análise , Linhagem Celular Tumoral , Citocinas/sangue , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Masculino , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/metabolismo , Ratos Sprague-Dawley , Receptores Opioides/genética , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo
8.
Life Sci ; 224: 232-240, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930116

RESUMO

AIMS: Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice. MAIN METHODS: We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses. KEY FINDINGS: Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, Low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group. SIGNIFICANCE: Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.


Assuntos
Densidade Óssea/efeitos dos fármacos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Osteoblastos/citologia , Receptores Opioides/química , Animais , Proliferação de Células , Células Cultivadas , Encefalina Metionina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Neurotransmissores/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo
9.
Artif Cells Nanomed Biotechnol ; 47(1): 927-932, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30873885

RESUMO

Labour is considered to be one of the most painful procedures in human experience. The most effective technique for pain relief during labour is neuraxial labour analgesia which provides analgesia without maternal or fetal sedation. Genetic predisposition may be of importance for pain perception and women experience varying degrees of pain in labour. Genetic variations in opioid receptor (OPR) genes may influence the response to epidural opioid analgesia during labour. The single-nucleotide polymorphism, A118G of the mu opioid receptor gene (oprm1), has been associated with altered pain perception. Targeted drug delivery reduces toxic side effects. Liposomes, nano-particles, nanofibres hydrogel, have been suggested to deliver anaesthetic drugs.


Assuntos
Analgesia Obstétrica , Analgésicos Opioides/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Dor/tratamento farmacológico , Receptores Opioides/genética , Transdução de Sinais/genética , Analgesia Epidural , Analgésicos Opioides/química , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Variação Genética , Humanos , Nanopartículas/administração & dosagem , Complicações do Trabalho de Parto/tratamento farmacológico , Gravidez
10.
Mol Pain ; 15: 1744806919828921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30665329

RESUMO

Little is known about the mechanisms involved in the regulation of nociceptin and its receptor (nociceptin opioid peptide receptor, NOP) in response to inflammation and pain in humans. In this study, specific signaling pathways contributing to the regulation of nociceptin and NOP in human peripheral blood leukocytes were investigated. After approval by the ethics committee, peripheral blood obtained from healthy donors was cultured with or without phorbol-12-myristate-13-acetate (PMA). Prepronociceptin (ppNOC) and NOP mRNA were analyzed by real-time quantitative polymerase chain reaction, and nociceptin concentrations in culture supernatants by fluorescent enzyme immunoassay. Nociceptin and NOP protein levels in blood leukocyte subsets were determined using flow cytometry. To examine the contribution of signaling pathways to ppNOC and NOP regulation, blood was pre-treated with kinase inhibitors specific for ERK, JNK, p38, and NFκB pathways prior to culturing with or without PMA. PMA dose-dependently upregulated ppNOC mRNA but downregulated NOP mRNA in human peripheral blood leukocytes. PMA 10 ng/ml increased ppNOC after 6 h and suppressed NOP after 3 h compared to controls (both P <0.005). Nociceptin concentrations were increased in supernatants of PMA-induced blood samples after 24 h ( P <0.005), whereas expression of cell-membrane NOP was decreased by PMA in blood leukocyte subsets (all P <0.05). Blockade of ERK or p38 pathways partially prevented PMA effects on ppNOC and NOP mRNA (all P <0.05). The combination of ERK and p38 inhibitors completely reversed the effects of PMA ( P <0.05). ERK and p38 are two major signaling pathways regulating nociceptin and its receptor in human peripheral blood leukocytes under inflammatory conditions.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/fisiologia , Leucócitos/metabolismo , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adolescente , Adulto , Relação Dose-Resposta a Droga , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Peptídeos Opioides/genética , Ésteres de Forbol/farmacologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Receptores Opioides/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Tempo , Adulto Jovem
11.
Brain Struct Funct ; 224(1): 219-238, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30302539

RESUMO

The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic structure identified in 2009 that receives strong inputs from the lateral habenula and other sources, sends dense inhibitory projections to midbrain dopamine (DA) neurons, and plays increasingly recognized roles in aversive learning, addiction, and other motivated behaviors. In general, little is known about the genetic identity of these neurons. However, recent work has identified the transcription factor FoxP1 as enhanced in the mouse RMTg (Lahti et al. in Development 143(3):516-529, 2016). Hence, in the current study, we used RNA sequencing to identify genes significantly enhanced in the rat RMTg as compared to adjacent VTA, and then examined the detailed distribution of two genes in particular, prepronociceptin (Pnoc) and FoxP1. In rats and mice, both Pnoc and FoxP1 were expressed at high levels in the RMTg and colocalized strongly with previously established RMTg markers. FoxP1 was particularly selective for RMTg neurons, as it was absent in most adjacent brain regions. We used these gene expression patterns to refine the anatomic characterization of RMTg in rats, extend this characterization to mice, and show that optogenetic manipulation of RMTg in mice bidirectionally modulates real-time place preference. Hence, RMTg neurons in both rats and mice exhibit distinct genetic profiles that correlate with their distinct connectivity and function.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Neurônios/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo , Proteínas Repressoras/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Comportamento Animal , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Masculino , Camundongos Transgênicos , Atividade Motora , Vias Neurais/metabolismo , Optogenética , Precursores de Proteínas/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Receptores Opioides/genética , Proteínas Repressoras/genética , Fatores de Tempo , Área Tegmentar Ventral/citologia
12.
Behav Brain Res ; 356: 120-126, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30142397

RESUMO

Aggressive behaviors can be considered symptoms of bipolar disorder, schizophrenia, post-traumatic stress, intermittent explosive, and personality disorders. Nociceptin/orphanin FQ (N/OFQ) is a peptide acting as endogenous ligand of the NOP receptor. Preclinical and clinical findings suggest the NOP receptor as an innovative target for the treatment of psychopathologies, such as anxiety, depression, and drug abuse. This study investigated the effects of NOP ligands and the behavioral phenotype of mice lacking the NOP receptor in an animal model of aggressiveness, the resident-intruder test. Mood stabilizers, such as valproate, lithium, and carbamazepine reduced aggressive behaviors of resident mice, while diazepam was inactive. In contrast, para-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, increased aggressiveness in mice. Similar to PCPA, the treatment with the NOP agonists Ro 65-6570 and AT-090 also increased aggressive behaviors. The systemic administration of the NOP antagonist SB-612111 did not modify the behavior of resident mice, but it prevented the aggressive behavior of Ro 65-6570. NOP receptor knockout mice did not display any behavioral difference compared to wild-type animals in the resident-intruder test. None of the treatments affected non-agonistic behaviors and spontaneous locomotion. In conclusion, NOP receptor agonists increased aggressiveness, while the pharmacological and genetic blockade of NOP receptor signaling did not modify agonistic behaviors. Ultimately, the aggressive profile of action of NOP agonists should be taken into account in the development of innovative psychiatric drugs targeting the NOP receptor.


Assuntos
Agressão/fisiologia , Comportamento Agonístico/fisiologia , Receptores Opioides/fisiologia , Animais , Ansiedade , Transtorno Bipolar , Carbamazepina/farmacologia , Cicloeptanos/farmacologia , Depressão , Transtorno Depressivo , Modelos Animais de Doenças , Fenclonina/farmacologia , Lítio/farmacologia , Masculino , Camundongos , Camundongos Knockout , Peptídeos Opioides/metabolismo , Piperidinas/farmacologia , Receptores Opioides/agonistas , Receptores Opioides/genética , Ácido Valproico/farmacologia
13.
J Mol Neurosci ; 67(1): 89-96, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30519864

RESUMO

Autism spectrum disorder (ASD) is characterized by repetitive stereotypic behaviors, restricted interests, social withdrawal, and communication deficits. Aggression and insensitivity to pain are largely unexplained in these cases. We analyzed nine mRNA expressions of the candidate genes related to aggression and insensitivity to pain in the peripheral blood of patients with ASD. Whole blood samples were obtained from 40 autistic patients (33 boys, 7 girls) and 50 age- and sex-matched controls (37 boys and 13 girls) to isolate RNA. Gene expression was assessed by quantitative Real-Time PCR (qRT-PCR) in the Erciyes University Genome and Stem Cell Center (GENKOK). All of the gene expressions except CRHR1 and SLC6A4 were found to be statistically different between the ASD patients and controls. Gene expression also differed according to gender. Alterations in the mRNA expression patterns of the HTR1E, OPRL1, OPRM1, TACR1, PRKG1, SCN9A and DRD4 genes provide further evidence for a relevant effect of the respective candidate genes on the pathophysiology of ASD. Future studies may determine the sensitivity of these candidate markers in larger samples including further neuropsychiatric diagnosis.


Assuntos
Transtorno do Espectro Autista/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , RNA Mensageiro/sangue , Receptor 5-HT1A de Serotonina/genética , Receptores de Dopamina D4/genética , Receptores Opioides/genética , Agressão , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/fisiopatologia , Biomarcadores/sangue , Pré-Escolar , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Feminino , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Percepção da Dor , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D4/metabolismo , Receptores Opioides/metabolismo
14.
Int Immunopharmacol ; 65: 76-83, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30290369

RESUMO

The goal of this work was to investigate how MENK could regulate the functions of CD8+T cells and to explore the relationship between this regulation and opioid receptor expression. Our results showed that the opioid receptors presented on the cell menbrane of CD8+T cells were MOR and DOR. MENK promoted the expression of opioid receptors as well as the elevation of the surface molecules such as CD28, PD-1, CTLA-4 and FasL and intracellular granzyme B. Selectively blocking the MOR by CTAP or DOR by NTI could result in inhibition of the corresponding CD8+T cells proliferation and the expressions of surface molecules. In addition, non-selectively blocking both MOR and DOR by NTX could further impair the functions and proliferation of CD8+T cells. Our currently data indicated that MENK could play a vital role in immune functions via precise regulation to subunits of opioid receptors.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Encefalina Metionina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Neurotransmissores/farmacologia , Receptores Opioides/metabolismo , Animais , Linfócitos T CD8-Positivos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Subunidades Proteicas , Receptores Opioides/genética
15.
J Avian Med Surg ; 32(3): 173-184, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30204017

RESUMO

To further knowledge of the physiology of opioid receptors in birds, the structure and expression of the µ-, δ-, and κ-opioid receptor genes were studied in a peregrine falcon ( Falco peregrinus), a snowy owl ( Bubo scandiacus), and a blue-fronted Amazon parrot ( Amazona aestiva). Tissue samples were obtained from birds that had been euthanatized for poor release prognosis or medical reasons. Samples were taken from the brain (telencephalon, thalamus, pituitary gland, cerebellum, pons, medulla oblongata, mesencephalon), the spinal cord and dorsal root ganglions, and plantar foot skin. Messenger RNA was recovered, and reverse transcription polymerase chain reaction (RT-PCR) was performed to generate complementary DNA (cDNA) sequences. Gene structures were documented by directly comparing cDNA sequences with recently published genomic sequences for the peregrine falcon and the blue-fronted Amazon parrot or by comparisons with genomic sequences of related species for the snowy owl. Structurally, the avian µ-opioid receptor messenger RNA (mRNA) species were complex, displaying differential splicing, alternative stop codons, and multiple polyadenylation signals. In comparison, the structure of the avian κ-receptor mRNA was relatively simple. In contrast to what is seen in humans, the avian δ-receptor mRNA structure was found to be complex, demonstrating novel 3-prime coding and noncoding exons not identified in mammals. The role of the δ-opioid receptor merits further investigation in avian species.


Assuntos
Amazona/metabolismo , Falconiformes/metabolismo , Receptores Opioides/metabolismo , Estrigiformes/metabolismo , Amazona/genética , Animais , Falconiformes/genética , Feminino , Variação Genética , Masculino , Receptores Opioides/genética , Especificidade da Espécie , Estrigiformes/genética
17.
Mol Med Rep ; 18(5): 4297-4302, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30152845

RESUMO

Previous studies have suggested that increased opioid receptor κ1 (OPRK1) and opioid receptor δ1 (OPRD1) methylation levels are involved in Alzheimer's disease (AD). In the present study, the methylation levels of two opioid receptor genes, opioid receptor µ1 (OPRM1) and opioid related nociceptin receptor 1 (OPRL1), were analyzed for their association with AD. Gene methylation levels were measured using bisulfite pyrosequencing in DNA samples derived from blood samples of 51 AD patients and 63 controls. The results indicated that there were significantly elevated promoter methylation levels of OPRM1 and OPRL1 in AD (OPRM1: P=0.007; OPRL1: P=2.987x10­6). Dual­luciferase reporter gene assays demonstrated that the promoter fragments of these two genes were able to promote gene expression (OPRM1: Fold­change=2.616, P=0.003; OPRL1: Fold change=11.395, P=0.007). In addition, receiver operating characteristic analyses further indicated that a methylation panel of four opioid receptor genes (area under the curve=0.848, sensitivity=0.723, and specificity=0.879) performed well in the prediction of AD. These results suggested that opioid receptor genes may be used as potential methylation biomarkers for the diagnosis of AD.


Assuntos
Doença de Alzheimer/genética , Metilação de DNA , Receptores Opioides mu/genética , Receptores Opioides/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Sequência de Bases , Biomarcadores , Estudos de Casos e Controles , Ilhas de CpG , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Regiões Promotoras Genéticas , Curva ROC
18.
J Mol Neurosci ; 66(1): 10-16, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30074175

RESUMO

Opioid receptor like 1 (ORL1) receptor activation displayed an anti-nociceptive effect at spinal level for acute and neuropathic pain. SCH221510, an orally active non-peptide ORL1 agonist, was reported to be effective in treating neuropathic pain. The present study used ORL1 antagonist and siRNA to investigate that ORL1 activation mediates intrathecal SCH221510 analgesia in neuropathic pain induced by chronic constrictive injury (CCI) to rat sciatic nerve. Paw withdrawal latency and 50% mechanical threshold were measured for thermal and mechanical hypersensitivity in rats. CCI significantly decreased paw withdrawal latency and mechanical threshold. SCH221510 (3, 10, 30 µg) or ORL1 antagonist ([Nphe1]nociceptin(1-13)NH2, 10 µg) was intrathecally injected to test the behavioral effects on neuropathic pain. Intrathecal siRNA was started on 1 day before CCI surgery and maintained for 7 days. L4-L5 spinal cord ORL1 mRNA and protein were measured by real-time PCR and Western blot. The effect of intrathecal siRNA on SCH2210510 was tested in CCI rats on day 7. Intrathecal SCH221510 dose-dependently reduced thermal and mechanical hypersensitivity induced by CCI. [Nphe1]nociceptin(1-13)NH2 blocked SCH221510 analgesia in CCI rats. Intrathecal siRNA blocked ORL1 mRNA and protein increase induced by CCI. Intrathecal ORL1 siRNA did not change thermal and mechanical hypersensitivity induced by nerve injury. Intrathecal siRNA blocked SCH221510 analgesia in neuropathic pain at spinal level. Conclusively, ORL1 activation mediates SCH221510 analgesia in neuropathic pain at spinal level. The results warrant a potential clinically applicable drug in treating neuropathic pain.


Assuntos
Analgésicos/farmacologia , Compostos Azabicíclicos/farmacologia , Neuralgia/metabolismo , Receptores Opioides/metabolismo , Analgésicos/uso terapêutico , Animais , Compostos Azabicíclicos/uso terapêutico , Masculino , Neuralgia/tratamento farmacológico , Peptídeos Opioides/farmacologia , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/agonistas , Receptores Opioides/genética , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões
19.
PLoS One ; 13(8): e0203021, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30161182

RESUMO

The Nociceptin/Orphanin FQ (N/OFQ) peptide NOP receptor is coupled to pertussis toxin (PTX)-sensitive G proteins (Gi/o) whose activation leads to the inhibition of both cAMP production and calcium channel activity, and to the stimulation of potassium currents. The label free dynamic mass redistribution (DMR) approach has been demonstrated useful for investigating the pharmacological profile of G protein-coupled receptors. Herein, we employ DMR technology to systematically characterize the pharmacology of a large panel of NOP receptor ligands. These are of peptide and non-peptide nature and display varying degrees of receptor efficacy, ranging from full agonism to pure antagonism. Using Chinese hamster ovary (CHO) cells expressing the human NOP receptor we provide rank orders of potency for full and partial agonists as well as apparent affinities for selective antagonists. We find the pharmacological profile of NOP receptor ligands to be similar but not identical to values reported in the literature using canonical assays for Gi/o-coupled receptors. Our data demonstrate that holistic label-free DMR detection can be successfully used to investigate the pharmacology of the NOP receptor and to characterize the cellular effects of novel NOP receptor ligands.


Assuntos
Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligantes , Peptídeos Opioides/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Opioides/agonistas , Receptores Opioides/genética
20.
Surg Technol Int ; 32: 306-314, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29791710

RESUMO

BACKGROUND: Multiple factors have been implicated in determining why certain patients have increased postoperative pain, with the potential to develop chronic pain. The purpose of this study was to: 1) identify and describe genes that affect postoperative pain perception and control; 2) address modifiable risk factors that result in epigenetic altered responses to pain; and 3) characterize differences in pain sensitivity and thresholds between opioid-naïve and opioid-dependent patients. MATERIALS AND METHODS: Three electronic databases were used to conduct the literature search: Pubmed, EBSCO host, and SCOPUS. A total of 372 abstracts were reviewed, of which 46 studies were deemed relevant and are included in this review. RESULTS: Specific gene alterations that were shown to affect postoperative pain control included single nucleotide polymorphisms in the mu, kappa, and delta opioid receptors, ion channel genes, cytotoxic T-cells, glutamate receptors and cytokine genes, among others. Alcoholism, obesity, and smoking were all linked with genetic polymorphisms that altered pain sensitivity. Opioid abuse was found to be associated with a poorer response to analgesics postoperatively, as well as a risk for prescription overdose. CONCLUSION: Although pain perception has multiple complex influences, the greatest variability seen in response to opioids among postoperative patients known to date can be traced to genetic differences in opioid metabolism. Further study is needed to determine the clinical significance of these genetic associations.


Assuntos
Analgésicos Opioides , Dor Crônica , Dor Pós-Operatória , Polimorfismo Genético/genética , Receptores Opioides/genética , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Humanos , Manejo da Dor , Percepção da Dor , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Fatores de Risco
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