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1.
Neuropeptides ; 74: 82-87, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30738575

RESUMO

BACKGROUND: Chimeric opioid MCRT was a novel multi-target ligand based on morphiceptin and PFRTic-NH2, and produced potent analgesia (ED50 = 0.03 nmol/mouse) with less upper gastrointestinal dysmotility. In this study, we sought to perform the tests to evaluate the pharmacological effects of MCRT on distal colon motility and defecation function. Moreover, opioid receptor antagonists and neuropeptide FF (NPFF) receptor antagonists were utilized to explore the mechanisms. METHODS: Isolated mouse colon bioassay and colonic bead expulsion were to characterize MCRT-induced inhibition of colonic motility in vitro and in vivo, respectively. Fecal pellet output was to evaluate the defecation function. RESULTS: (1) In vitro, MCRT increased colonic contraction via µ- and δ- opioid receptors (MOR and DOR). (2) In vivo, MCRT delayed colonic bead expulsion (ED50 = 1.1 nmol/mouse) independent of opioid and NPFF receptors. (3) In vivo, MCRT inhibited fecal number (ED50 = 1.43 nmol/mouse) and dry weight (ED50 = 1.63 nmol/mouse), which was mediated by DOR partially but not MOR. CONCLUSIONS: (1) Data indicated that MCRT was less prone to induce gastrointestinal dysmotility at analgesic doses, and provided a possibility for safer opioid analgesic. (2) Based on the mechanism explorations, we speculated on the existence of such an opioid receptor subtype or MOR/DOR heterodimer, which was involved in the central analgesia and the in vitro colonic contractions but not the central colonic dysmotility.


Assuntos
Analgésicos Opioides/administração & dosagem , Colo/fisiologia , Endorfinas/administração & dosagem , Motilidade Gastrointestinal , Receptores Opioides delta/fisiologia , Receptores Opioides mu/fisiologia , Animais , Colo/efeitos dos fármacos , Constipação Intestinal/induzido quimicamente , Endorfinas/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Receptores de Neuropeptídeos/fisiologia
2.
Animal ; 13(4): 777-783, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30139413

RESUMO

ß-Casomorphin is an opioid-like bioactive peptide derived from ß-casein of milk that plays a crucial role in modulating animal's feed intake, growth, nutrient utilization and immunity. However, the effect of ß-casomorphin on lipid metabolism in chickens and its mechanism remain unclear. The aim of this study was to investigate the effects of ß-casomorphin on fat deposition in broiler chickens and explore its mechanism of action. A total of 120 21-day-old Arbor Acres male broilers (747.94±8.85 g) was chosen and randomly divided into four groups with six replicates of five birds per replicate. Three groups of broilers were injected with 0.1, 0.5 or 1.0 mg/kg BW of ß-casomorphin in 1 ml saline for 7 days, whereas the control group received 1 ml saline only. The results showed that subcutaneous administration of ß-casomorphin to broiler chickens increased average daily gain, average daily feed intake and fat deposition, and decreased feed : gain ratio (P<0.05). The activity of malate dehydrogenase in the pectoral muscle, liver and abdominal adipose tissue was also increased along with the concentrations of insulin, very-low-density lipoprotein and triglyceride in the plasma (P<0.05). The activity of hormone-sensitive lipase in the liver and abdominal adipose tissue and the concentration of glucagon in the plasma were decreased by injection with ß-casomorphin (P<0.05). Affymetrix gene chip analysis revealed that administering 1.0 mg/kg BW ß-casomorphin caused differential expression of 168 genes in the liver with a minimum of fourfold difference. Of those, 37 genes are directly involved in lipid metabolism with 18 up-regulated genes such as very low density lipoprotein receptor gene and fatty acid synthase gene, and 19 down-regulated genes such as lipoprotein lipase gene and low density lipoprotein receptor gene. In conclusion, ß-casomorphin increased growth performance and fat deposition of broilers. Regulation of fat deposition by ß-casomorphin appears to take place through changes in hormone secretion and enzyme activities by controlling the gene expression of lipid metabolism and feed intake, increasing fat synthesis and deposition.


Assuntos
Gordura Abdominal/fisiologia , Galinhas , Endorfinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Gordura Abdominal/efeitos dos fármacos , Ração Animal , Animais , Endorfinas/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Fígado/enzimologia , Malato Desidrogenase/metabolismo , Masculino , Distribuição Aleatória , Triglicerídeos/metabolismo
3.
Adv Nutr ; 8(5): 739-748, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28916574

RESUMO

This is the first systematic review, to our knowledge, of published studies investigating the gastrointestinal effects of A1-type bovine ß-casein (A1) compared with A2-type bovine ß-casein (A2). The review is relevant to nutrition practice given the increasing availability and promotion in a range of countries of dairy products free of A1 for both infant and adult nutrition. In vitro and in vivo studies (all species) were included. In vivo studies were limited to oral consumption. Inclusion criteria encompassed all English-language primary research studies, but not reviews, involving milk, fresh-milk products, ß-casein, and ß-casomorphins published through 12 April 2017. Studies involving cheese and fermented milk products were excluded. Only studies with a specific gastrointestinal focus were included. However, inclusion was not delimited by specific gastrointestinal outcome nor by a specific mechanism. Inclusion criteria were satisfied by 39 studies. In vivo consumption of A1 relative to A2 delays intestinal transit in rodents via an opioid-mediated mechanism. Rodent models also link consumption of A1 to the initiation of inflammatory response markers plus enhanced Toll-like receptor expression relative to both A2 and nonmilk controls. Although most rodent responses are confirmed as opioid-mediated, there is evidence that dipeptidyl peptidase 4 stimulation in the jejunum of rodents is via a nonopioid mechanism. In humans, there is evidence from a limited number of studies that A1 consumption is also associated with delayed intestinal transit (1 clinical study) and looser stool consistency (2 clinical studies). In addition, digestive discomfort is correlated with inflammatory markers in humans for A1 but not A2. Further research is required in humans to investigate the digestive function effects of A1 relative to A2 in different populations and dietary settings.


Assuntos
Caseínas/efeitos adversos , Endorfinas/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Caseínas/administração & dosagem , Dieta , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Endorfinas/administração & dosagem , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Trato Gastrointestinal/metabolismo , Humanos , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Rev. esp. anestesiol. reanim ; 64(7): 384-390, ago.-sept. 2017. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-164834

RESUMO

Objetivo. Debido al conocido papel preventivo que juegan las bajas dosis de sulfato de magnesio en el tratamiento del dolor postoperatorio, en este estudio aleatorizado a doble ciego y controlado con placebo tratamos de investigar la posible relación entre la infusión intraoperatoria de sulfato de magnesio, la analgesia postoperatoria y el nivel de beta-endorfinas séricas en las histerectomías abdominales totales realizadas bajo anestesia general. Métodos. Se distribuyó aleatoriamente a 40 mujeres sometidas a histerectomía abdominal total en 2 grupos (20 en cada uno de ellos). Quince minutos antes de la inducción de anestesia, al grupo de estudio se le administró una infusión intravenosa de sulfato de magnesio (15mg/kg/h), y al grupo control con placebo se le administró el mismo volumen de solución salina isotónica. Las puntuaciones del dolor se evaluaron a las 0, 6, 12 y 24h posteriores a la intervención, utilizando la escala de calificación numérica verbal. Se registró de manera precisa el consumo de petidina. Se determinó el nivel sérico de beta-endorfinas 15min antes de la inducción y al finalizar las intervenciones, utilizando el método ELISA. Resultados. A las 6 y 12h posteriores a las intervenciones, el valor de la escala de calificación numérica verbal en el grupo de estudio fue considerablemente menor que en el grupo control con placebo (p=0,0001). A las 24h de la intervención, el consumo de petidina fue significativamente inferior en el grupo de estudio en comparación con el grupo control (p=0,0001). En el grupo de estudio, el nivel sérico de beta-endorfinas descendió considerablemente al final de las intervenciones, en comparación con el momento anterior a la inducción (p=0,04). Conclusión. Demostramos que la baja dosis preventiva e intraoperatoria de sulfato de magnesio reduce el dolor postoperatorio, tiene un efecto opioide moderado y disminuye la concentración sérica de beta-endorfinas en las histerectomías abdominales totales (AU)


Objective. Due to the known role of preventive low dose magnesium sulphate on postoperative pain management, in this randomized, double-blinded, placebo-controlled study, we tried to investigate the possible relationship between low dose intra-operative magnesium sulphate infusion, postoperative analgesia and the level of serum beta-endorphin during total abdominal hysterectomy under general anesthesia. Methods. Forty women undergoing total abdominal hysterectomy were randomly allocated into 2 groups (20 in each arm). Fifteen minutes before induction of anaesthesia, the case group received a continuous intravenous infusion of magnesium sulphate (15mg/kg/h) and placebo control group received the same volume of isotonic saline. Pain scores were assessed at 0, 6, 12, and 24h after operations using Verbal Numeric Rating Scale. Pethidine consumption was recorded precisely. Serum level of beta-endorphin just 15min before the induction and at the end of the operations was determined by ELISA technique. Results. At 6 and 12h after the operations, Verbal Numeric Rating Scale in the case group was significantly lower than that of placebo control group (P=.0001). Over 24h after the operations, pethidine consumption was significantly lower in the case group compared with control group (P=.0001). In the case group, serum level of beta-endorphin was significantly decreased at the end of the operations compared with before the induction (P=.04). Conclusion. We illustrated that preventive low dose intra-operative magnesium sulphate infusion reduces postoperative pain, has opioid sparing effect and declines serum beta-endorphin concentration during total abdominal hysterectomy (AU)


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Histerectomia/métodos , Sulfato de Magnésio/administração & dosagem , Percepção da Dor , Dor Pós-Operatória/tratamento farmacológico , Endorfinas/administração & dosagem , Anestesia Geral , Manejo da Dor/métodos , Endorfinas/uso terapêutico , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática
5.
J Pharm Pharmacol ; 69(9): 1244-1251, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28620922

RESUMO

OBJECTIVES: Chimeric peptide MCRT, based on morphiceptin and PFRTic-NH2 , was a bifunctional ligand of µ- and δ-opioid receptors (MOR-DOR) and produced potent analgesia in tail-withdrawal test. The study focused on the supraspinal effects of morphiceptin, PFRTic-NH2 and MCRT on gastrointestinal motility. Moreover, opioid receptor antagonists, naloxone (non-selective), cyprodime (MOR selective) and naltrindole (DOR selective) were utilized to explore the mechanisms. METHODS: Intracerebroventricular administration was achieved via the implanted cannula. Gastric emptying and intestinal transit were measured to evaluate gastrointestinal motility. KEY FINDINGS: (1) At supraspinal level, morphiceptin, PFRTic-NH2 and MCRT significantly decreased gastric emptying and intestinal transit; (2) MCRT at 1 nmol/mouse, far higher than its analgesic dose (ED50  = 29.8 pmol/mouse), failed to regulate the gastrointestinal motility; (3) MCRT-induced gastrointestinal dysfunction could be completely blocked by naloxone and naltrindole, but not affected by cyprodime. CONCLUSIONS: (1) Morphiceptin and PFRTic-NH2 played important roles in the regulation of gastrointestinal motility; (2) MCRT possessed higher bioactivity of pain relief than gastrointestinal regulation, suggesting its promising analgesic property; (3) MCRT-induced motility disorders were sensitive to DOR but not to MOR blockade, indicating the pain-relieving specificity of speculated MOR subtype or splice variant or MOR-DOR heterodimer.


Assuntos
Endorfinas/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Relação Dose-Resposta a Droga , Endorfinas/administração & dosagem , Injeções Intraventriculares , Masculino , Camundongos , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico
6.
Can J Physiol Pharmacol ; 94(9): 955-60, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27285300

RESUMO

The present study focused on the interactive pain regulation of endokinin A/B (EKA/B, the common C-terminal decapeptide in EKA and EKB) or endokinin C/D (EKC/D, the common C-terminal duodecapeptide in EKC and EKD) on chimeric peptide MCRT (YPFPFRTic-NH2, based on YPFP-NH2 and PFRTic-NH2) at the supraspinal level in mice. Results demonstrated that the co-injection of nanomolar EKA/B and MCRT showed moderate regulation, whereas 30 pmol EKA/B had no effect on MCRT. The combination of EKC/D and MCRT produced enhanced antinociception, which was nearly equal to the sum of the mathematical values of single EKC/D and MCRT. Mechanism studies revealed that pre-injected naloxone attenuated the combination significantly compared with the equivalent analgesic effects of EKC/D alone, suggesting that EKC/D and MCRT might act on two totally independent pathways. Moreover, based on the above results and previous reports, we made two reasonable hypotheses to explain the cocktail-induced analgesia, which may potentially pave the way to explore the respective regulatory mechanisms of EKA/B, EKC/D, and MCRT and to better understand the complicated pain regulation of NK1 and µ opioid receptors, as follows: (1) MCRT and endomorphin-1 possibly activated different µ subtypes; and (2) picomolar EKA/B might motivate the endogenous NPFF system after NK1 activation.


Assuntos
Endorfinas/farmacologia , Medição da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/farmacologia , Taquicininas/farmacologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Endorfinas/administração & dosagem , Endorfinas/antagonistas & inibidores , Infusões Intraventriculares , Masculino , Camundongos , Naloxona/farmacologia , Fragmentos de Peptídeos/administração & dosagem , Precursores de Proteínas/administração & dosagem , Precursores de Proteínas/antagonistas & inibidores , Taquicininas/administração & dosagem , Taquicininas/antagonistas & inibidores
7.
Cell Death Dis ; 6: e1683, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25766322

RESUMO

Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (~2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.


Assuntos
Membrana Celular/metabolismo , Encefalinas/metabolismo , Neuropeptídeos/metabolismo , Peptídeos Opioides/metabolismo , Precursores de Proteínas/metabolismo , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Dinorfinas/administração & dosagem , Dinorfinas/metabolismo , Endorfinas/administração & dosagem , Endorfinas/metabolismo , Encefalinas/genética , Humanos , Ligantes , Microscopia Confocal , Neuropeptídeos/administração & dosagem , Peptídeos Opioides/administração & dosagem , Células PC12 , Precursores de Proteínas/genética , Ratos , Transdução de Sinais/efeitos dos fármacos
8.
Peptides ; 65: 6-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25625371

RESUMO

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with population prevalence of approximately 60-70 per 10,000. Data shows that both opioid system function enhancement and opiate administration can result in autistic-like symptoms. Cow milk opioid peptides, including ß-casomorphin-7 (BCM7, Tyr-Pro-Phe-Pro-Gly-Pro-Ile), affect the µ-opioid receptor (MOR) and are subjected to degradation resulting from the proline dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme activity. The presence of MOR and DPPIV activity are crucial factors determining biological activity of BCM7 in the human body. Our study examined the effect of ß-casomorphin-7 on the MOR and DPPIV genes expression according to specific point mutations in these genes. In addition, we investigated frequency of A118G SNP in the MOR gene and rs7608798 of the DPPIV (A/G) gene in healthy and autistic children. Our research indicated correlation in DPPIV gene expression under the influence of BCM7 and hydrolyzed milk between healthy and ASD-affected children with genotype GG (P<0.0001). We also observed increased MOR gene expression in healthy children with genotype AG at polymorphic site A118G under influence of BCM7 and hydrolyzed milk. The G allele frequency was 0.09 in MOR gene and 0.68 in the DPPIV gene. But our results suggest no association between presence of the alleles G and A at position rs7608798 in DPPIV gene nor alleles A and G at position A118G of the MOR and increased incidence of ASD. Our studies emphasize the compulsion for genetic analysis in correlation with genetic factors affecting development and enhancement of autism symptoms.


Assuntos
Transtorno Autístico/genética , Dipeptidil Peptidase 4/genética , Endorfinas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Polimorfismo de Nucleotídeo Único , Hidrolisados de Proteína/administração & dosagem , Receptores Opioides mu/genética , Adolescente , Alelos , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/fisiopatologia , Estudos de Casos e Controles , Bovinos , Criança , Pré-Escolar , Dipeptidil Peptidase 4/metabolismo , Endorfinas/metabolismo , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Masculino , Proteínas do Leite/química , Fragmentos de Peptídeos/metabolismo , Polônia , Hidrolisados de Proteína/metabolismo , Receptores Opioides mu/metabolismo , Adulto Jovem
9.
Peptides ; 62: 144-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25281794

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease with heterogeneous clinical phenotypes reflecting genetic predisposition and exposure to environmental factors. Reactions to food may play a significant role especially in young children. Milk proteins are particularly strong allergens and are additional source of bioactive peptides including ß-casomorphin-7 (BCM7, Tyr-Pro-Phe-Pro-Gly-Pro-Ile). BCM7 exerts its influence on nervous, digestive, and immune functions via the µ-opioid receptor (MOR). Proline dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) appears to be the primary degrading enzyme of BCM7. Moreover, DPPIV is known to restrict activity of proinflammatory peptides. BCM7 is considered to modulate an immune response by affecting MOR and DPPIV genes expression. In this study, we determined the MOR and DPPIV genes expression in children diagnosed with a severe form of AD. 40 healthy children and 62 children diagnosed with severe AD (AD score ≥60) were included in the study. Peripheral blood mononuclear cells (PBMCs) from the studied subjects were incubated with the peptide extracts of raw and hydrolysed cow milk with defined ß-casein genotypes (A1A1, A2A2 and A1A2) and MOR and DPPIV genes expression was determined with real-time PCR. Incubation PBMCs with peptide extracts from cow milk caused an increase of the MOR gene expression (p<0.05; p<0.001) in AD children with a simultaneous decrease in the DPPIV gene expression (p<0.001). The obtained results supplement the knowledge on the BCM7 participation in AD etiology and provide an important diagnostic tool.


Assuntos
Dermatite Atópica/tratamento farmacológico , Endorfinas/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Hipersensibilidade a Leite/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Adolescente , Alérgenos/efeitos dos fármacos , Animais , Bovinos , Criança , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dipeptidil Peptidase 4/biossíntese , Endorfinas/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Hipersensibilidade a Leite/genética , Hipersensibilidade a Leite/patologia , Proteínas do Leite/efeitos adversos , Fragmentos de Peptídeos/metabolismo , Receptores Opioides mu/biossíntese
10.
Eur J Pharm Biopharm ; 87(1): 73-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24462793

RESUMO

A niosomal formulation, functionalized with N-palmitoylglucosamine, was developed as potential brain targeted delivery system of dynorphin-B. In fact, this endogenous neuropeptide, selective agonist of k opioid receptors, is endowed with relevant pharmacological activities on the central nervous system, including a marked antinociceptive effect, but is unable to cross the blood brain barrier (BBB), thus requiring intracerebroventricular administration. Statistical design of experiments was utilized for a systematic evaluation of the influence of variations of the relative amounts of the components of the vesicle membrane (Span 60, cholesterol and SolulanC24) on vesicle mean diameter, polydispersity index and drug entrapment efficiency, chosen as the responses to optimize. A Scheffé simplex-centroid design was used to obtain the coefficients of the postulated mathematical model. The study of the response surface plots revealed that variations of the considered factors had different effects on the selected responses. The desirability function enabled for finding the optimal mixture composition, which represented the best compromise to simultaneously optimize all the three responses. The experimental values obtained with the optimized formulation were very similar to the predicted ones, proving the validity of the proposed regression model. The optimized niosomal formulation of dynorphin-B administered intravenously to mice (100mg/kg) showed a pronounced antinociceptive effect, significantly higher (P<0.05) than that given by i.v. administration of the simple solution of the peptide at the same concentration, proving its effectiveness in enabling the peptide brain delivery. These positive results suggest that the proposed approach could be successfully extended to other neuro-active peptides exerting a strong central action, even at low doses, but unable to cross the BBB.


Assuntos
Analgésicos/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/química , Dinorfinas/administração & dosagem , Endorfinas/administração & dosagem , Glicolipídeos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Dinorfinas/farmacocinética , Dinorfinas/farmacologia , Dinorfinas/uso terapêutico , Endorfinas/farmacocinética , Endorfinas/farmacologia , Endorfinas/uso terapêutico , Glicolipídeos/síntese química , Injeções Intravenosas , Injeções Intraventriculares , Lipossomos , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Receptores Opioides kappa/agonistas
11.
Eur J Pharm Biopharm ; 85(3 Pt A): 381-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23791683

RESUMO

Inefficient drug delivery to the brain is a major obstacle for pharmacological management of brain diseases. We investigated the ability of bolavesicles - monolayer membrane vesicles self-assembled from synthetic bolaamphiphiles that contain two hydrophilic head groups at each end of a hydrophobic alkyl chain - to permeate the blood-brain barrier and to deliver the encapsulated materials into the brain. Cationic vesicles with encapsulated kyotorphin and leu-enkephalin (analgesic peptides) were prepared from the bolalipids GLH-19 and GLH-20 and studied for their analgesic effects in vivo in experimental mice. The objectives were to determine: (a) whether bolavesicles can efficiently encapsulate analgesic peptides, (b) whether bolavesicles can deliver these peptides to the brain in quantities sufficient for substantial analgesic effect, and to identify the bolavesicle formulation/s that provides the highest analgetic efficiency. The results indicate that the investigated bolavesicles can deliver analgesic peptides across the blood-brain barrier and release them in the brain in quantities sufficient to elicit efficient and prolonged analgesic activity. The analgesic effect is enhanced by using bolavesicles made from a mixture the bolas GLH-19 (that contains non-hydrolyzable acetylcholine head group) and GLH-20 (that contains hydrolysable acetylcholine head group) and by incorporating chitosan pendants into the formulation. The release of the encapsulated materials (the analgesic peptides kyotorphin and leu-enkephalin) appears to be dependent on the choline esterase (ChE) activity in the brain vs. other organs and tissues. Pretreatment of experimental animals with pyridostigmine (the BBB-impermeable ChE inhibitor) enhances the analgesic effects of the studied formulations. The developed formulations and the approach for their controlled decapsulation can serve as a useful modality for brain delivery of therapeutically-active compounds.


Assuntos
Analgésicos/administração & dosagem , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Nanopartículas , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Cátions , Quitosana/química , Colinesterases/metabolismo , Preparações de Ação Retardada , Modelos Animais de Doenças , Portadores de Fármacos/química , Endorfinas/administração & dosagem , Endorfinas/farmacocinética , Endorfinas/farmacologia , Encefalina Leucina/administração & dosagem , Encefalina Leucina/farmacocinética , Encefalina Leucina/farmacologia , Furanos/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/tratamento farmacológico , Peptídeos/química , Piridonas/química , Distribuição Tecidual
12.
Peptides ; 39: 89-94, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23159788

RESUMO

MCRT (YPFPFRTic-NH(2)) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH(2). In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and L-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH(2). When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection.


Assuntos
Analgésicos Opioides/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endorfinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Bradicardia/induzido quimicamente , Endorfinas/administração & dosagem , Hipotensão/induzido quimicamente , Injeções Intravenosas , Injeções Intraventriculares , Masculino , Morfinanos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Wistar
13.
Regul Pept ; 179(1-3): 23-8, 2012 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-22960407

RESUMO

A chimeric opioid peptide (MCRT, YPFPFRTic-NH(2)) was here designed and synthesized. This peptide was based on morphiceptin (YPFP-NH(2)) and a neuropeptide FF (NPFF) derivative (PFRTic-NH(2)) sharing one proline. This peptide is intended to produce potent analgesia. MCRT was found to induce analgesic activity in a dose- and time-dependent manner, as indicated by a tail flick latency test in mice to which it had been intracerebroventricularly administered (5-60 min, 0.025-2.5 nmol/kg (0.5-50 pmol per mouse), ED(50)=1.49 nmol/kg). At 2.5nmol/kg, MCRT showed significantly higher levels of analgesic activity than morphiceptin or PFR(Tic)amide at 2500 nmol/kg. Naltrindole and cyprodime were found to partially but significantly inhibit this analgesic activity, but naloxone blocked it completely. The kappa opioid receptor antagonist nor-BNI was found to slightly inhibit MCRT and morphiceptin. Pre-injection of BIBP3226 and co-administration of NPFF and MCRT showed that NPFF receptors were involved in the analgesia of MCRT. BIBP3226 was found to weaken the analgesic effects of MCRT, but BIBP3226 could not block the analgesic effects of PFR(Tic)amide. Overall, MCRT was found to have stronger analgesic activity than morphiceptin or PFR(Tic)amide when interacting with mixed µ/δ opioid receptor interactions. MCRT also showed partial interaction with NPFF receptors.


Assuntos
Analgésicos Opioides/farmacologia , Endorfinas/farmacologia , Neuropeptídeos/farmacologia , Peptídeos Opioides/farmacologia , Receptores de Neuropeptídeos/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Analgesia/métodos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/síntese química , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Relação Dose-Resposta a Droga , Endorfinas/administração & dosagem , Endorfinas/antagonistas & inibidores , Cobaias , Masculino , Camundongos , Morfinanos/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Neuropeptídeos/administração & dosagem , Neuropeptídeos/metabolismo , Peptídeos Opioides/administração & dosagem , Peptídeos Opioides/síntese química , Prolina/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/metabolismo , Fatores de Tempo
14.
Br J Pharmacol ; 163(5): 964-73, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21366550

RESUMO

BACKGROUND AND PURPOSE: Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood-brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide - KTP-NH(2) ). EXPERIMENTAL APPROACH: We synthesized KTP-NH(2) . This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH(2) . Binding to opioid receptors and toxicity were also measured. KEY RESULTS: KTP-NH(2) , unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH(2) inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone. CONCLUSIONS AND IMPLICATIONS: Amidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH(2) may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Dipeptídeos/administração & dosagem , Dipeptídeos/uso terapêutico , Endorfinas/administração & dosagem , Endorfinas/uso terapêutico , Dor/tratamento farmacológico , Doença Aguda , Administração Oral , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Barreira Hematoencefálica/metabolismo , Doença Crônica , Dipeptídeos/síntese química , Dipeptídeos/farmacocinética , Modelos Animais de Doenças , Endorfinas/síntese química , Endorfinas/farmacocinética , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Ligação Proteica , Ratos , Ratos Wistar , Receptores Opioides/metabolismo
15.
Peptides ; 31(8): 1617-24, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20434497

RESUMO

Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)), a tetrapeptide present in the enzymatic digest of bovine beta-casein, is a selective ligand of the mu-opioid receptor. In the present study, we describe the synthesis of a series of novel morphiceptin analogs modified in positions 1-3. Two of the obtained analogs, [Dmt(1), D-Ala(2), D-1-Nal(3)]morphiceptin and [Dmt(1), D-NMeAla(2), D-1-Nal(3)]morphiceptin (Dmt-2',6'-dimethyltyrosine and d-1-Nal-3-(1-naphthyl)-D-alanine)) displayed very high mu-receptor affinity, resistance to enzymatic degradation, and remarkable supraspinally mediated analgesia, as shown in the hot-plate test after intracerebroventricular but not intravenous administration, which indicated that they could not cross the blood-brain barrier. Therefore, these two analogs were further tested in vitro and in vivo towards their possible peripheral analgesic activity and inhibitory effect on gastrointestinal (GI) motility. We report that both peptides showed strong antinociceptive effect in the writhing test after intraperitoneal administration, inhibited smooth muscle contractility in vitro and GI motility in vivo. Taken together, these findings indicate that the novel morphiceptin analogs which induce peripheral, but not central antinociception, inhibit GI transit, and possess exceptional metabolic stability, may provide an interesting approach to the development of peripherally restricted agents for the treatment of GI motility disorders, such as diarrhea or diarrhea-predominant irritable bowel syndrome.


Assuntos
Endorfinas/química , Endorfinas/síntese química , Endorfinas/farmacologia , Neurotransmissores/síntese química , Neurotransmissores/farmacologia , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Fármacos do Sistema Nervoso Periférico/síntese química , Fármacos do Sistema Nervoso Periférico/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Antidiarreicos/síntese química , Antidiarreicos/química , Antidiarreicos/metabolismo , Antidiarreicos/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Desenho de Fármacos , Estabilidade de Medicamentos , Endorfinas/administração & dosagem , Endorfinas/metabolismo , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Técnicas In Vitro , Injeções Intraperitoneais , Injeções Intraventriculares , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neurotransmissores/química , Neurotransmissores/metabolismo , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Medição da Dor , Nervos Periféricos/efeitos dos fármacos , Fármacos do Sistema Nervoso Periférico/química , Fármacos do Sistema Nervoso Periférico/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
16.
Eksp Klin Farmakol ; 72(2): 3-5, 2009.
Artigo em Russo | MEDLINE | ID: mdl-19441718

RESUMO

The effect of human and bovine beta-casomorphins-7 on the behavior of mice under conditions of 5-hydroxytryptophan (5-HT) induced hyperactivation of the serotoninergic system (head twitch test) has been studied. Intraperitoneal administration of each peptide in a dose of 1 mg/kg was shown to suppress the head twitch response in mice approximately by half (p < 0.01). This effect was completely blocked by the opioid receptor antagonist naloxone (10 mg/kg), which did not alter the behavior of mice in the head twitch test by itself. Thus, the influence of casomorphins on the serotoninergic system in vivo has been demonstrated for the first time. The role of 5-HT and opioid receptors in the mechanism of casomorphin action is discussed.


Assuntos
5-Hidroxitriptofano/farmacologia , Comportamento Animal/fisiologia , Endorfinas/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Fragmentos de Peptídeos/farmacologia , Serotonina/fisiologia , 5-Hidroxitriptofano/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Bovinos , Antagonismo de Drogas , Endorfinas/administração & dosagem , Humanos , Masculino , Camundongos , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina
17.
J Neurochem ; 109(5): 1536-43, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19383084

RESUMO

L-Kyotorphin (L-KTP), an endogenous analgesic neuropeptide, is a substrate for aminopeptidases and a proton-coupled oligopeptide transporter, PEPT2. This study examined the CSF efflux, antinociceptive response, and hydrolysis kinetics in brain of L-KTP and its synthetic diastereomer D-kyotorphin (D-KTP) in wild-type and Pept2 null mice. CSF clearance of L-KTP was slower in Pept2 null mice than in wild-type animals, and this difference was reflected in greater L-KTP-induced analgesia in Pept2 null mice. Moreover, dose-response analyses showed that the ED50 of L-KTP in Pept2-deficient animals was one-fifth of the value observed in Pept2-competent animals (4 vs. 21 nmol for null vs. wild-type mice, respectively). In contrast, the ED50 of D-KTP was very similar between the two genotypes (9-10 nmol). Likewise, there was little difference between genotypes in slope factor or baseline effects of L-KTP and D-KTP. The enhanced antinociceptive response to L-KTP in Pept2 null mice could not be explained by differences in neuropeptide degradation as Vmax and Km values did not differ between genotypes. Our results demonstrate that PEPT2 can significantly impact the analgesic response to an endogenous neuropeptide by altering CSF (and presumably brain interstitial fluid) concentrations and that it may influence the disposition and response to exogenous peptide/mimetic substrates.


Assuntos
Analgésicos/administração & dosagem , Endorfinas/administração & dosagem , Dor/tratamento farmacológico , Simportadores/genética , Analgésicos/líquido cefalorraquidiano , Analgésicos/farmacocinética , Animais , Transporte Biológico/efeitos dos fármacos , Isótopos de Carbono/metabolismo , Relação Dose-Resposta a Droga , Endorfinas/líquido cefalorraquidiano , Endorfinas/farmacocinética , Feminino , Temperatura Alta/efeitos adversos , Injeções Intraventriculares/métodos , Masculino , Manitol/metabolismo , Camundongos , Camundongos Knockout , Dor/etiologia , Medição da Dor , Tempo de Reação/efeitos dos fármacos , Trítio/metabolismo
18.
Bull Exp Biol Med ; 145(2): 210-2, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19023971

RESUMO

We studied the effect of beta-casomorphin-7 on DNA synthesis in cell populations of newborn albino rats. Intraperitoneal administration of a beta-casein fragment heptapeptide beta-casomorphin-7 (1 mg/kg, 1 or 5 injections) activated proliferative processes in the myocardium and ectodermal and endodermal epithelium of newborn rats.


Assuntos
Animais Recém-Nascidos , Replicação do DNA/efeitos dos fármacos , Endorfinas/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , DNA/metabolismo , Endorfinas/administração & dosagem , Injeções Intraperitoneais , Fragmentos de Peptídeos/administração & dosagem , Ratos , Distribuição Tecidual
19.
Bull Exp Biol Med ; 141(2): 223-5, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16984102

RESUMO

A positive correlation was revealed between stimulation of protein and DNA synthesis in preadipocytes by norepinephrine or neokyotorphin and intracellular Ca2+ concentration in these cells. Kyotorphin abolished the stimulatory effect of norepinephrine on proliferation of cultured cells and cold-induced [3H]-thymidine incorporation into DNA of mouse brown adipose tissue in vivo. These changes correlated with peptide-induced suppression of slow calcium signaling in preadipocytes.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Endorfinas/farmacologia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Temperatura Baixa , DNA/biossíntese , Endorfinas/administração & dosagem , Técnicas In Vitro , Camundongos , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Termogênese/fisiologia
20.
Int J Sports Med ; 27(4): 257-66, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16572366

RESUMO

Together with the rapidly increasing knowledge on genetic therapies as a promising new branch of regular medicine, the issue has arisen whether these techniques might be abused in the field of sports. Previous experiences have shown that drugs that are still in the experimental phases of research may find their way into the athletic world. Both the World Anti-Doping Agency (WADA) and the International Olympic Committee (IOC) have expressed concerns about this possibility. As a result, the method of gene doping has been included in the list of prohibited classes of substances and prohibited methods. This review addresses the possible ways in which knowledge gained in the field of genetic therapies may be misused in elite sports. Many genes are readily available which may potentially have an effect on athletic performance. The sporting world will eventually be faced with the phenomena of gene doping to improve athletic performance. A combination of developing detection methods based on gene arrays or proteomics and a clear education program on the associated risks seems to be the most promising preventive method to counteract the possible application of gene doping.


Assuntos
Doping nos Esportes/métodos , Terapia Genética/métodos , Doping nos Esportes/legislação & jurisprudência , Doping nos Esportes/prevenção & controle , Endorfinas/administração & dosagem , Endorfinas/genética , Eritropoetina/administração & dosagem , Terapia Genética/legislação & jurisprudência , Humanos , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/genética , Músculo Esquelético/efeitos dos fármacos , Miostatina , Neurotransmissores/administração & dosagem , Neurotransmissores/genética , Esportes/legislação & jurisprudência , Detecção do Abuso de Substâncias/métodos , Fator de Crescimento Transformador beta/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/genética
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