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1.
Neuroscience ; 290: 472-84, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25639232

RESUMO

Astrocytes synthesize and release endozepines, a family of regulatory neuropeptides, including diazepam-binding inhibitor (DBI) and its processing fragments such as the octadecaneuropeptide (ODN). At the molecular level, ODN interacts with two types of receptors, i.e. it acts as an inverse agonist of the central-type benzodiazepine receptor (CBR), and as an agonist of a G protein-coupled receptor (GPCR). ODN exerts a wide range of biological effects mediated through these two receptors and, in particular, it regulates astrocyte activity through an autocrine/paracrine mechanism involving the metabotropic receptor. More recently, it has been shown that Müller glial cells secrete phosphorylated DBI and that bisphosphorylated ODN ([bisphospho-Thr(3,9)]ODN, bpODN) has a stronger affinity for CBR than ODN. The aim of the present study was thus to investigate whether bpODN is released by mouse cortical astrocytes and to compare its potency to ODN. Using a radioimmunoassay and mass spectrometry analysis we have shown that bpODN as well as ODN were released in cultured astrocyte supernatants. Both bpODN and ODN increased astrocyte calcium event frequency but in a very different range of concentration. Indeed, ODN stimulatory effect decreased at concentrations over 10(-10)M whereas bpODN increased the calcium event frequency at similar doses. In vivo effects of bpODN and ODN were analyzed in two behavioral paradigms involving either the metabotropic receptor (anorexia) or the CBR (anxiety). As previously described, ODN (100ng, icv) induced a significant reduction of food intake. Similar effect was achieved with bpODN but at a 10 times higher dose (1000 ng, icv). Similarly, and contrasting with our hypothesis, bpODN was also 10 times less potent than ODN to induce anxiety-related behavior in the elevated zero maze test. Thus, the present data do not support that phosphorylation of ODN is involved in receptor selectivity but indicate that it rather weakens ODN activity.


Assuntos
Astrócitos/metabolismo , Inibidor da Ligação a Diazepam/metabolismo , Inibidor da Ligação a Diazepam/farmacologia , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Ansiedade/induzido quimicamente , Cálcio/metabolismo , Células Cultivadas , Inibidor da Ligação a Diazepam/análise , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/análise , Fragmentos de Peptídeos/análise , Psicotrópicos/farmacologia , Ratos
2.
Mol Biol (Mosk) ; 46(6): 894-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23350235

RESUMO

Matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) regulate proteolysis of the extracellular matrix (ECM) and as a consequence are involved in a number of physiological and pathological states, including cancer. A crucial feature of cancer progression and metastasis is the disruption of the ECM and spreading of proliferating cancer cells. Over-expression of MMPs and uPA is common for most types of cancers and correlates well with the adverse prognosis. Compounds able to modulate the activity of these proteolytic enzymes may become important agents in cancer therapy. In the present study, we examined the effect of the mu-opioid receptor selective peptide, morphiceptin, and its two synthetic analogs on mRNA and protein levels of MMP-9 and uPA in three human cancer cell lines: MCF-7, HT-29, and SH-SY5Y. Our findings indicate that in all three cell lines morphiceptin and its analogs attenuated MMP-9 expression and secretion and that this effect is not mediated by opioid receptors but is under control of the nitric oxide system. On the other hand, tested opioids up-regulated uPA levels through a mechanism that involved opioid-receptors. Different pathways by which opioid peptides exert their actionin cancer cells can explain their contradictory influence on the level of cancer markers.


Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 9 da Matriz/biossíntese , Proteínas de Neoplasias/biossíntese , Neoplasias/enzimologia , Neurotransmissores/farmacologia , Peptídeos Opioides/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/biossíntese , Analgésicos/farmacologia , Linhagem Celular Tumoral , Endorfinas/farmacologia , Matriz Extracelular/metabolismo , Humanos , Neoplasias/patologia , Proteólise/efeitos dos fármacos , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo
3.
Curr Pharm Des ; 16(9): 1126-35, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20030621

RESUMO

Opioid receptors and opioid peptides constitute the endogenous opioid system. The most relevant function of the opioid system seems to be the inhibitory modulation of nociceptive information at supraspinal, spinal and peripheral sites, although it is also implicated in the modulation of many other processes in the body. Centrally acting plant opiates, such as morphine, are the most frequently used analgesics for the relief of severe pain, even though their undesired side-effects are serious limitation to their usefulness. Opioid peptides have the potential to be pharmaceutical agents for the treatment of pain, devoid of side-effects accompanying morphine. Unfortunately, peptides are generally hydrophilic compounds that will not enter the central nervous system via passive diffusion, due to the existence of the blood-brain barrier. Peptides are also easily degraded by proteolytic enzymes which further reduces their therapeutic value. Therefore, the design of peptide analogs based on the sequence of endogenous opioid peptides must be focused on increasing bioavailability and enhancing brain uptake.


Assuntos
Analgésicos Opioides/uso terapêutico , Descoberta de Drogas/métodos , Peptídeos Opioides/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides/agonistas , Sequência de Aminoácidos , Analgésicos Opioides/farmacologia , Animais , Sistemas de Liberação de Medicamentos/métodos , Humanos , Antagonistas de Entorpecentes , Peptídeos Opioides/metabolismo , Peptídeos Opioides/farmacologia , Relação Estrutura-Atividade
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