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1.
Peptides ; 27(12): 3183-92, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17088012

RESUMO

Synthetic derivative of C-terminal fragment of CART (55-102) with reduced thiol groups, [Abu(86,94)]CART (85-102)(red), given together with amphetamine (5 mg/kg, s.c.) or cocaine (15 mg/kg, s.c.), reversed hyperlocomotion induced by these drugs at a dose of 0.1 microg but not at a higher dose. In the cerebral cortex homogenate, [Abu(86,94)]CART (85-102)(red) was nonspecifically cleaved from N- and C-termini. This peptide contains two chemically blocked Cys residues, and two others in reduced form. Concomitant with cleavage, rapid cyclization occurred. The newly formed cyclic peptides were stable. The cyclic peptide [Abu(86,94)]CART (85-102)(ox) failed to inhibit amphetamine- and cocaine-induced locomotor activity. The ability to inhibit the locomotor-stimulant activity of amphetamine was retained in [Abu(86,88,94,101)]CART (85-102), in which all Cys were replaced with 2-aminobutyric acid to prevent their pairing. Disulfide bridge formation may be an interesting mechanism that prevents proteolysis of [Abu(86,94)]CART (85-102)(red) and terminates its ability to reverse amphetamine-induced hyperlocomotion.


Assuntos
Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fragmentos de Peptídeos/fisiologia , Psicotrópicos/farmacologia , Anfetaminas/farmacologia , Animais , Cocaína/farmacologia , Cistina/genética , Cistina/metabolismo , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Fragmentos de Peptídeos/genética , Ratos , Relação Estrutura-Atividade
2.
Peptides ; 27(8): 1926-33, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16730858

RESUMO

Cocaine- and amphetamine-regulated transcript (CART) peptides attracted much attention after the discovery that the level of CART mRNA is increased in rat striatum after acute administration of cocaine and amphetamine. The most widely investigated sequence is CART (55-102), whose roles were confirmed in modulation of various physiological processes such as feeding, energy expenditure, stress control, endocrine secretion, and reward. However, peptides other than (55-102) may be generated from the CART precursor as well. This review describes biological activity of peptides derived from the CART precursor in vivo, and of synthetic CART fragments that have not been found in the nature. In particular, the activity of CART (85-102) is described, whose ability to exert behavioral responses was confirmed by the observed attenuation of the expression of sensitization to morphine-induced hyperlocomotion. This fragment also decreased the number of escape jumps evoked by naloxone in morphine-addicted mice after intracerebroventricular administration.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/fisiologia , Sequência de Aminoácidos , Animais , Humanos , Injeções Intraventriculares , Dados de Sequência Molecular , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/farmacologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/síntese química , Precursores de Proteínas/genética , Homologia de Sequência de Aminoácidos
3.
Eur J Pharmacol ; 503(1-3): 95-8, 2004 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-15496302

RESUMO

It has been suggested that drugs modulating the glutamate/N-methyl-D-aspartate (NMDA) receptor system may be useful in the treatment of alcohol dependence. The effect of neramexane, a low-to-moderate affinity uncompetitive NMDA receptor antagonist, was examined on the development and expression of ethanol dependence (withdrawal-associated audiogenic seizures) and ethanol-induced conditioned place preference. Neramexane hydrochloride (3.5 mg/kg and higher) inhibited both the development and expression of ethanol dependence. Neramexane hydrochloride also inhibited the acquisition (1.75 mg/kg and higher) and expression (3.5 mg/kg and higher) of ethanol-induced place preference. Our data support therapeutic potential of neramexane as a treatment for alcohol abuse.


Assuntos
Dissuasores de Álcool , Alcoolismo/psicologia , Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Ciclopentanos/farmacologia , Etanol/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Taurina/análogos & derivados , Acamprosato , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Reforço Psicológico , Convulsões/fisiopatologia , Síndrome de Abstinência a Substâncias/psicologia , Taurina/farmacologia
4.
Neuropeptides ; 38(5): 277-82, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15464192

RESUMO

Our previous studies demonstrated that endogenous ligand of nociceptin (NOP) receptor, nociceptin(1-17) (also known as orphanin FQ), inhibits morphine-withdrawal syndrome measured as wet dog shakes in rats [Life Sci. 66 (2000) PL119]. This peptide is metabolized in the spinal cord, both in vitro and in vivo, to shorter fragments, including nociceptin(1-11) and nociceptin(1-6). These fragments, formed after cleavage by endogenous peptidase, are behaviorally active and modulate nociception in a bi-phasic process [Peptides 20 (1999) 239]. As these peptides induced transient naloxone-reversible analgesia in behavioral tests [Peptides 20 (1999) 239], in the present study we tested the influence of nociceptin(1-11) (10 and 20 microg) and nociceptin(1-6) (10, 20 and 40 microg) on the morphine-withdrawal syndrome in rats. Furthermore, the modified fragment of nociceptin(1-6) with an opioid-message domain achieved by replacement of Phe1 with Tyr was tested. Morphine-withdrawal syndrome was precipitated by the i.p. injection of naloxone hydrochloride (2 mg/kg), 72 h after implantation of morphine pellets. The wet-dog shakes were chosen for statistical analyses of the abstinence signs. The results show that nociceptin(1-11) and (1-6) attenuate this morphine-withdrawal symptom. The replacement of Phe1 with Tyr in nociceptin(1-6) fragment did not potentiate the influence of nociceptin(1-6) on wet dog shakes precipitated by naloxone in morphine-dependent rats.


Assuntos
Dependência de Morfina , Peptídeos Opioides , Fragmentos de Peptídeos , Síndrome de Abstinência a Substâncias , Tirosina/metabolismo , Animais , Masculino , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/química , Peptídeos Opioides/farmacologia , Peptídeos Opioides/uso terapêutico , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Ratos , Ratos Wistar , Receptores Opioides/agonistas , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Vasodilatadores/química , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Nociceptina
5.
Postepy Hig Med Dosw (Online) ; 58: 209-15, 2004 Apr 15.
Artigo em Polonês | MEDLINE | ID: mdl-15114256

RESUMO

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide discovered in the middle of the 1990. It possesses an amino acid sequence very similar to those of endogenous opioid peptides (particularly dynorphin A). However, N/OFQ lacks the N-terminal tyrosine necessary for activation of mu-, kappa- and delta- opioid receptors and therefore does not bind to opioid receptors but to its own nociceptin receptor (NOP). Opioid peptides also do not bind to the NOP receptor. In spite of structural similarities, the pharmacological profile of N/OFQ is different from and, in many cases, opposite to that of the opioids. Intracerebroventricular injection of N/OFQ induces hyperalgesia and decreases the analgesic actions of opioids, but induces analgesia when given intrathecally. N/OFQ blocks the rewarding effects of morphine, ethanol, and psychostimulants such as cocaine and amphetamine, but given alone it does not have rewarding effect. N/OFQ is metabolized to shorter fragments, such as N/OFQ(1-13), N/OFQ(1-11), N/OFQ(1-7) and N/OFQ(1-6). These fragments show biological activity. The effects of N/OFQ include regulation of the release of numerous neurotransmitters and hormones, as NOP receptors are located presynaptically in different brain structures. The aim of this review was to present current opinion on the role of N/OFQ in nociception, reward and drug dependence.


Assuntos
Peptídeos Opioides/administração & dosagem , Peptídeos Opioides/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Receptores Opioides/metabolismo , Animais , Hormônios/metabolismo , Humanos , Hiperalgesia/induzido quimicamente , Injeções Intraventriculares , Injeções Espinhais , Neurotransmissores/metabolismo , Peptídeos Opioides/química , Dor/fisiopatologia , Fragmentos de Peptídeos/química , Recompensa , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Receptor de Nociceptina
6.
Eur J Pharmacol ; 474(2-3): 233-9, 2003 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-12921868

RESUMO

Nociceptin (also called orphanin FQ), a 17-amino-acid peptide, is the natural ligand of the nociceptin opioid peptide (NOP) receptor. This peptide shows similarities, in its structure, to opioid peptides, mainly to dynorphin A. However, unlike opioid peptides, it does not produce a conditioned place preference or aversion but inhibits rewarding effect of drugs of abuse. The present study was designed to examine the ability of nociceptin to block the acquisition of amphetamine-induced place preference, and the development of amphetamine-induced sensitization to stereotypy in rats. Our experiments indicated that repeated administration of nociceptin at increasing doses during conditioning significantly attenuated the reinforcing effect of amphetamine in conditioned place preference paradigm. Nociceptin did not change the acute effect of amphetamine-induced stereotypy but prevented the development of sensitization to stereotypy measured on the challenge day. Our results suggest the involvement of nociceptin in long-lasting neuronal adaptation after repeated amphetamine treatment.


Assuntos
Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Peptídeos Opioides/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Condicionamento Psicológico/fisiologia , Masculino , Ratos , Ratos Wistar , Comportamento Estereotipado/fisiologia , Nociceptina
7.
Neuroreport ; 14(4): 601-4, 2003 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-12657894

RESUMO

The non-peptidergic opioid receptor-like 1 (ORL1, OP4) receptor ligand, Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one], is a full agonist of the OP4 receptor. The aim of this study was to evaluate whether this compound influences morphine antinociception and dependence in mice. Ro 64-6198 inhibits the acute analgesic effect of morphine in the tail-immersion test, however, when given chronically during the acquisition of morphine dependence, development of this dependence is not prevented. The acute injection of Ro 64-6198 suppresses withdrawal escape jumps in morphine dependent mice, though this effect may be a result of the loss of locomotor activity induced by this compound and/or its myorelaxant action. The study provides evidence that stimulation of the OP4 receptor suppresses acute morphine antinociception, but is not sufficient to inhibit the development of morphine dependence in mice.


Assuntos
Imidazóis/farmacologia , Dependência de Morfina , Morfina/antagonistas & inibidores , Receptores Opioides/agonistas , Compostos de Espiro/farmacologia , Animais , Comportamento Animal , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Reação de Fuga/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/metabolismo , Medição da Dor/efeitos dos fármacos , Pentobarbital/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Fatores de Tempo , Receptor de Nociceptina , Nociceptina
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