RESUMO
One of the causes of sudden cardiac death is arrhythmia after acute myocardial ischemia. After ischemia, endogenous orphanin (N/OFQ) plays a role in the development of arrhythmias. It is discussed in this paper how nonpeptide orphanin receptor (ORL1) antagonists such as J-113397, SB-612111 and compound-24 (C-24) affect arrhythmia in rats following acute myocardial ischemia and what the optimal concentrations for these antagonists are. The electrocardiogram of the rat was recorded as part of the experiment. The concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the myocardium were measured following euthanasia. Following the use of three antagonists, we found the lowest inflammatory factor concentrations and the smallest number of ischemic arrhythmia episodes. All of them had a small impact on cardiac function. LF/HF values were significantly reduced in all three antagonist groups, suggesting that they are involved in the regulation of sympathetic nerves. In conclusion, pretreatment with the three antagonist groups can effectively reduce the concentration of TNF-α and IL-1ß, and the occurrence of arrhythmias after ischemia can also be significantly reduced. Inflammation and sympathetic activity may be related to the mechanism of action of antagonists.
Assuntos
Doença da Artéria Coronariana , Isquemia Miocárdica , Ratos , Animais , Fator de Necrose Tumoral alfa , Isquemia Miocárdica/complicações , Isquemia Miocárdica/patologia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/patologia , Miocárdio/patologia , Isquemia/patologiaRESUMO
BACKGROUND: The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. METHODS: Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the "drinking in the dark" (DID) model in C57BL/6J mice. RESULTS: We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake. CONCLUSIONS: The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.
Assuntos
Dissuasores de Álcool/uso terapêutico , Consumo de Bebidas Alcoólicas/prevenção & controle , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Animais , Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Consumo Excessivo de Bebidas Alcoólicas/genética , Consumo Excessivo de Bebidas Alcoólicas/psicologia , Depressores do Sistema Nervoso Central/sangue , Cicloeptanos/farmacologia , Escuridão , Relação Dose-Resposta a Droga , Etanol/sangue , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacologia , Receptores Opioides/agonistas , Receptores Opioides/genética , Receptor de NociceptinaRESUMO
Nociceptin/Orphanin FQ (N/OFQ) and its NOP receptor are highly expressed in motor areas of the rodent, nonhuman, and human primate brain, such as primary motor cortex, thalamus, globus pallidus, striatum, and substantia nigra. Endogenous N/OFQ negatively regulates motor behavior and dopamine transmission through NOP receptors expressed by dopaminergic neurons of the substantia nigra compacta. Consistent with the existence of an N/OFQ tone over dopaminergic transmission, blockade of NOP receptor antagonists increases striatal dopamine release. In this chapter, we will review the evidence linking the N/OFQ-NOP receptor system to Parkinson's disease (PD). We will first discuss data showing that the central N/OFQ-NOP receptor system undergoes plastic changes in different basal ganglia nuclei following dopamine depletion. Then we will show that NOP receptor antagonists relieve motor deficits in different rodent and nonhuman primate models of PD. Mechanistically, NOP receptor blockade in substantia nigra reticulata results in rebalancing of the inhibitory GABAergic and excitatory glutamatergic inputs impinging on nigro-thalamic GABAergic neurons, leading to thalamic disinhibition. We will also present data showing that, in addition to motor symptoms, N/OFQ also plays a role in the parkinsonian neurodegeneration. In fact, NOP receptor antagonists possess neuroprotective/neurorescue properties in in vitro and in vivo models of PD.
Assuntos
Peptídeos Opioides/farmacologia , Doença de Parkinson , Substância Negra/metabolismo , Animais , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos Opioides/química , Peptídeos Opioides/metabolismo , Doença de Parkinson/fisiopatologia , Ratos , Ratos Sprague-Dawley , Substância Negra/química , NociceptinaRESUMO
To investigate whether the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) contributes to the death of dopamine neurons in Parkinson's disease, we undertook a genetic and a pharmacological approach using NOP receptor knockout (NOP(-/-)) mice, and the selective and potent small molecule NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). Stereological unbiased methods were used to estimate the total number of dopamine neurons in the substantia nigra of i) NOP(-/-) mice acutely treated with the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), ii) naïve mice subacutely treated with MPTP, alone or in combination with SB-612111, iii) rats injected with a recombinant adeno-associated viral (AAV) vector overexpressing human mutant p.A53T α-synuclein, treated with vehicle or SB-612111. NOP(-/-) mice showed a 50% greater amount of nigral dopamine neurons spared in response to acute MPTP compared to controls, which was associated with a milder motor impairment. SB-612111, given 4 days after MPTP treatment to mimic the clinical condition, prevented the loss of nigral dopamine neurons and striatal dopaminergic terminals caused by subacute MPTP. SB-612111, administered a week after the AAV injections in a clinically-driven protocol, also increased by 50% both the number of spared nigral dopamine neurons and striatal dopamine terminals, and prevented accompanying motor deficits induced by α-synuclein. We conclude that endogenous N/OFQ contributes to dopamine neuron loss in pathogenic and etiologic models of Parkinson's disease through NOP receptor-mediated mechanisms. NOP receptor antagonists might prove effective as disease-modifying agents in Parkinson's disease, through the rescue of degenerating nigral dopamine neurons and/or the protection of the healthy ones.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Receptores Opioides/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia , Animais , Cicloeptanos/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Deleção de Genes , Locomoção/efeitos dos fármacos , Intoxicação por MPTP , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas de Entorpecentes/administração & dosagem , Transtornos Parkinsonianos/genética , Piperidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Opioides/genética , Substância Negra/efeitos dos fármacos , Receptor de NociceptinaRESUMO
The role of stress in the etiology of depression has been largely reported. In this line, exogenous glucocorticoids are employed to mimic the influence of stress on the development of depression. The N/OFQ-NOP receptor system has been implicated in the modulation of stress and emotional behaviors. In fact, the blockade of NOP receptors induces antidepressant effects and increases resilience to acute stress. This study investigated the effects of the NOP receptor blockade on dexamethasone-treated mice exposed to acute and prolonged swimming stress. Swiss and NOP(+/+) and NOP(-/-) mice were treated with dexamethasone, and the protective effects of the NOP antagonist SB-612111 (10 mg/kg, ip) or imipramine (20 mg/kg, ip) were investigated in three swimming sessions. The re-exposure to swim stress increased immobility time in Swiss and NOP(+/+), but not in NOP(-/-) mice. Acute and repeated dexamethasone administration induced a further increase in the immobility time, and facilitated body weight loss in Swiss mice. Single administration of SB-612111, but not imipramine, prevented swimming stress- and dexamethasone-induced increase in the immobility time. Repeated administrations of SB-612111 prevented the deleterious effects of 5 days of dexamethasone treatment. Imipramine also partially prevented the effects of repeated glucocorticoid administration on the immobility time, but did not affect the body weight loss. NOP(-/-) mice were more resistant than NOP(+/+) mice to inescapable swimming stress, but not dexamethasone-induced increase in the immobility time and body weight loss. In conclusion, the blockade of the NOP receptor facilitates an active stress copying response and attenuates body weight loss due to repeated stress.
RESUMO
SB612111 ((5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol) is a potent and selective antagonist of the nociception/orphanin FQ peptide (NOP) receptor. In the process of synthesizing cis-SB612111 to support ongoing animal studies, several key steps of the published syntheses in the patent literature proceeded in low yields in our hands, particularly with the route to the key intermediate piperidine 3, the reduction of amide 14, lactone 17 formation and the final reductive amination between 18 and 3 in the diastereoselective synthesis. We have thus explored various reaction conditions and successfully improved the yields for the necessary synthetic steps. We herein report our modified synthesis of SB612111 as the cis-diastereomers.
RESUMO
RATIONALE: Pharmacological and genetic evidence support antidepressant-like effects elicited by the blockade of the NOP receptor. The learned helplessness (LH) model employs uncontrollable and unpredictable electric footshocks as a stressor stimulus to induce a depressive-like phenotype that can be reversed by classical antidepressants. OBJECTIVES: The present study aimed to evaluate the action of NOP receptor antagonists in helpless mice. METHODS: Male Swiss mice were subjected to the three steps of the LH paradigm (i.e., (1) induction, (2) screening, and (3) test). Only helpless animals were subjected to the test session. During the test session, animals were placed in the electrified chamber and the latency to escape after the footshock and the frequency of escape failures were recorded. The effect of the following treatments administered before the test session were evaluated: nortriptyline (30 mg/kg, ip, 60 min), fluoxetine (30 mg/kg, ip, four consecutive days of treatment), and NOP antagonists SB-612111 (1-10 mg/kg, ip, 30 min) and UFP-101 (1-10 nmol, icv, 5 min). To rule out possible biases, the effects of treatments on controllable stressful and non stressful situations were assessed. RESULTS: In helpless mice, nortriptyline, fluoxetine, UFP-101 (3-10 nmol), and SB-612111 (3-10 mg/kg) significantly reduced escape latencies and escape failures. No effects of drug treatments were observed in mice subjected to the controllable electric footshocks and non stressful situations. CONCLUSIONS: Acute treatment with NOP antagonists reversed helplessness similarly to the classical antidepressants. These findings support the proposal that NOP receptor antagonists are worthy of development as innovative antidepressant drugs.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cicloeptanos/farmacologia , Fluoxetina/farmacologia , Desamparo Aprendido , Antagonistas de Entorpecentes/farmacologia , Nortriptilina/farmacologia , Peptídeos Opioides/farmacologia , Piperidinas/farmacologia , Animais , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos , Peptídeos Opioides/antagonistas & inibidores , Receptores Opioides , Transdução de Sinais/efeitos dos fármacos , Receptor de Nociceptina , NociceptinaRESUMO
BACKGROUND AND PURPOSE: Nociceptin/orphanin FQ (N/OFQ) receptor (NOP) agonists produce anxiolytic-like effects in rodents while antagonists promote antidepressant-like effects. The aim of this study was to investigate the effect on anxiety and depression of NOP receptor partial agonists such as the peptides [F/G]N/OFQ(1-13)NH2 and UFP-113 and the non-peptide AT-090. EXPERIMENTAL APPROACH: In vitro AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 were tested for their ability to promote NOP/G-protein and NOP/ß-arrestin 2 interaction, using a bioluminescence resonance energy transfer assay. In vivo, they were tested in mice in the elevated plus maze (EPM) and in the forced swim (FST) tests. NOP partial agonists effects were systematically compared to those of full agonists (N/OFQ and Ro 65-6570) and antagonists (UFP-101 and SB-612111). KEY RESULTS: In vitro, AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 promoted NOP/G protein interaction, with maximal effects lower than those evoked by N/OFQ and Ro 65-6570. AT-090 behaved as a NOP partial agonist also in inducing ß-arrestin 2 recruitment, while UFP-113 and [F/G]N/OFQ(1-13)NH2 were inactive in this assay. In vivo, AT-090 induced anxiolytic-like effects in the EPM but was inactive in the FST. Opposite results were obtained with UFP-113 and [F/G]N/OFQ(1-13)NH2. CONCLUSIONS AND IMPLICATIONS: NOP ligands producing similar effects on NOP/G protein interaction (partial agonism) but showing different effects on ß-arrestin 2 recruitment (partial agonism vs antagonism) elicited different actions on anxiety and mood. These results suggest that the action of a NOP ligand on emotional states is better predicted based on its ß-arrestin 2 rather than G-protein efficacy.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Receptores Opioides/efeitos dos fármacos , beta-Arrestina 2/metabolismo , Animais , Cicloeptanos/farmacologia , Emoções/efeitos dos fármacos , Proteínas de Ligação ao GTP/agonistas , Células HEK293 , Humanos , Imidazóis/farmacologia , Ligantes , Camundongos , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Natação/psicologia , beta-Arrestina 2/agonistas , Receptor de NociceptinaRESUMO
The nociceptin receptor (NOP) and its ligand nociceptin/orphanin FQ (N/OFQ) have been shown to exert a modulatory effect on immune cells during sepsis. We evaluated the suitability of an experimental lipopolysaccharide (LPS)-induced sepsis model for studying changes in the nociceptin system. C57BL/6 mice BALB/c mice and Wistar rats were inoculated with different doses of LPS with or without a nociceptin receptor antagonist (UFP-101 or SB-612111). In C57BL/6 mice LPS 0.85 mg/kg injection produced no septic response, whereas 1.2mg/kg produced a profound response within 5h. In BALB/c mice, LPS 4 mg/kg produced no response, whereas 7 mg/kg resulted in a profound response within 24h. In Wistar rats LPS 15 mg/kg caused no septic response in 6/10 animals, whereas 25mg/kg resulted in marked lethargy before 24h. Splenic interleukin-1ß mRNA in BALB/c mice, and serum TNF-α concentrations in Wistar rats increased after LPS injection in a dose-dependent manner, but were undetectable in control animals, indicating that LPS had stimulated an inflammatory reaction. IL-1ß and TNF-α concentrations in LPS-treated animals were unaffected by administration of a NOP antagonist. Similarly NOP antagonists had no effect on survival or expression of mRNA for NOP or ppN/OFQ (the N/OFQ precursor) in a variety of tissues. In these animal models, the dose-response curve for LPS was too steep to allow use in survival studies and no changes in the N/OFQ system occurred within 24h. We conclude that LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis.
Assuntos
Lipopolissacarídeos/toxicidade , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Sepse/metabolismo , Animais , Cicloeptanos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos Opioides/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Sepse/patologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor de Nociceptina , NociceptinaRESUMO
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.