RESUMO
RATIONALE: Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis. OBJECTIVES: Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists. METHODS: Mice were treated prior to stress with the NOP agonist Ro 65-6570, and immobility time in the forced swimming task and corticosterone levels were measured. Additionally, the role of endogenous glucocorticoids and CRF was investigated using the glucocorticoid receptor antagonist mifepristone and the CRF1 antagonist antalarmin in the mediation of the effects of Ro 65-6570. RESULTS: The NOP agonist in a dose-dependent manner further increased the immobility of mice in the second swimming session compared to vehicle. By contrast, under the same conditions, the administration of the NOP antagonist SB-612111 before stress reduced immobility, while the antidepressant nortriptyline was inactive. Concerning in-serum corticosterone in mice treated with vehicle, nortriptyline, or SB-612111, a significant decrease was observed after re-exposition to stress, but no differences were detected in Ro 65-6570-treated mice. Administration of mifepristone or antalarmin blocked the Ro 65-6570-induced increase in the immobility time in the second swimming session. CONCLUSIONS: Present findings suggest that NOP agonists increase vulnerability to depression by hyperactivating the HPA axis and then increasing stress circulating hormones and CRF1 receptor signaling.
Assuntos
Cicloeptanos , Imidazóis , Peptídeos Opioides , Piperidinas , Receptores Opioides , Compostos de Espiro , Camundongos , Animais , Receptores Opioides/fisiologia , Peptídeos Opioides/metabolismo , Glucocorticoides/farmacologia , Nortriptilina/farmacologia , Receptor de Nociceptina , Corticosterona/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Mifepristona/farmacologia , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
The ability to successfully cope with stress is known as 'resilience', and resilient individuals are less prone to develop psychopathologies. Understanding the neurobiological mechanisms of resilience may be instrumental to improve current therapies and benefit high-risk subjects. This review summarizes the complex interplay that exists between physiological and pathological responses to stressful events and the nociceptin/orphanin FQ (N/OFQ) - N/OFQ receptor (NOP) system, including: the effects of stress in regulating N/OFQ release and NOP expression; the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal axis; behavioral studies; and evidence in humans correlating this peptidergic system with psychopathologies. Available findings support the view that N/OFQ signaling stimulates the hypothalamic-pituitary-adrenal axis, thus increasing stress circulating hormones and corticotropin-releasing factor signaling. Additionally, activation of the NOP receptor inhibits monoamine transmission, including 5-HT, and this may contribute to maladaptive outcomes of stress. Ultimately, the N/OFQ system seems to have an important role in stress vulnerability, and blockade of NOP signaling may provide an innovative strategy for the treatment of stress related psychopathologies.
Assuntos
Peptídeos Opioides/fisiologia , Receptores Opioides/fisiologia , Estresse Psicológico/etiologia , Animais , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Antagonistas de Entorpecentes/farmacologia , Sistema Hipófise-Suprarrenal/fisiologia , Estresse Psicológico/tratamento farmacológico , Receptor de Nociceptina , 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
Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65-6570 (0.01-1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001-0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1-10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder.
Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/fisiopatologia , Hipercinese/fisiopatologia , Imidazóis/administração & dosagem , Metilfenidato/administração & dosagem , Receptores Opioides/fisiologia , Compostos de Espiro/administração & dosagem , Animais , Feminino , Hipercinese/induzido quimicamente , Camundongos , Receptores Opioides/agonistas , Ácido Valproico/administração & dosagem , Receptor de NociceptinaRESUMO
RATIONALE: Depression and anxiety frequently co-occur, and this has important clinical implications. Previous studies showed that activation of the nociceptin/orphanin FQ receptor (NOP) elicits anxiolytic effects, while its blockade promotes consistent antidepressant actions. NOP antagonists are effective in reversing footshock-induced depressive-like behaviors, but their effects on stress-induced anxiety are still unclear. OBJECTIVE: This study aimed to investigate the effects of the NOP antagonist SB-612111 on footshock stress-induced anxiety behaviors. METHODS: Male Swiss mice were exposed to inescapable electric footshock stress, and behavioral phenotype was screened based on the ability to escape from footshock (i.e., helpless or non-helpless). Animals were then treated with diazepam (1 mg/kg) and SB-612111 (0.1-10 mg/kg), and their behavior was assessed in the elevated plus-maze (EPM) and open field test. RESULTS: When compared with non-stressed mice, helpless, but not non-helpless, animals displayed significant reductions in the time spent in and entries into open arms in the EPM. Diazepam significantly increased open arms exploration in helpless, non-helpless, and non-stressed mice. However, treatment with the NOP antagonist SB-612111 was inactive in naive mice, while it reversed anxiogenic-related behaviors in helpless mice and increased anxiety states in non-helpless mice. No effects on locomotion were observed. CONCLUSION: Helpless mice displayed increased anxiety compared to non-stressed and non-helpless animals, thus supporting use of this approach as an animal model to investigate anxiety/depression comorbidity. Additionally, SB-612111 modulated anxiety-like behaviors in male mice depending on individual stress susceptibility. Ultimately, NOP antagonists could be useful for treating anxiety in depressed patients.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Cicloeptanos/uso terapêutico , Piperidinas/uso terapêutico , Receptores Opioides/fisiologia , Estresse Psicológico/tratamento farmacológico , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/psicologia , Depressão/tratamento farmacológico , Depressão/psicologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Masculino , Camundongos , Estresse Psicológico/psicologia , Receptor de NociceptinaRESUMO
Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor named NPS receptor. The NPS system controls several biological functions, including anxiety, wakefulness, locomotor activity, food intake, and pain transmission. A growing body of evidence supports facilitatory effects for NPS over dopaminergic neurotransmission. The present study was aimed to investigate the role of dopamine receptors signaling in the antinociceptive effects of NPS in the mouse formalin test. The following dopamine receptor antagonists were employed: SCH 23390 (selective dopamine D1 antagonist, 0.05â¯mg/kg, ip), haloperidol (non-selective dopamine D2-like receptor antagonist; 0.03â¯mg/kg, ip), and sulpiride (selective dopamine D2-like receptor antagonist; 25â¯mg/kg, ip). Mice were pretreated with dopamine antagonists before the supraspinal administration of NPS (0.1â¯nmol, icv). Morphine (5â¯mg/kg, sc) and indomethacin (10â¯mg/kg, ip) were used as positive controls to set up the experimental conditions. Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was only active at phase 2. Central NPS significantly reduced formalin-induced nociception during both phases. The systemic administration of SCH 23390 slightly blocked the effects of NPS only during phase 2. Haloperidol prevented NPS-induced antinociceptive effects. Similar to haloperidol, sulpiride also counteracted the antinociceptive effects of NPS in both phases of the formalin test. In conclusion, the present findings suggest that the analgesic effects of NPS are linked with dopaminergic neurotransmission mainly through dopamine D2-like receptor signaling.
Assuntos
Analgésicos/farmacologia , Formaldeído/efeitos adversos , Neuropeptídeos/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.
Assuntos
Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Resiliência Psicológica/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Cicloeptanos/administração & dosagem , Cicloeptanos/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Nortriptilina/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/genética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologia , Estresse Psicológico/fisiopatologia , Receptor de Nociceptina , NociceptinaRESUMO
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 , Receptor de Nociceptina , NociceptinaRESUMO
RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests. OBJECTIVES: The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice. METHODS: Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests. RESULTS: Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketamine in the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine. CONCLUSIONS: NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.
Assuntos
Antidepressivos/farmacologia , Fluoxetina/farmacologia , Desamparo Aprendido , Ketamina/farmacologia , Nortriptilina/farmacologia , Peptídeos Opioides/agonistas , Anestésicos Dissociativos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Fluoxetina/antagonistas & inibidores , Imidazóis/farmacologia , Masculino , Camundongos , Nortriptilina/antagonistas & inibidores , Peptídeos Opioides/metabolismo , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Compostos de Espiro/farmacologia , Natação/fisiologia , Natação/psicologia , NociceptinaRESUMO
The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the G-protein-coupled receptor NOP. Cells from the immune system express the precursor preproN/OFQ and the NOP receptor, as well as secrete N/OFQ. The activation of the N/OFQ-NOP pathway can regulate inflammatory and immune responses. Several immune activities, including leukocyte migration, cytokine and chemokine production, and lymphocytes proliferation are influenced by NOP activation. It was demonstrated that cytokines and other stimuli such as Toll-like receptor agonist (e.g., lipopolysaccharide) induce N/OFQ production by cells from innate and adaptive immune response. In this context, N/OFQ could modulate the outcome of inflammatory diseases, such as sepsis and immune-mediated pathologies by mechanisms not clearly elucidated. In fact, clinical studies revealed increased levels of N/OFQ under sepsis, arthritis, and Parkinson's disease. Preclinical and clinical studies pointed to the blockade of NOP receptor signaling as successful strategy for the treatment of inflammatory diseases. This review is focused on experimental and clinical data that suggest the participation of N/OFQ-NOP receptor activation in the modulation of the immune response, highlighting the immunomodulatory potential of NOP antagonists in the inflammatory and immunological disturbances.
Assuntos
Doenças Autoimunes/metabolismo , Autoimunidade , Imunidade Inata , Leucócitos/metabolismo , Modelos Imunológicos , Peptídeos Opioides/metabolismo , Receptores Opioides/agonistas , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Leucócitos/imunologia , Estresse Oxidativo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Receptores Opioides/metabolismo , Transdução de Sinais , Estresse Fisiológico , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Receptor de Nociceptina , NociceptinaRESUMO
Studies have shown a close relationship between anxiety and aversive memory processing, but few animal models are suitable for investigating the effects of a given compound on anxiety and memory simultaneously. A growing body of evidence suggests anxiolytic and amnesic effects of nociceptin/orphanin FQ (N/OFQ). The mouse elevated T-maze (ETM) has been shown to detect the effects of drugs on anxiety and memory at the same time. In this study, the effects of intracerebroventricular N/OFQ injected before or immediately after training session were assessed in the ETM task. When pretraining injected, N/OFQ 0.1 nmol significantly decreased the latency to enter an open arm in the training session compared to control, which is suggestive of anxiolysis. In addition, N/OFQ (0.1 and 1 nmol) significantly reduced the latency to enter an open arm during the test session compared to control, thus suggesting memory impairments. However, when N/OFQ was administered posttraining, it did not affect memory retrieval. No alterations in locomotion were detected in N/OFQ-treated mice in the open field test. In conclusion, these findings are discussed considering the simultaneous anxiolytic and amnesic effects of N/OFQ.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Memória/efeitos dos fármacos , Peptídeos Opioides/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , NociceptinaRESUMO
AIMS: The present study aimed to investigate the intraplantar (ipl) and central (icv) effects of neuropeptide S (NPS) in the formalin test and to evaluate the role of adenosine receptors, mainly A1 and A2A, in mediating such effects. MAIN METHODS: The ipl injection of formalin was used to assess the nociceptive activity. Moreover, by pretreating mice with non-selective and selective antagonists of adenosine receptors, the effects of icv NPS on formalin-induced ongoing nociception were assessed. KEY FINDINGS: Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was active only at the later nociceptive phase. The ipl injection of NPS (alone or combined with formalin) did not modify the nociceptive response. However, icv NPS significantly reduced formalin-induced nociception during both phases. Caffeine (3 mg/kg, ip), a non-selective adenosine receptor antagonist, prevented NPS-induced antinociceptive effects. Similar to caffeine, icv ZM241385 (0.01 nmol), an A2A receptor antagonist, prevented the antinociceptive effects of NPS. Moreover, icv DPCPX (0.001 nmol), an A1 receptor antagonist, blocked the effects of NPS only during phase 1. SIGNIFICANCE: The above findings suggest that: (i) NPS evokes central antinociceptive effects by activating both A1 and A2A receptors during phase 1, but (ii) only the adenosine A2A receptor during phase 2 of the formalin test.
Assuntos
Neuropeptídeos/química , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Receptor A1 de Adenosina/fisiologia , Receptor A2A de Adenosina/fisiologia , Adenosina/química , Animais , Formaldeído/química , Masculino , Camundongos , Medição da Dor/efeitos dos fármacosRESUMO
Neuropeptide S (NPS) is a 20-aminoacid peptide that selectively activates a G-protein coupled receptor named NPSR. Preclinical studies have shown that NPSR activation promotes anxiolysis, hyperlocomotion, arousal and weakfullness. Previous findings suggest that dopamine neurotransmission plays a role in the actions of NPS. Based on the close relationship between dopamine and Parkinson disease (PD) and on the evidence that NPSR are expressed on brain dopaminergic nuclei, the present study investigated the effects of NPS in motor deficits induced by intracerebroventricular (icv) administration of the dopaminergic neurotoxin 6-OHDA in the mouse rotarod test. 6-OHDA injection evoked motor deficits and significantly reduced tyrosine hidroxylase (TH)-positive cells in the substantia nigra (SN) and ventral tegmental area. However, a positive correlation was found only between the motor performance of 6-OHDA-injected mice and the number of TH-positive cells in SN. The systemic administration of l-DOPA+benserazide (25+6.25 mg/kg) counteracted 6-OHDA-induced motor deficits in mice. Similar to L-DOPA, the icv injection of NPS (0.1 and 1 nmol) reversed motor deficits evoked by 6-OHDA. In conclusion, NPS attenuated 6-OHDA-induced motor impairments in mice assessed in the rota-rod test. We discussed the beneficial actions of NPS based on a putative facilitation of dopaminergic neurotransmission in the brain. Finally, these findings candidate NPSR agonists as a potential innovative treatment for PD.
Assuntos
Adrenérgicos/toxicidade , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/etiologia , Oxidopamina/toxicidade , Receptores Acoplados a Proteínas G/uso terapêutico , Análise de Variância , Animais , Área Sob a Curva , Modelos Animais de Doenças , Dopaminérgicos/uso terapêutico , Feminino , Levodopa/uso terapêutico , Camundongos , Teste de Desempenho do Rota-Rod , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Neuropeptide S (NPS) and its receptor were recently discovered in the central nervous system. In rodents, NPS promotes hyperlocomotion, wakefulness, anxiolysis, anorexia, and analgesia and enhances memory when injected intracerebroventricularly (i.c.v.). Herein, NPS at different doses (0.01, 0.1 and 1nmol) was i.c.v. administered in mice challenged with pentylenetetrazole (PTZ; 60mg/kg) repeatedly injected. Aiming to assess behavioral alterations and oxidative damage to macromolecules in the brain, NPS was injected 5min prior to the last dose of PTZ. The administration of NPS only at 1nmol increased the duration of seizures evoked by PTZ, without modifying frequency and latency of seizures. Biochemical analysis revealed that NPS attenuated PTZ-induced oxidative damage to proteins and lipids in the hippocampus and cerebral cortex. In contrast, the administration of NPS to PTZ-treated mice increased DNA damage in the hippocampus, but not cerebral cortex. In conclusion, this is the first evidence of the potential proconvulsive effects of NPS in mice. The protective effects of NPS against lipid and protein oxidative damage in the mouse hippocampus and cerebral cortex evoked by PTZ-induced seizures are quite unexpected. The present findings were discussed analyzing the paradoxical effects of NPS: facilitation of convulsive behavior and protection against oxidative damage to lipids and proteins.
Assuntos
Neuropeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Convulsões/tratamento farmacológico , Animais , Comportamento Animal , Peroxidação de Lipídeos , Masculino , Camundongos , Neuropeptídeos/uso terapêutico , Convulsões/metabolismoRESUMO
Activation of adenosine receptors modifies the action of classic neurotransmitters (i.e. dopamine, glutamate and acetylcholine) and other neuromodulators, like vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide S (NPS). Similarly to adenosine, NPS is involved in the regulation of stimulus and response to fear and arousal. Thus, the present study investigates the effects of NPS on locomotor activity in mice treated with or without α,ß-methylene adenosine 5'-diphosphate (AOPCP), the inhibitor of ecto-5'-nucleotidase. Additionally, we evaluate the activity of ecto-5'-nucleotidase in brain slices of mice treated with or without NPS. Male adult CF-1 mice received i.c.v. NPS as 0.1 nmol injection with or without pre-treatment with 1 nmol α,ß-methylene adenosine 5'-diphosphate (AOPCP), the selective inhibitor of ecto-5'-nucleotidase, to evaluate locomotor activity. In another set of experiments, mice received i.c.v. infusion of 0.1 nmol NPS to assay enzymatic activity in brain slices. The results demonstrated that the pre-treatment with AOPCP, which was inactive per se, prevented NPS-induced hyperlocomotion in mice. The dose of 0.1 nmol NPS was efficient to induce hyperlocomotion in animals during the observation period in the activity cage. Regarding enzymatic activity, i.c.v. NPS injection did not induce any significant alterations in ATP and AMP hydrolysis in striatum and hippocampus brain slices of mice. The present study shows that the hyperlocomotor effect of NPS depends on the ecto-5'-nucleotidase activity.
Assuntos
5'-Nucleotidase/metabolismo , Adenosina/farmacologia , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/farmacologia , 5'-Nucleotidase/antagonistas & inibidores , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Injeções Intraventriculares , Masculino , Camundongos , Neostriado/efeitos dos fármacos , Neostriado/metabolismoRESUMO
Neuropeptide S (NPS) is the endogenous ligand of a G-protein-coupled receptor named as NPSR. Behavioral effects have been recently attributed to NPS, i.e. hyperlocomotion, anxiolysis, and wakefulness. However, little is known about the mechanisms by which NPS evokes such biological actions. The present study aimed to investigate the role played by the adenosine A(2A) and A(1) receptors in hyperlocomotion induced by NPS. Spontaneous locomotion was assessed in an activity cage for 30 min in mice acutely treated with caffeine (a nonselective adenosine receptor antagonist), ZM241385 (a selective A(2A) receptor antagonist), or CPT (a selective A(1) receptor antagonist) before NPS challenge (0.1 nmol, i.c.v.), which induce hyperlocomotion in mice. The pretreatment with caffeine (3 mg/kg, i.p.), in an inactive dose per se, prevented the increase in locomotion evoked by NPS. The co-administration of NPS (0.1 nmol, i.c.v.) and ZM241385 (0.1 pmol, i.c.v.) counteracted hyperlocomotion evoked by NPS. The co-administration of NPS and CPT (0.1 pmol, i.c.v.) slightly facilitated the increase in locomotion evoked by NPS alone. In summary, the pharmacological blockade of A(2A) receptors significantly attenuated the stimulatory effects of NPS. By contrast, the antagonism of A(1) receptors facilitated NPS-induced hyperlocomotion in mice, but we cannot rule out a merely additive effect of two stimulatory systems in the brain. Altogether, this is the first evidence of a putative role played by A(2A) and A(1) receptors in modulating hyperlocomotion induced by NPS.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/farmacologia , Animais , Cafeína/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Triazinas/farmacologia , Triazóis/farmacologiaRESUMO
OBJECTIVE: The aim of this study was investigate the effects of nociceptin/orphanin FQ (N/OFQ) and ([Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2)) (UFP-101), the endogenous N/OFQ peptide receptor (NOP) ligand and a selective NOP antagonist, respectively, in the inflammatory response after cecal ligation and puncture (CLP) model of sepsis in rats. DESIGN: Prospective, controlled experiment. SETTING: Animal basic science laboratory. SUBJECTS: Male Wistar rats, weighing 300-350 g. INTERVENTIONS: Rats subjected to CLP were treated with N/OFQ (0.001, 0.01 or 0.1 mg/kg) or UFP-101 (0.03, 0.03 or 0.3 mg/kg) subcutaneously administered immediately after surgery. MEASUREMENTS AND MAIN RESULTS: Twelve hours after surgery, blood was collected by cardiac puncture and bronchoalveolar (BAL) and peritoneal lavage were performed. In a separate set of experiments mortality was evaluated monitoring CLP rats for 10 days. Our findings showed that UFP-101 (0.03 mg/kg, sc, but not 0.003 mg/kg) modified parameters related to the systemic inflammatory response by effectively preventing cells migration, bacterial dissemination, and by modulating the release of pro-inflammatory cytokines and chemokines, and reducing animal mortality in a clinically relevant model of sepsis. By contrast, N/OFQ (0.1 mg/kg, sc) increased mortality in the CLP model. CONCLUSIONS: Our findings point to a functional relationship between the N/OFQ-NOP receptor system and inflammatory response in the CLP model of sepsis and suggest that NOP receptor antagonists are worthy of testing as innovative drugs for the treatment of sepsis.
Assuntos
Antagonistas de Entorpecentes , Receptores Opioides/imunologia , Sepse/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Sepse/sangue , Receptor de NociceptinaRESUMO
Nociceptin/orphanin FQ (N/OFQ) and nocistatin are two neuropeptides originated from the same precursor prepronociceptin/orphanin FQ (ppN/OFQ). N/OFQ is the endogenous ligand of the NOP receptor, while the target of action of nocistatin is still unknown. N/OFQ modulates various biological functions, including anxiety. Conversely, nocistatin either behaves as a functional N/OFQ antagonist or evokes per se effects opposite to those of N/OFQ. Here we investigated the interaction between the anxiolytic-like effects of N/OFQ and the anxiogenic-like action of nocistatin with those evoked by GABA(A) receptor ligands in the mouse elevated plus maze. The anxiogenic-like effects of the GABA(A) receptor antagonist pentylenetetrazol (20mg/kg; intraperitoneal, i.p.) were abolished by the co-treatment with N/OFQ (10pmol; intracerebroventricular, i.c.v.) while potentiated by the administration of nocistatin (0.01pmol; i.c.v.). The anxiolytic-like effects of the benzodiazepine receptor agonist diazepam (0.75mg/kg, i.p.) were reversed by nocistatin (0.1pmol; i.c.v.), whereas signs of sedation were observed when mice were co-treated with diazepam and N/OFQ (3pmol). Interesting enough, the i.p. treatment with flumazenil (1mg/kg) blocked the anxiolytic-like effects of N/OFQ (10pmol; i.c.v.), but not the anxiogenic effect elicited by nocistatin. Collectively, our findings suggest that the effects on anxiety elicited by pentylenetetrazol and diazepam can be counteracted or potentiated in the presence of N/OFQ and nocistatin. In addition, the effects on anxiety of N/OFQ, but not nocistatin, appear to be dependent on the benzodiazepine site of the GABA(A) receptor.
Assuntos
Ansiolíticos/farmacologia , Agonistas de Receptores de GABA-A , Aprendizagem em Labirinto/efeitos dos fármacos , Peptídeos Opioides/farmacologia , Animais , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Ligantes , Masculino , Camundongos , Receptores de GABA-A/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/farmacologia , NociceptinaRESUMO
. Nocistatin (NST) antagonizes several actions of nociceptin/orphanin FQ (N/OFQ), but acts on distinct receptors. As N/OFQ exerts anxiolytic-like actions in various tests, its behavioural actions in the elevated plus-maze (EPM) test were compared with those of bovine NST. 2. Five minutes after i.c.v. treatment, mice were placed on the EPM for 5 min and entries into and time spent on open and closed arms were recorded alongside other parameters. 3. NST (0.1 - 3 pmol) reduced percentages of entries into (control 39.6+/-3.1%, peak effect at 1 pmol NST 8.5+/-2.9%) and time spent on open arms (control 30.8+/-2.3%, NST 2.7+/-1.5%). The C-terminal hexapeptide of NST (NST-C6; 0.01 - 10 pmol) closely mimicked these actions of NST, with peak effects at 0.1 pmol. 4. N/OFQ (1 - 100 pmol) increased percentages of entries into (control 38.5+/-3.4%; peak effect at 10 pmol N/OFQ 67.9+/-4.9%) and time spent on open arms (control 32.0+/-3.8%; N/OFQ 74.9+/-5.8%). Closed arm entries, an index of locomotor activity, were unchanged by all peptides. 5. Effects of NST or NST-C6, but not N/OFQ, were still detectable 15 min after injection. Behaviour of animals co-injected with NST (1 pmol) or NST-C6 (0.1 pmol) plus N/OFQ (10 pmol) was indistinguishable from that of controls. 6. These results reveal potent anxiogenic-like actions of NST and NST-C6, and confirm the anxiolytic-like properties of N/OFQ. As NST and N/OFQ both derive from preproN/OF, anxiety may be modulated in opposing directions depending on how this precursor is processed.