RESUMEN
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.
Asunto(s)
Cicloheptanos , Imidazoles , Péptidos Opioides , Piperidinas , Receptores Opioides , Compuestos de Espiro , Ratones , Animales , Receptores Opioides/fisiología , Péptidos Opioides/metabolismo , Glucocorticoides/farmacología , Nortriptilina/farmacología , Receptor de Nociceptina , Corticosterona/farmacología , Sistema Hipotálamo-Hipofisario/metabolismo , Mifepristona/farmacología , Sistema Hipófiso-Suprarrenal/metabolismoRESUMEN
Activation of nociceptin opioid peptide receptors (NOP, a.k.a. opioid-like receptor-1, ORL-1) by the ligand nociceptin/orphanin FQ, leads to G protein-dependent regulation of Cav2.2 (N-type) voltage-gated calcium channels (VGCCs). This typically causes a reduction in calcium currents, triggering changes in presynaptic calcium levels and thus neurotransmission. Because of the widespread expression patterns of NOP and VGCCs across multiple brain regions, the dorsal horn of the spinal cord, and the dorsal root ganglia, this results in the alteration of numerous neurophysiological features. Here we review the regulation of N-type calcium channels by the NOP-nociceptin system in the context of neurological conditions such as anxiety, addiction, and pain.
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Canales de Calcio Tipo N , Enfermedades del Sistema Nervioso , Humanos , Analgésicos Opioides , Calcio , Receptor de NociceptinaRESUMEN
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.
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Péptidos Opioides/fisiología , Receptores Opioides/fisiología , Estrés Psicológico/etiología , Animales , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Antagonistas de Narcóticos/farmacología , Sistema Hipófiso-Suprarrenal/fisiología , Estrés Psicológico/tratamiento farmacológico , Receptor de Nociceptina , NociceptinaRESUMEN
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.
Asunto(s)
Antimaníacos/administración & dosificación , Trastorno Bipolar/fisiopatología , Hipercinesia/fisiopatología , Imidazoles/administración & dosificación , Metilfenidato/administración & dosificación , Receptores Opioides/fisiología , Compuestos de Espiro/administración & dosificación , Animales , Femenino , Hipercinesia/inducido químicamente , Ratones , Receptores Opioides/agonistas , Ácido Valproico/administración & dosificación , Receptor de NociceptinaRESUMEN
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.
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Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Cicloheptanos/uso terapéutico , Piperidinas/uso terapéutico , Receptores Opioides/fisiología , Estrés Psicológico/tratamiento farmacológico , Animales , Ansiolíticos/farmacología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ansiedad/psicología , Depresión/tratamiento farmacológico , Depresión/psicología , Emociones/efectos de los fármacos , Emociones/fisiología , Masculino , Ratones , Estrés Psicológico/psicología , Receptor de NociceptinaRESUMEN
BACKGROUND: An imbalance between neuropeptides that promote stress and resilience, such as corticotropin-releasing factor and nociceptin, has been postulated to underlie relapse in addiction. The objective of this study was to develop a paradigm to image the in vivo interaction between stress-promoting neuropeptides and nociceptin (NOP) receptors in humans. METHODS: [11C]NOP-1A positron emission tomography was used to measure the binding to NOP receptors at baseline (BASE) and following an intravenous hydrocortisone challenge (CORT) in 19 healthy control subjects. Hydrocortisone was used as a challenge because in microdialysis studies it has been shown to increase corticotropin-releasing factor release in extrahypothalamic brain regions such as the amygdala. [11C]NOP-1A total distribution volume (VT) in 11 regions of interest were measured using a 2-tissue compartment kinetic analysis. The primary outcome measure was hydrocortisone-induced ΔVT calculated as (VT CORT - VT BASE)/VT BASE. RESULTS: Hydrocortisone led to an acute increase in plasma cortisol levels. Regional [11C]NOP-1A VT was on average 11% to 16% higher in the post-hydrocortisone condition compared with the baseline condition (linear mixed model, condition, p = .005; region, p < .001; condition × region, p < .001). Independent Student's t tests in all regions of interest were statistically significant and survived multiple comparison correction. Hydrocortisone-induced ΔVT was significantly negatively correlated with baseline VT in several regions of interest. CONCLUSIONS: Hydrocortisone administration increases NOP receptor availability. Increased NOP in response to elevated cortisol might suggest a compensatory mechanism in the brain to counteract corticotropin-releasing factor and/or stress. The [11C]NOP-1A and hydrocortisone imaging paradigm should allow for the examination of interactions between stress-promoting neuropeptides and NOP in addictive disorders.
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Hidrocortisona , Neuropéptidos , Humanos , Cinética , Péptidos Opioides , Receptores Opioides , Receptor de Nociceptina , NociceptinaRESUMEN
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.
Asunto(s)
Péptidos Opioides/metabolismo , Receptores Opioides/metabolismo , Resiliencia Psicológica/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Cicloheptanos/administración & dosificación , Cicloheptanos/farmacología , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/administración & dosificación , Imidazoles/farmacología , Masculino , Ratones , Ratones Noqueados , Nortriptilina/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Receptores Opioides/efectos de los fármacos , Receptores Opioides/genética , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacología , Estrés Psicológico/fisiopatología , Receptor de Nociceptina , NociceptinaRESUMEN
Generalized pain and fatigue are both hallmarks of fibromyalgia, a syndrome with an indefinite etiology. The treatment options for fibromyalgia are currently limited, probably because of its intricate pathophysiology. Thus, further basic and clinical research on this condition is currently needed. This study investigated the effects of nociceptin/orphanin FQ (N/OFQ) receptor (NOPr) ligands and the modulation of the NOP system in the preclinical mouse model of reserpine-induced fibromyalgia. The effects of administration of the natural agonist N/OFQ and the selective NOPr antagonists (UFP-101 and SB-612111) were evaluated in fibromyalgia-related symptoms in reserpine-treated mice. The expression of prepronociceptin/orphanin FQ and NOPr was assessed in central and peripheral sites at different time points after reserpine administration. Nociceptin/orphanin FQ displayed dual effects in the behavioral changes in the reserpine-elicited fibromyalgia model. The peptide NOPr antagonist UFP-101 produced analgesic and antifatigue effects, by preventing alterations in brain activity and skeletal muscle metabolism, secondary to fibromyalgia induction. The nonpeptide NOPr antagonist SB-612111 mirrored the favorable effects of UFP-101 in painful and fatigue alterations induced by reserpine. A time-related up- or downregulation of prepronociceptin/orphanin FQ and NOPr was observed in supraspinal, spinal, and peripheral sites of reserpine-treated mice. Our data shed new lights on the mechanisms underlying the fibromyalgia pathogenesis, supporting a role for N/OFQ-NOP receptor system in this syndrome.
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Analgésicos/farmacología , Fatiga/tratamiento farmacológico , Fibromialgia/tratamiento farmacológico , Péptidos Opioides/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Antagonistas de Narcóticos/farmacología , Dolor/tratamiento farmacológico , Precursores de Proteínas/farmacología , Receptores Opioides/efectos de los fármacos , Receptor de Nociceptina , NociceptinaRESUMEN
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.
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Agresión/fisiología , Conducta Agonística/fisiología , Receptores Opioides/fisiología , Animales , Ansiedad , Trastorno Bipolar , Carbamazepina/farmacología , Cicloheptanos/farmacología , Depresión , Trastorno Depresivo , Modelos Animales de Enfermedad , Fenclonina/farmacología , Litio/farmacología , Masculino , Ratones , Ratones Noqueados , Péptidos Opioides/metabolismo , Piperidinas/farmacología , Receptores Opioides/agonistas , Receptores Opioides/genética , Ácido Valproico/farmacología , Receptor de Nociceptina , NociceptinaRESUMEN
Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating anxiety- and mood-related disorders. Evidence supports the view that the activation of NOP receptors with agonists elicits anxiolytic-like effects, while its blockade with NOP antagonists promotes antidepressant-like actions in rodents. Genetic studies showed that NOP receptor knockout mice display an antidepressant-like phenotype, and NOP antagonists are inactive in these animals. In contrast, the genetic blockade of NOP receptor signaling generally displays an increase of anxiety states in the elevated plus-maze test. In this chapter we summarized the most relevant findings of NOP receptor ligands in the modulation of anxiety and mood disorders, and the putative mechanisms of action are discussed.
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Antidepresivos/farmacología , Trastornos del Humor , Péptidos Opioides/farmacología , Receptores Opioides/metabolismo , Animales , Antidepresivos/uso terapéutico , Ansiedad , Ligandos , Ratones , Péptidos Opioides/metabolismo , Receptores Opioides/química , Receptores Opioides/efectos de los fármacos , Receptor de NociceptinaRESUMEN
Animal models have suggested that prenatal ethanol exposure (PEE) alters the κ opioid receptor system. The present study investigated the brain expression of dynorphin and nociceptin/orphanin FQ related genes and assessed anxiety-like behavior in the light-dark box (LDB), shelter-seeking and risk-taking behaviors in the concentric square field (CSF) test, and ethanol-induced locomotion in the open field (OF), in infant or adolescent Wistar rats that were exposed to PEE (0.0 or 2.0â¯g/kg, intragastrically, gestational days 17-20). We measured brain mRNA levels of prodynorphin (PDYN), κ opioid receptors (KOR), the nociceptin/orphanin FQ opioid peptide precursor prepronociceptin (ppN/OFQ) and nociceptine/orphanin FQ receptors (NOR). Prenatal ethanol exposure upregulated PDYN and KOR mRNA levels in the ventral tegmental area (VTA) in infant and adolescent rats and KOR mRNA levels in the prefrontal cortex in infant rats. The changes in gene expression in the VTA were accompanied by a reduction of DNA methylation at the PDYN gene promoter, and by a reduction of DNA methylation at the KOR gene promoter. The PEE-induced upregulation of PDYN/KOR in the VTA was accompanied by lower NOR gene expression in the VTA, and lower PDYN gene expression in the nucleus accumbens. PEE rats exhibited hypolocomotion in the OF, greater avoidance of the white and brightly lit areas in the LDB and CSF, and greater preference for the sheltered area in the CSF test. These results suggest that PEE upregulates the dynorphin system, resulting in an anxiety-prone phenotype and triggering compensatory responses in the nociceptin/orphanin FQ system. These findings may help elucidate the mechanisms that underlie the effects of PEE and suggest that the dynorphin and nociceptin/orphanin FQ systems may be possible targets for the prevention and treatment of PEE-induced alterations.
Asunto(s)
Ansiedad/metabolismo , Encefalinas/metabolismo , Trastornos del Espectro Alcohólico Fetal/metabolismo , Trastornos del Espectro Alcohólico Fetal/psicología , Precursores de Proteínas/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides/metabolismo , Animales , Animales no Consanguíneos , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/toxicidad , Metilación de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Etanol/toxicidad , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Wistar , Asunción de Riesgos , Receptor de NociceptinaRESUMEN
RATIONALE: Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin-mediated mechanisms modulate GABAergic nigrotectal connections. OBJECTIVES: Therefore, the aim of this work was to study the role of opioid and NOP receptors in the SNpr during the modulation of defence reactions organised by the dlSC. METHODS: The SNpr was pretreated with either opioid or NOP receptor agonists and antagonists, followed by dlSC treatment with bicuculline. RESULTS: Blockade of GABAA receptors in the dlSC elicited fear-related defensive behaviour. Pretreatment of the SNpr with naloxone benzoylhydrazone (NalBzoH), a µ-, δ-, and κ1-opioid receptor antagonist as well as a NOP receptor antagonist, decreased the aversive effect of bicuculline treatment on the dlSC. Either µ-opioid receptor activation or blockade by SNpr microinjection of endomorphin-1 (EM-1) and CTOP promoted pro-aversive and anti-aversive actions, respectively, that modulated the defensive responses elicited by bicuculline injection into the dlSC. Pretreatment of the SNpr with the selective NOP receptor antagonist JTC801 decreased the aversive effect of bicuculline, and microinjections of the selective NOP receptor agonist NNC 63-0532 promoted the opposite effect. CONCLUSIONS: These results demonstrate that opioid pathways and orphanin-mediated mechanisms have a critical role in modulating the activity of nigrotectal GABAergic pathways during the organisation of defensive behaviours.
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Aminoquinolinas/administración & dosificación , Benzamidas/administración & dosificación , Miedo/efectos de los fármacos , Oligopéptidos/administración & dosificación , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Receptores Opioides , Somatostatina/análogos & derivados , Analgésicos Opioides/administración & dosificación , Animales , Bicuculina/administración & dosificación , Relación Dosis-Respuesta a Droga , Miedo/fisiología , Masculino , Naloxona/administración & dosificación , Naloxona/análogos & derivados , Péptidos Opioides/administración & dosificación , Porción Reticular de la Sustancia Negra/fisiología , Ratas , Ratas Wistar , Receptores Opioides/fisiología , Somatostatina/administración & dosificación , Colículos Superiores/efectos de los fármacos , Colículos Superiores/fisiología , Ácido gamma-Aminobutírico/administración & dosificación , Receptor de Nociceptina , NociceptinaRESUMEN
Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have structural homology with classic opioids, but constitute a distinct neurotransmitter system because they lack affinity for the opioid peptides and receptors. This neurotransmission is implicated in several physiologic processes, but the role played by NOP receptors during stress situations remains unclear. The acute restraint stress (RS) is a model of unavoidable stress, characterized by sustained increases in mean arterial pressure (MAP), heart rate (HR) and a drop in tail temperature. On another side, the prelimbic (PL) and infralimbic (IL) cortices, subdivisions of the medial prefrontal cortex (MPFC), are implicated in the modulation of functional responses caused by RS. Considering that, the objective of the present study was to investigate the involvement of PL and IL NOP receptors in the control of autonomic responses induced by RS. Bilateral microinjection of nociceptin (NOP agonist) into the PL reduced the cardiovascular responses evoked by RS. Bilateral microinjection of UPF-101 (NOP antagonist) into the PL potentiated the pressor and tachycardiac responses evoked by RS, in a dose-dependent manner. Local pretreatment with UPF-101 blocked the RS-evoked changes following nociceptin administration into the PL. None of these treatments affected the drop in tail temperature induced by RS. Otherwise, the administration of nociceptin or UPF-101 into the IL had no effect on RS-evoked autonomic changes. To investigate the peripheral mechanism involved in the increase in the RS-evoked cardiovascular responses induced by the blockade of PL NOP receptors, rats were intravenous pretreated with either homatropine or atenolol. The intravenous treatment with homatropine blunted the increase in the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101, while the intravenous treatment with atenolol did not affect the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101. In conclusion, our study shows an influence of the PL N/OFQ neurotransmission, but not the IL NOP receptors, in the control of cardiovascular responses observed during acute stress, by increasing cardiac parasympathetic activity.
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Sistema Nervioso Autónomo/fisiología , Fenómenos Fisiológicos Cardiovasculares , Péptidos Opioides/administración & dosificación , Péptidos Opioides/fisiología , Corteza Prefrontal/fisiopatología , Receptores Opioides/fisiología , Estrés Psicológico/fisiopatología , Animales , Presión Arterial/efectos de los fármacos , Sistema Nervioso Autónomo/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Opioides/agonistas , Restricción Física , Receptor de Nociceptina , NociceptinaRESUMEN
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.
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Ansiolíticos/farmacología , Antidepresivos/farmacología , Proteínas de Unión al GTP/metabolismo , Receptores Opioides/efectos de los fármacos , Arrestina beta 2/metabolismo , Animales , Cicloheptanos/farmacología , Emociones/efectos de los fármacos , Proteínas de Unión al GTP/agonistas , Células HEK293 , Humanos , Imidazoles/farmacología , Ligandos , Ratones , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Natación/psicología , Arrestina beta 2/agonistas , Receptor de NociceptinaRESUMEN
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.
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Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Inmunidad Innata , Leucocitos/metabolismo , Modelos Inmunológicos , Péptidos Opioides/metabolismo , Receptores Opioides/agonistas , Animales , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Humanos , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/metabolismo , Leucocitos/inmunología , Estrés Oxidativo , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores Opioides/metabolismo , Transducción de Señal , Estrés Fisiológico , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Receptor de Nociceptina , NociceptinaRESUMEN
Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. In PD, as well as in other neurodegenerative disorders, it has been proposed that the combination of multiple factors might contribute to the onset of the disease. Indeed, several authors have suggested that environmental factors, such as pollutants and chemicals, might be associated with the onset of several neurodegenerative disorders. On the other hand, several studies have described that the nociceptin/orphanin-NOP and prodynorphin-KOP opioid systems are implicated in the pathology of Parkinson's disease. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of our study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Our results showed that after paraquat/maneb (5/15 mg kg(-1) ) treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb (5/15 mg kg(-1) ) induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 656-663, 2015.
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Fungicidas Industriales/toxicidad , Herbicidas/toxicidad , Maneb/toxicidad , Paraquat/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Agricultura , Animales , Regulación hacia Abajo , Encefalinas/metabolismo , Expresión Génica/efectos de los fármacos , Masculino , Péptidos Opioides/metabolismo , Precursores de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismo , Sustancia Negra , Tirosina 3-Monooxigenasa/metabolismo , Receptor de Nociceptina , NociceptinaRESUMEN
Depression and anxiety disorders present several genetic and neurobiological similarities. Drugs with antidepressant activity are effective in the treatment of a wide spectrum of anxiety disorders. Preclinical results showed that acute and chronic treatment with the NOP antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101) produced antidepressant-like effects in rodents. Thus, the present study aimed to investigate the effect of central administration of UFP-101 on the anxiety-related behavior in rats as evaluated in the elevated T-maze (ETM) test. Our results showed that UFP-101 reduced the latency of inhibitory avoidance in the ETM, indicating an anxiolytic-like effect. The endogenous peptide N/OFQ prevented this anxiolytic-like action of UFP-101, demonstrating its modulation via central NOP receptors. However, UFP-101 failed to interfere with the latency to escape. No change was observed in locomotor activity after UFP-101 treatment, ruling out any nonspecific motor effect. In conclusion, our results showed that the central administration of UFP-101 presents an anxiolytic-like effect in rats evaluated in the ETM test, providing new insights for drug development to treat anxiety disorders targeting the N/OFQ-NOP receptor system.
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Ansiolíticos/administración & dosificación , Ansiedad/tratamiento farmacológico , Aprendizaje por Laberinto/efectos de los fármacos , Análisis de Varianza , Animales , Ansiedad/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Conducta Exploratoria/efectos de los fármacos , Masculino , Antagonistas de Narcóticos , Péptidos Opioides , Ratas , Ratas Wistar , Receptores Opioides/agonistas , Receptor de NociceptinaRESUMEN
The role of 5-hydroxytryptamine (5-HT)(4), 5-HT(6), and 5-HT(7) receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia. Pretreatment (-10min) with cromoglycate (195-1950nmol/paw) partially inhibited acute nociceptive behaviors and completely prevented secondary allodynia and hyperalgesia on day 6 after injection. Ipsilateral peripheral pretreatment with the selective 5-HT(4) (ML-10302, 1-100nmol/paw), 5-HT(6) (EMD-386088, 0.001-0.01nmol/paw), and 5-HT(7) (LP-12, 0.01-100nmol/paw) receptor agonists significantly increased secondary allodynia and hyperalgesia in both paws. In contrast, ipsilateral peripheral pretreatment with the selective 5-HT(4) (GR-125487, 1-100nmol/paw), 5-HT(6) (SB-258585, 0.00001-0.001nmol/paw), and 5-HT(7) (SB-269970, 0.1-10nmol/paw) receptor antagonists significantly prevented formalin-induced secondary allodynia and hyperalgesia in both paws. The pronociceptive effect of ML-10302 (100nmol/paw), EMD-386088 (0.01nmol/paw), and LP-12 (100nmol/paw) were completely prevented by GR-125487 (5-HT(4) antagonist, 1nmol/paw), SB-258585 (5-HT(6) antagonist, 0.00001nmol/paw), and SB-269970 (5-HT(7), antagonist, 0.01nmol/paw), respectively. Ipsilateral peripheral posttreatment with cromoglycate or GR-125487 (1-100nmol/paw), SB-258585 (0.001-0.1nmol/paw), and SB-269970 (0.1-10nmol/paw) reversed formalin-induced secondary allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors participate in the development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia in the rat. 5-hydroxytryptamine (5-HT) released in peripheral tissues after formalin injection sensitized primary afferent neurons via 5-HT(4), 5-HT(6), and 5-HT(7) receptors, leading to development and maintenance of secondary allodynia and hyperalgesia.
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Hiperalgesia/metabolismo , Umbral del Dolor/fisiología , Receptores de Serotonina/metabolismo , Animales , Antiasmáticos/farmacología , Área Bajo la Curva , Cromolin Sódico/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Formaldehído/efectos adversos , Hiperalgesia/inducido químicamente , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Opioides , Receptores de Serotonina 5-HT4/metabolismo , Serotoninérgicos/farmacología , Factores de Tiempo , Receptor de NociceptinaRESUMEN
This study assesses the effects of peripheral or intrathecal pre-treatment or post-treatment with micro, delta, kappa and nociceptin/orphanin FQ (NOP) opioid receptor agonists (morphine, U-50488 [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride], DADLE [D-Ala2-Leu5-enkephalin] and nociceptin, respectively) on formalin-induced secondary mechanical allodynia and hyperalgesia in rats. 1% Formalin injection produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term tactile secondary allodynia and hyperalgesia. Neither peripheral (into the formalin-injected paw) nor intrathecal morphine post-treatment reversed formalin-induced secondary allodynia and hyperalgesia. In contrast, morphine pre-treatment prevented the development of these pain behaviors. Intrathecal and peripheral post- but not pre-treatment with U-50488 or DADLE significantly reduced secondary allodynia and hyperalgesia. Interestingly, nociceptin reduced both pain behaviors regardless of the administration site or treatment time. Local antinociceptive effects of morphine, DADLE, U-50488 or nociceptin were blocked by naltrexone, naltrindole, 5-guanidinonaltrindole and [Nphe(1)]nociceptin(1-13)NH(2), respectively. These results suggest that the long-term nociceptive behaviors induced by formalin are differentially modulated by selective opioid receptor agonists. In addition, data suggest that peripheral and spinal delta and kappa opioid receptors are important when nociceptive behaviors are established. In contrast, micro opioid receptors are more important at the beginning of the injury when the sensory system has not changed. NOP receptors participate diminishing both the development and maintenance of nociceptive behaviors. Results suggest that a barrage of afferent input induced by formalin injection initiates a long-term differential change in peripheral and spinal processing that affect the efficacy of opioid receptor agonists.
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Formaldehído/farmacología , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Dolor/inducido químicamente , Dolor/metabolismo , Receptores Opioides/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Leucina Encefalina-2-Alanina/farmacología , Leucina Encefalina-2-Alanina/uso terapéutico , Femenino , Hiperalgesia/tratamiento farmacológico , Morfina/farmacología , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Ratas , Ratas Wistar , Receptores Opioides/agonistas , Receptor de NociceptinaRESUMEN
There is no information concerning signal transduction mechanisms downstream of the opioid/nociceptin receptors in the human epileptic brain. The aim of this work was to evaluate the level of G-proteins activation mediated by DAMGO (a mu receptor selective peptide) and nociceptin, and the binding to mu and nociceptin (NOP) receptors and adenylyl cyclase (AC) in neocortex of patients with pharmacoresistant temporal lobe epilepsy. Patients with temporal lobe epilepsy associated with mesial sclerosis (MTLE) or secondary to tumor or vascular lesion showed enhanced [3H]DAMGO and [3H]forskolin binding, lower DAMGO-stimulated [35S]GTPgammaS binding and no significant changes in nociceptin-stimulated G-protein. [3H]Nociceptin binding was lower in patients with MTLE. Age of seizure onset correlated positively with [3H]DAMGO binding and DAMGO-stimulated [35S]GTPgammaS binding, whereas epilepsy duration correlated negatively with [3H]DAMGO and [3H]nociceptin binding, and positively with [3H]forskolin binding. In conclusion, our present data obtained from neocortex of epileptic patients provide strong evidence that a) temporal lobe epilepsy is associated with alterations in mu opioid and NOP receptor binding and signal transduction mechanisms downstream of these receptors, and b) clinical aspects may play an important role on these receptor changes.