Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848237 (acute stress)
 4,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orphanin FQ (OFQ, Nociceptin) is a recently discovered 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not bind opioid receptors. OFQ has been proposed to act as an anti-opioid peptide, but its widespread sites of action in the brain suggest that it may have more general functions. Here we show that OFQ plays an important role in higher brain functions because it can act as an anxiolytic to attenuate the behavioral inhibition of animals acutely exposed to stressful/anxiogenic environmental conditions. OFQ anxiolytic-like effects were consistent across several behavioral paradigms generating different types of anxiety states in animals (light-dark preference, elevated plus-maze, exploratory behavior of an unfamiliar environment, pharmacological anxiogenesis, operant conflict) and were observed at low nonsedating doses (0.1-3 nmol, intracerebroventricular). Like conventional anxiolytics, OFQ interfered with regular sensorimotor function at high doses (>3 nmol). Our results show that an important role of OFQ is to act as an endogenous regulator of acute anxiety responses. OFQ, probably in concert with other major neuropeptides, exerts a modulatory role on the central integration of stressful stimuli and, thereby, may modulate anxiety states generated by acute stress.
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PMID:Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress. 940 3

1. The central administration of the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) produces marked cardiovascular depressor and renal sympathoinhibitory responses in conscious animals. These findings are evidence that central N/OFQ may modulate the cardiovascular and renal responses to acute environmental stress. 2. The changes in cardiovascular and renal function produced by intracerebroventricular (i.c.v.) N/OFQ were measured in conscious spontaneously hypertensive rats (SHR) under basal conditions and during the acute environmental stimulus of air jet stress. 3. In SHR, central N/OFQ produced profound hypotensive, bradycardic, renal sympathoinhibitory (delayed) and water-diuretic effects by a pathway that does not involve activation of central alpha2-adrenoceptors or classical opioid receptors. 4. Intracerebroventricular injection of N/OFQ prevented the pressor response and blunted the tachycardia to air jet stress. A similar renal sympathoexcitatory and antinatriuretic response was observed in conscious SHR during air stress, before and after i.c.v. N/OFQ. 5. These findings are evidence that, in conscious SHR, i.c.v. N/OFQ selectively inhibited the neural responses to air jet stress by attenuating sympathetic outflow to the heart and, potentially, vasculature, but not to the kidneys. Central endogenous N/OFQ systems may be activated and contribute to regional changes in sympathetic outflow during acute stress.
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PMID:Nociceptin/orphanin FQ modulates the cardiovascular, but not renal, responses to stress in spontaneously hypertensive rats. 1190 94

We examined the effects of acute and chronic stress on neurotransmission of nociceptin/orphanin FQ (N/OFQ) in a variety of brain regions. Four groups of rats were exposed to chronic variable stress, and/or a single acute stress before decapitation. Group 1 served as unstressed controls. The rats in group 2 (chronic stress/no acute stress) were exposed to a 10-day regimen of chronic stress (two unpredictable stressors per day). These rats were decapitated 20 h after the last stressor. The rats in group 3 (no chronic stress/acute stress) were not exposed to chronic stress, but they were restrained for 30 min prior to decapitation. The rats in group 4 (chronic stress/acute stress) were chronically stressed for 10 days, and were then restrained prior to decapitation. Trunk blood was collected, and plasma adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) were assayed by radioimmunoassay (RIA). The rats' brains were dissected, and N/OFQ content was measured by RIA in a variety of brain regions, and in spinal cord. Chronic stress exposure altered the hormonal responses to the acute stress exposure. In the rats that were exposed to chronic stress without acute stress (group 2), N/OFQ content did not differ from the content of the unstressed controls in any of the dissected brain regions. In the two groups that were stressed acutely just before decapitation (groups 3 and 4), N/OFQ content was decreased by 25-30% in the basal forebrain. Accordingly, the neuronal content of N/OFQ is decreased in basal forebrain neurones during acute stress exposure. In light of our previous finding that N/OFQ administration increases circulating ACTH and CORT concentrations, and augments hormonal responses to an acute stressor, the current finding raises the possibility that endogenous N/OFQ participates in neuronal regulation of hormonal responses to acute stress exposure.
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PMID:Nociceptin/orphanin FQ content is decreased in forebrain neurones during acute stress. 1253 71

The influence of peripheral nociceptin/orphanin FQ (N/OFQ) on cold restraint-induced gastric mucosal damage in the rat was investigated. Exposure to cold-restraint for 3 and 4h caused the formation of hemorrhagic lesions in the glandular portion of the stomach. N/OFQ dose-dependently decreased lesion formation, in the range 0.03-1 microg/kg/h i.p. Its effect was reversed by the selective NOP receptor antagonist [Nphe(1)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-101), 30 microg/kg/h ip. The selective NOP receptor agonist [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), 0.01-0.3 microg/kg/h i.p., similarly reduced lesion formation. Light and scanning electron microscopy confirmed the protective activity of N/OFQ. Cold-restraint stress causes a reduction in mucus content and in adhering mucus layer, partly counteracted by N/OFQ. These results suggest that N/OFQ counteracts acute stress-induced gastric mucosal damage by interacting with NOP receptor and by influencing mucous cell activity.
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PMID:Nociceptin/orphanin FQ prevents gastric damage induced by cold-restraint stress in the rat by acting in the periphery. 1765 65

Nociceptin/orphanin FQ (N/OFQ) and its NOP receptors are present in the central nervous system and in the periphery playing important roles in the modulation of gastrointestinal functions and pain. The aim of this study was to investigate the role of central and peripheral N/OFQ-NOP receptor system in the nociceptive response to colorectal distension (CRD) in basal condition and in two models of gut hypersensitivity triggered by both inflammation and stress. Male Wistar rats were tested in basal and in post-inflammatory conditions, i.e., 5 days after IC TNBS instillation (80 mg/Kg) and received N/OFQ (2 nmol/Kg IP), UFP-101 (a selective NOP receptor antagonist, 10 nmol/Kg IP), N/OFQ+UFP-101, N/OFQ (0.5 nmol/rat ICV) or vehicle. Female rats were tested in basal and after partial restraint stress receiving the same pharmacological treatment. CRD was performed using barostat and abdominal contractions were recorded by electromyography. In basal condition, N/OFQ, ICV and IP injected, did not modify basal visceral sensitivity. Both in TNBS and stress-induced hyperalgesia, IP but not ICV injection of N/OFQ significantly decreased the number of abdominal contractions. Peripheral injection of UFP-101 antagonized N/OFQ effect. Moreover, in post-inflammatory colitis, UFP-101, injected alone, exacerbated visceral hyperalgesia to CRD compared with vehicle. These findings indicate that in rats, N/OFQ, only peripherally injected, reduces visceral hypersensitivity triggered by inflammation or stress without affecting basal sensitivity. N/OFQ visceral anti-hyperalgesic effect involves peripheral NOP receptors. In a post-inflammatory, but not in an acute stress colitis model, N/OFQergic system is endogenously activated.
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PMID:Peripheral anti-nociceptive effect of nociceptin/orphanin FQ in inflammation and stress-induced colonic hyperalgesia in rats. 1914 91

Anxiety disorders, caused by continuous or acute stress or fear, have been highly prevailing psychiatric disorders. For the acute treatment of the disorders, benzodiazepines have been widely used despite having liabilities that limit their utility. Alternatively, endogenous nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor (or opioid-receptor-like-1 receptor) have important roles in the integration of emotional components, e.g. anxiolytic activity is the key behavioral action of nociceptin/orphanin FQ in brain. In our preceding study, various structurally novel 1,2-disubstituted benzimidazole derivatives were designed and synthesized as highly potent nociceptin/orphanin FQ peptide receptor selective full agonists in vitro with high or moderate nociceptin/orphanin FQ peptide receptor occupancy in the mice brain per os based on appropriate physicochemical properties for the oral brain activity [Hayashi et al. (2009) J Med Chem;52:610-625]. In the present study, drug design and structure-activity relationships for Vogel anticonflict activities in mice per os, metabolic stabilities in human liver microsome, CYP2D6 inhibitions, serum protein bindings, and human ether-a-go-go related gene binding affinities of novel nociceptin/orphanin FQ peptide receptor agonists were investigated. Through the series of coherent drug discovery studies, the strongest nociceptin/orphanin FQ peptide receptor agonist, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole was designed and identified as a new-class orally potent anxiolytic with little side-effects, as significant findings.
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PMID:Discovery of 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: integrated drug-design and structure-activity relationships for orally potent, metabolically stable and potential-risk reduced novel non-peptide nociceptin/orphanin FQ receptor agonist as antianxiety drug. 1969 71

Antagonists of the NOP receptor have antidepressant effects in rodent models, suggesting that the N/OFQ-NOP system may play an important role in affective disorders. Furthermore, multiple lines of experimental evidence link N/OFQ neurotransmission with physiological and behavioral responses to stress. One possibility is that disregulated expression of the N/OFQ peptide neurotransmitter and/or the NOP receptor may participate in the etiology of stress-induced psychopathology. In the present set of experiments, we compared gene expression for prepro-N/OFQ and NOP receptor in groups of rats that were exposed to differing regimens of social defeat stress. Male Long-Evans rats were exposed to no social defeat, a single, acute social defeat or to repeated social defeats with or without an acute defeat on the final day. In situ hybridization was conducted with (35)S-labelled riboprobes aimed at prepro-N/OFQ mRNA or NOP receptor mRNA. Expression was analyzed by quantification of optical density in limbic and extra-limbic forebrain regions. There were no statistically significant changes in prepro-N/OFQ mRNA expression after stress exposure in any of the brain regions analyzed. However, the rats that were exposed to acute social defeat displayed elevations in NOP receptor mRNA expression in the central and basomedial nuclei of the amygdala and in the paraventricular nucleus of the hypothalamus. Additionally, the rats that were acutely stressed after a history of repeated social defeat also displayed elevated levels of NOP receptor mRNA expression in the paraventricular nucleus of the hypothalamus. These results suggest that the N/OFQ-NOP receptor system is affected by acute stress exposure, particularly in limbic regions. This stress-induced upregulation of NOP receptor gene expression further supports the possibility that disregulation of the N/OFQ-NOP system may contribute to behavioral and hormonal disregulation following stress.
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PMID:Nociceptin/orphanin FQ and NOP receptor gene regulation after acute or repeated social defeat stress. 1972 Mar 95

Corticotropin releasing factor (CRF) is the primary mediator of stress responses, and nociceptin/orphanin FQ (N/OFQ) plays an important role in the modulation of these stress responses. Thus, in this multidisciplinary study, we explored the relationship between the N/OFQ and the CRF systems in response to stress. Using in situ hybridization (ISH), we assessed the effect of body restraint stress on the gene expression of CRF and N/OFQ-related genes in various subdivisions of the amygdala, a critical brain structure involved in the modulation of stress response and anxiety-like behaviors. We found a selective upregulation of the NOP and downregulation of the CRF1 receptor transcripts in the CeA and in the BLA after body restraint. Thus, we performed intracellular electrophysiological recordings of GABAA-mediated IPSPs in the central nucleus of the amygdala (CeA) to explore functional interactions between CRF and N/OFQ systems in this brain region. Acute application of CRF significantly increased IPSPs in the CeA, and this enhancement was blocked by N/OFQ. Importantly, in stress-restraint rats, baseline CeA GABAergic responses were elevated and N/OFQ exerted a larger inhibition of IPSPs compared with unrestraint rats. The NOP antagonist [Nphe1]-nociceptin(1-13)NH2 increased the IPSP amplitudes in restraint rats but not in unrestraint rats, suggesting a functional recruitment of the N/OFQ system after acute stress. Finally, we evaluated the anxiety-like response in rats subjected to restraint stress and nonrestraint rats after N/OFQ microinjection into the CeA. Intra-CeA injections of N/OFQ significantly and selectively reduced anxiety-like behavior in restraint rats in the elevated plus maze. These combined results demonstrate that acute stress increases N/OFQ systems in the CeA and that N/OFQ has antistress properties.
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PMID:Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. 2440 38

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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PMID:NOP receptors in the prelimbic cortex have an inhibitory influence on cardiovascular responses induced by restraint stress. 2693 48