Corticotropin-releasing Factor Receptor Research Articles

Стресс-вызванная анальгезия: роль гормонов гипоталамо-гипофизарно-адренокортикальной системы

One of adaptive consequences of the stress response is a short-term decrease in pain sensitivity in humans and animals known as “stress-induced analgesia” (SIA). The HPA axis is a key system that activates during stress and provides organism adaptation. One of the mechanisms of SIA may be associated with the HPA hormones, in particular with corticotropin-releasing factor (CRF), the major hormone of the HPA axis, and glucocorticoids, whose analgesic properties are well known and used in medical practice. Based on the results of our research and literature review, the aim of the paper was to analyze SIA mechanisms related to CRF and glucocorticoid hormones mediated by CRF receptors 1 and 2 as well as glucocorticoid and opioid receptors.

Influence of adrenalectomy on protective effects of urocortin I, a corticotropin-releasing factor (CRF)-related peptide, against indomethacin-induced enteropathy in rats

The influence of adrenalectomy on indomethacin-induced enteropathy in rats was examined and the possible involvement of adrenal glucocorticoids in protective effects of urocortin I, a CRF agonist, was investigated. Male SD rats were administered indomethacin (10 mg/kg) s.c., killed 24 h later, and small intestines were examined for hemorrhagic lesions. Urocortin I (20 μg/kg) was given i.v. 10 min before indomethacin. Bilateral adrenalectomy was performed a week before the experiment. Indomethacin caused hemorrhagic lesions in small intestines, accompanied by intestinal hypermotility, enterobacterial invasion and iNOS expression. Adrenalectomy markedly increased ulcerogenic and motility responses caused by indomethacin, with further enhanced bacterial invasion and iNOS expression. This worsening effect was reproduced by pretreatment with mifepristone. Urocortin I prevented indomethacin-induced enteropathy; this effect was abrogated by astressin 2B, a CRF2 receptor antagonist, but was not affected by either adrenalectomy or mifepristone pretreatment. These results suggest that adrenalectomy aggravates indomethacin-induced enteropathy, and intestinal hypermotility response may be the key element in the mechanism underlying this aggravation, while endogenous glucocorticoids play a role in intestinal mucosal defense against these lesions but do not account for protective effects of urocortin I, which are mediated by peripheral CRF2 receptors.

The Endocrine System and Alcohol Drinking in Females.

Sexually dimorphic effects of alcohol exposure throughout life have been documented in clinical and preclinical studies. In the past, rates of alcohol use disorder (AUD) were higher in men than in women, but over the past 10 years, the difference between sexes in prevalence of AUD and binge drinking has narrowed. Recent evidence adds to historical data regarding the influence of sex steroids on alcohol drinking and the interaction with stress-related steroids. This review considers the contribution of the endocrine system to alcohol drinking in females, with a focus on the hypothalamic pituitary gonadal axis and the hypothalamic pituitary adrenal axis and their reciprocal interactions. Emphasis is given to preclinical studies that examined genomic and rapid membrane effects of estrogen, progesterone, glucocorticoids, and GABAergic neurosteroids for their effects on alcohol drinking and models of relapse. Pertinent comparisons to data in males highlight divergent effects of sex and stress steroids on alcohol drinking and emphasize the importance of considering sex in the development of novel pharmacotherapeutic targets for the treatment of AUD. For instance, pharmacological strategies targeting the corticotropin releasing factor and glucocorticoid receptor systems may be differentially effective in males and females, whereas strategies to enhance GABAergic neurosteroids may represent a biomarker of treatment efficacy in both sexes.

Amygdalar corticotropin-releasing factor mediates stress-induced anxiety

The extended amygdala, including the Central nucleus of the Amygdala (CeA) and the Bed Nucleus of the Stria Terminalis (BNST), is a complex structure that plays a pivotal role in emotional behavior. The CeA and the BNST are highly interconnected, being the amygdala traditionally more associated with fear and the BNST with anxiety. Yet, studies using excitotoxic lesions also show the involvement of the CeA in the development of stress-induced anxiety. Likewise, others have also highlighted the role of corticotropin-releasing factor (CRF), a neuropeptide highly expressed in CeA, as an anxiogenic factor and, consequently, important for in anxiety disorders.Here, we used an inducible RNAi lentiviral system to assess the effects of reducing CRF expression in CeA in the development of anxiety-like behavior in a model of Chronic Unpredictable Stress. In addition, we evaluated CRF RNAi-mediated alterations in the stress-triggered molecular signature in the BNST.Knockdown of CRF in the CeA decreased stress-induced anxiety levels. No differences were found in a fear-potentiated startle paradigm. Additionally, we observed that stress-induced alterations in the expression of CRF receptors within the BNST are attenuated by CRF knockdown in the CeA.These results emphasize the importance of the role that amygdalar CRF plays in the modulation of anxiety-like behavior and in the molecular signature of stress in the BNST.

CRF1 Receptor Signaling via the ERK1/2-MAP and Akt Kinase Cascades: Roles of Src, EGF Receptor, and PI3-Kinase Mechanisms.

In the present study, we determined the cellular regulators of ERK1/2 and Akt signaling pathways in response to human CRF1 receptor (CRF1R) activation in transfected COS-7 cells. We found that Pertussis Toxin (PTX) treatment or sequestering Gβγ reduced CRF1R-mediated activation of ERK1/2, suggesting the involvement of a Gi-linked cascade. Neither Gs/PKA nor Gq/PKC were associated with ERK1/2 activation. Besides, CRF induced EGF receptor (EGFR) phosphorylation at Tyr1068, and selective inhibition of EGFR kinase activity by AG1478 strongly inhibited the CRF1R-mediated phosphorylation of ERK1/2, indicating the participation of EGFR transactivation. Furthermore, CRF-induced ERK1/2 phosphorylation was not altered by pretreatment with batimastat, GM6001, or an HB-EGF antibody indicating that metalloproteinase processing of HB-EGF ligands is not required for the CRF-mediated EGFR transactivation. We also observed that CRF induced Src and PYK2 phosphorylation in a Gβγ-dependent manner. Additionally, using the specific Src kinase inhibitor PP2 and the dominant-negative-SrcYF-KM, it was revealed that CRF-stimulated ERK1/2 phosphorylation depends on Src activation. PP2 also blocked the effect of CRF on Src and EGFR (Tyr845) phosphorylation, further demonstrating the centrality of Src. We identified the formation of a protein complex consisting of CRF1R, Src, and EGFR facilitates EGFR transactivation and CRF1R-mediated signaling. CRF stimulated Akt phosphorylation, which was dependent on Gi/βγ subunits, and Src activation, however, was only slightly dependent on EGFR transactivation. Moreover, PI3K inhibitors were able to inhibit not only the CRF-induced phosphorylation of Akt, as expected, but also ERK1/2 activation by CRF suggesting a PI3K dependency in the CRF1R ERK signaling. Finally, CRF-stimulated ERK1/2 activation was similar in the wild-type CRF1R and the phosphorylation-deficient CRF1R-Δ386 mutant, which has impaired agonist-dependent β-arrestin-2 recruitment; however, this situation may have resulted from the low β-arrestin expression in the COS-7 cells. When β-arrestin-2 was overexpressed in COS-7 cells, CRF-stimulated ERK1/2 phosphorylation was markedly upregulated. These findings indicate that on the base of a constitutive CRF1R/EGFR interaction, the Gi/βγ subunits upstream activation of Src, PYK2, PI3K, and transactivation of the EGFR are required for CRF1R signaling via the ERK1/2-MAP kinase pathway. In contrast, Akt activation via CRF1R is mediated by the Src/PI3K pathway with little contribution of EGFR transactivation.

Correction to: MicroRNA-34 Contributes to the Stress-related Behavior and Affects 5-HT Prefrontal/GABA Amygdalar System through Regulation of Corticotropin-releasing Factor Receptor 1.

The original version of this article unfortunately contained a mistake in Figure 3. The drawing superimposed on photomicrographs to identify the region of Dorsal raphè Nuclei was inappropriately positioned. The corrected figure is given below.

Inhibitory Control of Basolateral Amygdalar Transmission to the Prefrontal Cortex by Local Corticotrophin Type 2 Receptor.

BackgroundBasolateral amygdalar projections to the prefrontal cortex play a key role in modulating behavioral responses to stress stimuli. Among the different neuromodulators known to impact basolateral amygdalar-prefrontal cortex transmission, the corticotrophin releasing factor (CRF) is of particular interest because of its role in modulating anxiety and stress-associated behaviors. While CRF type 1 receptor (CRFR1) has been involved in prefrontal cortex functioning, the participation of CRF type 2 receptor (CRFR2) in basolateral amygdalar-prefrontal cortex synaptic transmission remains unclear.MethodsImmunofluorescence anatomical studies using rat prefrontal cortex synaptosomes devoid of postsynaptic elements were performed in rats with intra basolateral amygdalar injection of biotinylated dextran amine. In vivo microdialysis and local field potential recordings were used to measure glutamate extracellular levels and changes in long-term potentiation in prefrontal cortex induced by basolateral amygdalar stimulation in the absence or presence of CRF receptor antagonists.ResultsWe found evidence for the presynaptic expression of CRFR2 protein and mRNA in prefrontal cortex synaptic terminals originated from basolateral amygdalar. By means of microdialysis and electrophysiological recordings in combination with an intra-prefrontal cortex infusion of the CRFR2 antagonist antisauvagine-30, we were able to determine that CRFR2 is functionally positioned to limit the strength of basolateral amygdalar transmission to the prefrontal cortex through presynaptic inhibition of glutamate release.ConclusionsOur study shows for the first time to our knowledge that CRFR2 is expressed in basolateral amygdalar afferents projecting to the prefrontal cortex and exerts an inhibitory control of prefrontal cortex responses to basolateral amygdalar inputs. Thus, changes in CRFR2 signaling are likely to disrupt the functional connectivity of the basolateral amygdalar-prefrontal cortex pathway and associated behavioral responses.

Activation of CRF2 receptor increases gastric vagal afferent mechanosensitivity.

Gastric vagal afferent (GVA) sensing of food-related mechanical stimuli is a crucial mechanism in the control of feeding behavior and gastric function. Stress is an important factor contributing to eating disorders and gastric diseases. Chronic stress has been shown to increase the mechanosensitivity of GVAs in mice and to reduce food intake and body weight. Whether the mechanosensitivity of GVAs is modulated by stress hormones is not known. This study aimed to determine the effect of stress hormones on GVA mechanosensitivity. The expression of stress hormone receptors in GVA cell bodies was determined in 8-wk-old male C57BL/6 mice using quantitative RT-PCR combined with laser capture microdissection. The mechanosensitivity of GVAs was determined in the absence and presence of stress hormones using an in vitro single-fiber recording preparation. NR3C1 and CRHR2 (mRNA isoforms of glucocorticoid receptor and CRF2 receptor, respectively) were expressed in GVA neurons. The glucocorticoid receptor agonist corticosterone had no effect on the mechanosensitivity of either tension or mucosal GVAs. Activation of CRF2 receptor by its specific analog, urocortin 3, significantly increased the mechanosensitivity of both tension and mucosal GVAs, an effect prevented by the CRF2 receptor antagonist astressin 2B. In conclusion, activation of CRF2 receptor increases the mechanosensitivity of GVAs. This may contribute to the stress- and CRF2 receptor-associated changes in feeding behavior and gastric function, possibly contributing to the hypersensitivity of GVAs in chronic stress conditions.NEW & NOTEWORTHY Gastric vagal afferents (GVAs) relay food-related signals to the central nervous system, where they are processed, eventually leading to modulation of food intake and gastric function. GVA signaling can be modulated by an array of hormones. Stress has been shown to induce GVA hypersensitivity. This study demonstrates that GVA neurons express subtypes of stress hormone receptors, specifically CRF2. Furthermore, activation of CRF2 receptor increases GVA mechanosensitivity, which could have implications for food intake and gastric function.

Sini San ameliorates duodenal mucosal barrier injury and low‑grade inflammation via the CRF pathway in a rat model of functional dyspepsia.

The gut-brain interaction is associated with impaired duodenal mucosal integrity and low-grade inflammation, which have been proven to be important pathological mechanisms of functional dyspepsia (FD). Sini San (SNS) is a classical Chinese medicine used to treat FD, but its underlying mechanisms are poorly understood. The aim of the present study was to evaluate the effects of SNS on duodenal mucosal barrier injury and low-grade inflammation with FD, and to assess its potential molecular mechanisms on the brain-gut axis. FD rats were established using the iodoacetamide and tail-squeezed methods. The expression of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF-R1) and CRF-R2, were determined by western blot analysis and/or immunohistochemistry (IHC). In addition, mast cell (MC) migration was assessed by IHC with an anti-tryptase antibody, and histamine concentration was quantified using ELISA. The mRNA expression levels of tryptase and protease-activated receptor 2 (PAR-2) were quantified using reverse transcription-quantitative PCR, and the protein expression levels of zona occludens protein 1 (ZO-1), junctional adhesion molecule 1 (JAM-1), β-catenin and E-cadherin were determined via western blot analysis. It was demonstrated that the expression level of CRF was downregulated in the central nervous system and duodenum following SNS treatment, and that SNS modulated the expression of both CRF-R1 and CRF-R2. In addition, SNS suppressed MC infiltration and the activity of the tryptase/PAR-2 pathway in the duodenum. Furthermore, treatment with SNS restored the normal expression levels of ZO-1, JAM-1 and β-catenin in FD rats. These findings suggested that the therapeutic effects of SNS on FD were achieved by restoring mucosal barrier integrity and suppressing low-grade inflammation in the duodenum, which was at least partially mediated via the CRF signaling pathway.

Effects of early trauma and corticotropin-releasing factor receptor 1 gene polymorphism on adult visual spatial memory.

BackgroundThe study sought to determine the effects of earthquake on the working memory of adults who experienced earthquake either as infants or fetuses and also investigates whether earthquake exposure and corticotropin‐releasing factor receptor 1 (CRHR1) variants rs242924 and rs7209436 interacted with each other in modulating working memory.MethodsWe enrolled subjects who experienced the Tangshan Earthquake as fetuses (group I) or infants (group II), as well as those who did not experience the earthquake (group III). Their working memory was measured using Brief Visuospatial Memory Test‐Revised (BVMT‐R) and Hopkins Verbal Learning Test‐Revised (HVLT‐R). Two single‐nucleotide polymorphisms (SNPs) of CRHR1 rs242924 and rs7209436 were analyzed by fluorescence quantitative polymerase chain reaction (PCR).ResultsThe study enrolled 535 subjects, including 172 subjects in group I, 176 subjects group II, and 187 subjects in group III. Both group I and II had significantly lower BVMT‐R scores than group III (p < .05). Moreover, no difference was observed in HVLT‐R scores among the three groups (p > .05). The allele frequency was 84.7% for AA, 82.8% for TT, 13.6% for AC, and 15.9% for TC. C gene carriers in group II (t = −4.231, p < .01) and group I (t = −3.201, p < .05) had significantly lower visual spatial memory scores than group III. Furthermore, AT gene carriers had significantly lower visual spatial memory scores than C gene carriers in group III (t = 2.215, p < .05). Moreover, there was significant interaction between earthquake exposure and CRHR1 genotype in their effects on visual spatial memory (F = 4.028, p < .05).ConclusionsOur cross‐sectional study has demonstrated that infant or fetus exposure to earthquake impairs visual spatial memory during adulthood and CRHR1 polymorphisms and earthquake exposure may interact with each other to accentuate this impairment.

Phosphodiesterase-2 Inhibitor Bay 60-7550 Ameliorates Aβ-Induced Cognitive and Memory Impairment via Regulation of the HPA Axis.

The dysfunction of the hypothalamus–pituitary–adrenal (HPA) axis is often seen in Alzheimer’s disease (AD) patients with cognitive deficits. Selective inhibition of phosphodiesterase (PDE) 4 and 5 has already proven to be effective in reducing beta-amyloid 1–42 (Aβ1–42)-mediated pathology by regulating corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, suggesting that PDE-dependent signaling is involved in Aβ1–42-induced HPA axis dysfunction. However, nausea and vomiting are the side effects of some PDE4 inhibitors, which turn our attention to other PDEs. PDE2 are highly expressed in the hippocampus and cortex, which associate with learning and memory, but not in the area postrema that would cause vomiting. The present study suggested that microinjection of Aβ1–42 to the intracerebroventricle induced learning and memory impairments and dysregulation of the HPA axis by increased expression of CRF and GR. However, the PDE2 inhibitor Bay 60-7550 significantly ameliorated the learning and memory impairment in the Morris water maze (MWM) and step-down passive avoidance tests. The Aβ1–42-induced increased CRF and GR levels were also reversed by the treatment with Bay 60-7550. These Bay 60-7550’s effects were prevented by pretreatment with the PKG inhibitor KT5823. Moreover, the Bay 60-7550-induced downstream phosphorylation of cyclic AMP response element binding (pCREB) and brain-derived neurotrophic factor (BDNF) expression was also prevented (or partially prevented) by KT5823 or the PKA inhibitor H89. These results may lead to the discovery of novel strategies for the treatment of age-related cognitive disorders, such as AD, which affects approximately 44 million people worldwide.

The value of extended amygdala structures in emotive effects of narcogenic with diverse chemical structure

Introduction: Studies on the mechanisms of the reinforcing action of opioid and non-opioid narcotics confirmed the existence in the brain of a specialized system named the extended amygdala.&#x0D; Materials and methods: To clarify the value of the extended amygdala structures (bed nucleus, central nucleus of the amygdala and nucleus accumbens shell) in the mechanisms of unconditioned and conditioned reinforcement activated by various narcogenic, this paper carried out a neuropharmacological analysis of these effects, using blockade of dopamine receptors, GABA, opioids and CRF receptors within these brain structures, as well as an analysis of behavioral responses by self-stimulation (unconditioned reinforcement) and conditioned place preference (CPP) (conditioned reinforcement).&#x0D; Results and discussion: The central amygdala and the bed nucleus have a controlling influence on the hypothalamus, which is predominantly of CRF-, GABA- and dopaminergic nature. Through D1 dopamine receptors,, a direct positive (activating) effect on the lateral hypothalamus is made. The D2 receptor blockade of the nucleus accumbens prevents narcogenic from exerting the reinforcing properties, which are primarily stimulating. The blockade of the D1 receptors of the nucleus accumbens by SCH-23390 prevents the expression of unconditioned and conditioned reinforcing properties of predominantly opiates and opioids. The blockade of GABAA receptors in the nucleus accumbens with bicuculline prevents the manifestation of the primary and secondary reinforcing properties (CPP) of psychostimulant drugs (amphetamine), without affecting the effects of opiates and opioids (fentanyl and leu-enkephalin).&#x0D; Conclusion: The pharmacological analysis proves that CRF, dopamine and GABA receptors are most important for the correction of reinforcement activated by various narcogenic.

The role of peripheral corticotropin-releasing factor signaling in a rat model of stress-induced gastric hyperalgesia

BackgroundFunctional dyspepsia (FD) is a common gastrointestinal disorder associated with persistent or recurrent upper gastrointestinal tract symptoms such as pain without any obvious pathological changes. Psychological and psychiatric factors might have a pathogenic role in FD. Changes in the sensation of stomach pain were determined after application of stress to adult rats. The involvement of corticotropin-releasing factor (CRF), Type 2 CRF receptor (CRF2) and inflammatory cytokine interleukin-6 (IL-6) was also investigated in the gastric hyperalgesia observed in this model. ResultsRepeated water avoidance stress (WA-S) produced gastric hyperalgesia, with no obvious lesions in the gastric mucosa. Gastric hyperalgesia was inhibited by CRF and CRF2 antagonists, suggesting their involvement in gastric hyperalgesia observed after application of stress. Gastric hyperalgesia was inhibited by IL-6 neutralizing antibody. Immunofluorescence staining demonstrated CRF, CRF2, urocortin (Ucn)1, and Ucn2-positive cells in the gastric mucosa. CRF2-positive cells increased after WA-S, compared to sham stress. CRF2 and Ucn2 were expressed in the mast cells in the gastric mucosa. ConclusionsCRF2 plays an important role in gastric hyperalgesia produced by stress. CRF2 signaling may be a useful therapeutic target for functional dyspepsia.

The importance of target binding kinetics for measuring target binding affinity in drug discovery: a case study from a CRF1 receptor antagonist program

In drug discovery, it is essential to accurately measure drug-target binding affinity. Here, we revisit the fact that target binding kinetics impact the measurement of affinity, using a case study: development of corticotropin-releasing factor antagonists. Slow dissociation of the drug-target complex results in affinity assays being far from equilibrium, which results in erroneous estimates of affinity. This scenario can impair prediction of human dosing, assessment of target selectivity, identification of high-affinity ligands and determination of SAR. We describe strategies to detect lack of equilibration in affinity assays and methods to correctly measure affinity of slowly dissociating compounds. These considerations will facilitate drug discovery by ensuring reliable measurement of drug-target binding affinity.

Corticotropin-releasing factor receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [30]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B.

Contribution of Corticotropin-Releasing Factor Receptor 1 (CRF1) to Serotonin Receptor 5-HT2CR Function in Amygdala Neurons in a Neuropathic Pain Model.

The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT2CR in the basolateral amygdala (BLA) contributes to increased CeA output and neuropathic pain-like behaviors. Here, we tested the novel hypothesis that 5-HT2CR in the BLA drives CRF1 receptor activation to increase CeA neuronal activity in neuropathic pain. Extracellular single-unit recordings of CeA neurons in anesthetized adult male rats detected increased activity in neuropathic rats (spinal nerve ligation model) compared to sham controls. Increased CeA activity was blocked by local knockdown or pharmacological blockade of 5-HT2CR in the BLA, using stereotaxic administration of 5-HT2CR short hairpin RNA (shRNA) viral vector or a 5-HT2CR antagonist (SB242084), respectively. Stereotaxic administration of a CRF1 receptor antagonist (NBI27914) into the BLA also decreased CeA activity in neuropathic rats and blocked the facilitatory effects of a 5-HT2CR agonist (WAY161503) administered stereotaxically into the BLA. Conversely, local (BLA) knockdown of 5-HT2CR eliminated the inhibitory effect of NBI27914 and the facilitatory effect of WAY161503 in neuropathic rats. The data suggest that 5-HT2CR activation in the BLA contributes to neuropathic pain-related amygdala (CeA) activity by engaging CRF1 receptor signaling.

Central angiotensin II type 1 receptor as a therapeutic target against frequent urination.

The goal of this study was to test whether central corticotropin-releasing factor (CRF) was involved in angiotensin II (Ang II) and Ang II type 1 (AT1) receptor-mediated facilitation of micturition reflex and to investigate whether peripherally administered telmisartan, AT1 receptor antagonist, suppresses the central Ang II-induced facilitation of micturition reflex in rats. Urethane anesthetized male Wistar rats were placed under continuous cystometry before and after intracerebroventricular administration of each drug. Rats were intracerebroventricularly administered telmisartan (AT1 receptor antagonist), CP154526 (CRF1 receptor antagonist), or K41498 (CRF2 receptor antagonist) 30 minutes before intracerebroventricular administration of Ang II. Some male Wistar rats were perorally pretreated with either vehicle, AT1 receptor antagonist telmisartan or valsartan, once daily for 8 days, then measured blood pressure. Thereafter, Ang II was intracerebroventricularly administered for continuous cystometry. Intracerebroventricularly administered telmisartan or CP154526 dose-dependently suppressed the central Ang II-induced intercontraction interval (ICI) reduction. In contrast, intracerebroventricularly administered K41498 did not affect the central Ang II-induced response compared to vehicle pretreatment. Peripherally administered telmisartan but not valsartan suppressed the central Ang II-induced ICI reduction in rats compared to vehicle administration without altering blood pressure. Central Ang II induced facilitation of the micturition reflex through AT1 and CRF1 receptors. Peripherally administered telmisartan suppressed central Ang II-induced facilitation of micturition reflex.

Hypothalamic mechanisms associated with neuropeptide K-induced anorexia in Japanese quail (Coturnix japonica)

Central administration of neuropeptide K (NPK), a 36-amino acid peptide, is associated with anorexigenic effects in rodents and chickens. The mechanisms underlying the potent anorexigenic effects of NPK are still poorly understood. Thus, the aim of the present study was to identify the hypothalamic nuclei and neuropeptides that mediate anorexic effects of NPK in 7 day-old Japanese quail (Coturnix japonica). After a 6 h fast, intracerebroventricular (ICV) injection of NPK decreased food and water intake for 180 min post-injection. Quail injected with NPK had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), lateral hypothalamus, and paraventricular nucleus (PVN) compared to the birds that were injected with the vehicle. In the ARC of NPK-injected quail, there was decreased neuropeptide Y (NPY), NPY receptor sub-type 1, and agouti-related peptide mRNA, and increased CART, POMC, and neurokinin receptor 1 mRNA. NPK-injected quail expressed greater amounts of corticotropin-releasing factor (CRF), CRF receptor sub-type 2, melanocortin receptors 3 and 4, and urocortin 3 mRNA in the PVN. In conclusion, results provide insights into understanding NPK-induced changes in hypothalamic physiology and feeding behavior, and suggest that the anorexigenic effects of NPK involve the ARC and PVN, with increased CRF and melanocortin and reduced NPY signaling.

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Key points Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system.The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem.Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities.Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms.Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. Environmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non‐damaging still causing long‐lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin‐3 (UCN3) is the endogenous ligand for corticotropin‐releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age‐matched wild‐type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3‐deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild‐type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3‐expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds.

Structural determinants governing β-arrestin2 interaction with PDZ proteins and recruitment to CRFR1

β-Arrestins are multifunctional adaptor proteins best know for their vital role in regulating G protein coupled receptor (GPCR) trafficking and signaling. β-arrestin2 recruitment and receptor internalization of corticotropin-releasing factor receptor 1 (CRFR1), a GPCR whose antagonists have been shown to demonstrate both anxiolytic- and antidepressant-like effects, have previously been shown to be modulated by PDZ proteins. Thus, a structural characterization of the interaction between β-arrestins and PDZ proteins can delineate potential mechanism of PDZ-dependent regulation of GPCR trafficking. Here, we find that the PDZ proteins PSD-95, MAGI1, and PDZK1 interact with β-arrestin2 in a PDZ domain-dependent manner. Further investigation of such interaction using mutational analyses revealed that mutating the alanine residue at 175 residue of β-arrestin2 to phenylalanine impairs interaction with PSD-95. Additionally, A175F mutant of β-arrestin2 shows decreased CRF-stimulated recruitment to CRFR1 and reduced receptor internalization. Thus, our findings show that the interaction between β-arrestins and PDZ proteins is key for CRFR1 trafficking and may be targeted to mitigate impaired CRFR1 signaling in mental and psychiatric disorders.