Endogenous Corticotropin-releasing Factor Research Articles

The effects of corticotropin-releasing factor on motor learning

Corticotropin-releasing factor (CRF) is mainly secreted from the hypothalamic paraventricular nuclei and plays a crucial role in stress-related responses. Recent studies have reported that CRF is a neuromodulator in the central nervous system. In the cerebellum, CRF is essential for the induction of long-term depression (LTD) at the parallel fiber-Purkinje cell synapses. Given that LTD is thought to be one of the fundamental mechanisms of motor learning, CRF may affect motor learning. However, the role of CRF in motor learning in vivo remains unclear. In this study, we aimed to examine the role of CRF in motor learning. This was achieved through a series of behavioral experiments involving the in vivo administration of CRF and its antagonists. Rats injected with CRF directly into the cerebellum exhibited superior performance on the rotarod test, especially during initial training phases, compared to control subjects. Conversely, rats receiving a CRF receptor antagonist demonstrated reduced endurance on the rotating rod compared to controls. Notably, CRF mRNA expression levels in the cerebellum did not show significant variance between the CRF-injected and control groups. These findings imply a critical role of endogenous CRF in cerebellar motor learning and suggest that exogenous CRF can augment this process. (199 words)

Corticotropin-releasing factor potentiates glutamatergic input and excitability of presympathetic neurons in the hypothalamus in spontaneously hypertensive rats

Hyperactivity of presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) plays a key role in generating excess sympathetic output in hypertension. However, the mechanisms driving hyperactivity of PVN presympathetic neurons in hypertension are unclear. In this study, we determined the role of corticotropin-releasing factor (CRF) in the PVN in augmented glutamatergic input, neuronal excitability and sympathetic outflow in hypertension. The number of CRF or c-Fos immunoreactive neurons and CRF/c-Fos double-labeled neurons in the PVN was significantly greater in spontaneously hypertensive rats (SHRs) than in normotensive Wistar-Kyoto (WKY) rats. Blocking glutamatergic input reduced the CRF-potentiated excitability of spinally projecting PVN neurons. Furthermore, CRF knockdown via Crispr/Cas9 in the PVN decreased the frequencies of spontaneous firing and miniature excitatory postsynaptic currents (mEPSCs) in spinally projecting PVN neurons in SHRs. In addition, the mRNA and protein levels of CRFR1, but not CRFR2, in the PVN were significantly higher in SHRs than in WKY rats. Blocking CRFR1 with NBI-35965, but not blocking CRFR2 with Antisauvagine-30, reduced the frequencies of spontaneous firing and mEPSCs of spinally projecting PVN neurons in SHRs. Also, microinjection of NBI-35965 into the PVN significantly reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in anesthetized SHRs, but not in WKY rats. However, microinjection of Antisauvagine-30 into the PVN had no effect on ABP or RSNA in WKY rats and SHRs. Our findings suggest that endogenous CRF in the PVN potentiates glutamatergic input and firing activity of PVN presympathetic neurons via CRFR1, resulting in augmented sympathetic outflow in hypertension.

Трудности и ошибки диагностики вторичного гипокортицизма у больных старческого возраста

Adrenal insufficiency is a relatively rare condition, especially among individuals older than 65 years. Therefore, the specific manifestations of primary and secondary adrenal insufficiency are understudied in elderly patients. The article elucidates new data on the senile physiological hyperplasia of the zona fasiculata of the adrenal cortex: human aging is tightly linked to an increasing secretion of glucocorticoids. A clinical case of secondary adrenal insufficiency due to empty sella syndrome (ESS) and hydrocephalus in a senile patient is described. The patient’s medical history included two key elements aggravating the adrenal insufficiency: adrenalectomy and chemotherapy with platinum derivatives which could have impact on the adrenal glands. The specific symptoms experienced by the patient and the clinical course of the disease correlated with the residual secretion of adrenocorticotropic hormone (ACTH), cerebral disorders (ESS) and the compensatory secretion of corticotropin releasing factor. The clinical presentation of adrenal insufficiency was vague and atypical. In addition, it was found that the patient had hyposecretion of anabolic androgenic steroids. In turn, it caused a muscle hypotrophy and facilitated the recurrence of pelvic organ prolapse after the earlier performed pelvic floor reconstructive surgery. In such clinical cases the treatment should be aimed at improving the state of the hypothalamic-pituitary system and increasing the production of endogenous corticotropin releasing factor, ACTH, and cortisol. Androgen replacement therapy in androgen-deficient elderly patients has not been developed. KEYWORDS: secondary adrenal insufficiency, adrenocorticotropic hormone; empty sella syndrome, glucocorticoids. FOR CITATION: Tereshchenko I.V. Difficulties and diagnostic errors in old patients with secondary adrenal insufficiency. Russian Medical Inquiry. 2022;6(9):534–537 (in Russ.). DOI: 10.32364/2587-6821-2022-6-9-534-537.

Agonist bias and agonist-dependent antagonism at corticotrophin releasing factor receptors.

The corticotropin‐releasing factor (CRF) receptors represent potential drug targets for the treatment of anxiety, stress, and other disorders. However, it is not known if endogenous CRF receptor agonists display biased signaling, how effective CRF receptor antagonists are at blocking different agonists and signaling pathways or how receptor activity‐modifying proteins (RAMPs) effect these processes. This study aimed to address this by investigating agonist and antagonist action at CRF1 and CRF2 receptors. We used CRF1 and CRF2 receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP1), and extracellular signal‐regulated kinase 1/2 signaling and determined the ability of antagonists to block agonist‐stimulated cAMP and IP1 accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF1 receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF2 receptor, UCN1 and UCN2 displayed similar signaling profiles, whereas CRF and UCN3 displayed bias away from IP1 accumulation over cAMP. The antagonist potency was dependent on the receptor, agonist, and signaling pathway. CRF1 and CRF2 receptors had no effect on RAMP1 or RAMP2 surface expression. The presence of biased agonism and agonist‐dependent antagonism at the CRF receptors offers new avenues for developing drugs tailored to activate a specific signaling pathway or block a specific agonist. Our findings suggest that the already complex CRF receptor pharmacology may be underappreciated and requires further investigation.

Pretreatment with a CRF antagonist amplifies feeding inhibition induced by fourth ventricular cocaine- and amphetamine-regulated transcript peptide

BackgroundPre-treatment with the corticotropin-releasing factor antagonist α-helical CRF9-41 prevents inhibition of gastric emptying by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level, but its inhibition of sucrose intake is not affected. This is suggestive of separable underlying mechanisms of action in the caudal brainstem for cocaine-and amphetamine-regulated transcript peptide with regard to food intake and gastrointestinal functions. Here we further examine cocaine-and amphetamine-regulated transcript peptide—corticotropin-releasing factor receptor interactions in caudal brainstem controls of solid food intake. Injections of combinations of vehicle, cocaine-and amphetamine-regulated transcript peptide (0.5 μg or 1 μg) or α-helical CRF9-41 were given into the fourth cerebral ventricle of rats. Nocturnal solid food intake was recorded over 22 h.ResultsPre-treatment with α-helical CRF9-41 into the fourth ventricle significantly increased the responsivity to cocaine-and amphetamine-regulated transcript peptide on hypophagia. In a separate control experiment, α-helical CRF9-41 pre-treatment blocked CRF-induced food intake inhibition indicative of its antagonistic effectiveness.ConclusionsWe conclude that an endogenous Corticotropin-releasing factor agonist may modulate suppression of food intake caused by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level in the absence of stress. A potential caudal brainstem mechanism whereby cocaine-and amphetamine-regulated transcript peptide effects on food intake is attenuated via corticotropin-releasing factor receptor activity causing tonic inhibition, is suggested.

Working Memory Impairing Actions of Corticotropin-Releasing Factor (CRF) Neurotransmission in the Prefrontal Cortex.

The prefrontal cortex (PFC) regulates cognitive processes critical for goal-directed behavior. PFC cognitive dysfunction is implicated in multiple psychopathologies, including attention deficit hyperactivity disorder (ADHD). Although it has long been known that corticotropin-releasing factor (CRF) and CRF receptors are prominent in the PFC, the cognitive effects of CRF action within the PFC are poorly understood. The current studies examined whether CRF receptor activation in the PFC modulates cognitive function in rats as measured in a delayed response task of spatial working memory. CRF dose-dependently impaired working memory performance when administered either intracerebroventricularly (ICV) or directly into the PFC. The working memory actions of CRF in the PFC were topographically organized, with impairment observed only following CRF infusions into the caudal dorsomedial PFC (dmPFC). Additional studies examined whether endogenous CRF modulates working memory. Both ICV and intra-dmPFC administration of the nonselective CRF antagonist, D-Phe-CRF, dose-dependently improved working memory performance. To better assess the translational potential of CRF antagonists, we examined the cognitive effects of systemic administration of the CRF1 receptor selective antagonist, NBI 35965. Similar procognitive actions were observed in these studies. These results are the first to demonstrate that CRF acts in the PFC to regulate PFC-dependent cognition. Importantly, the ability of CRF antagonists to improve working memory is identical to that seen with all approved treatments for ADHD. These observations suggest that CRF antagonists may represent a novel approach for the treatment of ADHD and other disorders associated with dysregulated prefrontal cognitive function.

Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.

Corticotropin-releasing factor (CRF) mediates our body's overall responses to stress. The role of central CRF in stress-stimulated colonic motility is well characterized. We hypothesized that transient perturbation in expression of enteric CRF is sufficient to change stress-induced colonic motor and secretory responses. Sprague-Dawley rats (adult, male) were subjected to 1-h partial restraint stress (PRS) and euthanized at 0, 4, 8, and 24h. CRF mRNA and peptide levels in the colon were quantified by real-time RT-PCR, enzyme immuno-assay and immunohistochemistry. Double-stranded RNA (dsRNA) designed to target CRF (dsCRF) was injected into the colonic wall to attain RNA interference-mediated inhibition of CRF mRNA expression. DsRNA for β-globin was used as a control (dsControl). Four days after dsRNA injection, rats were subjected to 1-h PRS. Fecal output was measured. Ussing chamber techniques were used to assess colonic mucosal ion secretion and transepithelial tissue conductance. Exposure to PRS elevated CRF expression and increased CRF release in the rat colon. Injection of dsCRF inhibited basal CRF expression and prevented the PRS-induced increase in CRF expression, whereas CRF expression in dsControl-injected colons remained high after PRS. In rats treated with dsControl, PRS caused a significant increase in fecal pellet output, colonic baseline ion secretion, and transepithelial tissue conductance. Inhibition of CRF expression in the colon prevented PRS-induced increase in fecal output, baseline ion secretion, and transepithelial tissue conductance. These results provide direct evidence that transient perturbation in peripherally expressed CRF prevents colonic responses to stress.

Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala.

Ethanol (EtOH) modulation of central amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin-releasing factor (CRF) receptor (CRFR) system. Previous work has predominantly focused on EtOH×CRF interactions on the CeA GABA circuitry; however, our laboratory recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine whether EtOH modulates CeA glutamate transmission via activation of CRF signaling. The effects of EtOH on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRF(CeAhDTR) ) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRF(DTA) mice) ablated CRF neurons throughout the central nervous system, as assessed by quantitative reverse transcriptase polymerase chain reaction quantification of CRF mRNA. Acute bath application of EtOH significantly increased sEPSC frequency in a concentration-dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRFR1 and CRFR2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, EtOH did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of EtOH to enhance CeA sEPSC frequency was not altered in CRF(CeAhDTR) mice despite a ~78% reduction in CeA CRF cell counts. The ability of EtOH to enhance CeA sEPSC frequency was also not altered in the CRF(DTA) mice despite a 3-fold reduction in CRF mRNA levels. These findings demonstrate that EtOH enhances spontaneous glutamatergic transmission in the CeA via a CRFR-dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF.

Effects of the endogenous CRF on the biological phenotypes of mouse mesenteric lymph nodes den-dritic cells

Objective To investigate the expression of corticotropin-releasing factor (CRF) and its receptors including CRFR1 and CRFR2 on mouse mesenteric lymph nodes dendritic cells (MLNDC), and to analyze their effects on the biological phenotypes of intestinal dendritic cells. Methods The MLNDCs were isolated from C57BL/6 mice by using magnetic bead sorting. The purity of CD11c+ DCs was identified by flow cytometry. The double-labeling immunofluorescence and the reverse transcriptase-polymerase chain reaction (RT-PCR) were performed to detect the expression of CRF, CRFR1 and CRFR2 on MLNDCs. The MLNDCs were exposed to CRF with or without the interference of CRFR1 and CRFR2 antagonists. Flow cytometry was used to measure the changes of surface molecules (MHCⅠ and MHCⅡ) and co-stimulatory molecules (CD80 and CD86). Results The CD11c+ DCs accounted for (80.12±6.34)% of the isolate cells with a high cell viability of more than 90%. The expression of CRF, CRFR1 and CRFR2 at mRNA level were detected in MLNDCs by RT-PCR. Results of the immunofluorescent staining assay indicated that both CRFR1 and CRFR2 were expressed on the surface of MLNDCs. The expression of CD86 on MLNDCs was inhibited by the treatment of MLNDCs with CRFR1 antagonist, but enhanced by the treatment with CRFR2 antagonist. Conclusion Both CRF and CRFRs were detected in the MLNDCs isolated from the C57BL/6 mice. The CRF could alter the biological phenotypes of MLNDCs through binding to different CRFRs (CRFR1 and CRFR2), which affected the phenotypes of MLNDCs in opposite ways. Key words: Corticotropin-releasing factor; Mesenteric lymph nodes; Dendritic cell

Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions

The central amygdala is a critical brain region for many aspects of alcohol dependence. Much of the work examining the mechanisms by which the central amygdala mediates the development of alcohol dependence has focused on the interaction of acute and chronic ethanol with central amygdala corticotropin releasing factor signaling. This work has led to a great deal of success in furthering the general understanding of central amygdala neurocircuitry and its role in alcohol dependence. Much of this work has primarily focused on the hypothesis that ethanol utilizes endogenous corticotropin releasing factor signaling to upregulate inhibitory GABAergic transmission in the central amygdala. Work that is more recent suggests that corticotropin releasing factor also plays an important role in mediating anxiety-like behaviors via the enhancement of central amygdala glutamatergic transmission, implying that ethanol/corticotropin releasing factor interactions may modulate excitatory neurotransmission in this brain region. In addition, a number of studies utilizing optogenetic strategies or transgenic mouse lines have begun to examine specific central amygdala neurocircuit dynamics and neuronal subpopulations to better understand overall central amygdala neurocircuitry and the role of neuronal subtypes in mediating anxiety-like behaviors. This review will provide a brief update on this literature and describe some potential future directions that may be important for the development of better treatments for alcohol addiction.

Increased alcohol consumption in urocortin 3 knockout mice is unaffected by chronic inflammatory pain.

Stress neurocircuitry may modulate the relationship between alcohol drinking and chronic pain. The corticotropin-releasing factor (CRF) system is crucial for regulation of stress responses. The current study aimed to elucidate the role of the endogenous CRF ligand Urocortin 3 (Ucn3) in the relationship between alcohol drinking behavior and chronic pain using a genetic approach. Ucn3 (KO) and wildtype (WT) littermates were subjected to a 24-h access drinking procedure prior to and following induction of chronic inflammatory pain. Ucn3 KO mice displayed significantly increased ethanol intake and preference compared with WT across the time course. There were no long-term effects of chronic pain on alcohol drinking behavior, regardless of genotype, nor any evidence for alcohol-induced analgesia. The increased drinking in Ucn3 KO supports a role for this peptide in alcohol-related behavior. These data suggest the necessity for more research exploring the relationship between alcohol drinking, chronic pain and the CRF system in rodent models.

Role of hypothalamic corticotropin-releasing factor in mediating alcohol-induced activation of the rat hypothalamic–pituitary–adrenal axis

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis through brain-based mechanisms in which endogenous corticotropin-releasing factor (CRF) plays a major role. This review first discusses the evidence for this role, as well as the possible importance of intermediates such as vasopressin, nitric oxide and catecholamines. We then illustrate the long-term influence exerted by alcohol on the HPA axis, such as the ability of a first exposure to this drug during adolescence, to permanently blunt neuroendocrine responses to subsequent exposure of the drug. In view of the role played by CRF in addiction, it is likely that a better understanding of the mechanisms through which this drug stimulates the HPA axis may lead to the development of new therapies used in the treatment of alcohol abuse, including clinically relevant CRF antagonists.

De amygdala, een schakelstation voor het aan- en uitzetten van pijn: de rol van limbisch corticotropin-releasing factor bij neuropathische pijn

Corticotropin-releasing factor (CRF) plays a prominent role in mood disorders like anxiety and depression. Upon experimentally-induced neuropathy, it is up-regulated in limbic structures such as the amygdala. This review discusses the literature on the role of CRF in pain processing and highlights the amygdala as key center in pain control. Not only has CRF analgesic effects following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). We here postulate a central mechanism for pain control with the amygdala as critical brain component in turning the sensation of pain on and off. Upon painful stimuli, CRFR1 in the amygdala is activated by CRF and induces hyperalgesia. The activated CRFR1 is then internalized (pain initiation) to trigger the translocation of the cytoplasmic CRFR2 to the plasma membrane. This CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, such as urocortins, which leads to analgesia (pain termination). Redistribution of the CRF receptors to their initial locations and activity states completes the on-off switching. We propose that in neuropathic pain, this mechanism is dysregulated, which leads to a state of permanent hyperalgesia, and we present an integrative (patho)physiological model for the way disturbed CRF receptor signaling in the amygdala could initiate neuropathic pain.

The amygdala, a relay station for switching on and off pain

Neuropathic pain is strongly associated with mood disorders like anxiety and depression. Corticotropin-releasing factor (CRF) plays a prominent role in these disorders as it is up-regulated in limbic structures such as the amygdala, upon experimentally induced neuropathy. This review discusses recent literature on the role of CRF in pain processing and highlights the amygdala as a potential hot spot in supraspinal descending pain control. Many studies have demonstrated analgesic effects of CRF following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). On the basis of the reviewed literature, we postulate a central mechanism for pain control in which the amygdala plays a critical role by switching on and off chronic pain. In this mechanism, upon pain stimuli, CRFR1 in the amygdala is activated by CRF to induce hyperalgesia. When the activated CRFR1 is internalized (pain initiation), it triggers the translocation of the cytoplasmic CRF type 2 receptor (CRFR2) to the plasma membrane. Here, CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, the urocortins, leading to analgesia (pain termination). This on-off switching of pain is completed by redistribution of the CRF receptors to their initial activity state. We furthermore propose that in neuropathic pain, this mechanism is dysregulated and causes a state of permanent hyperalgesia, and present an integrative (patho)physiological model for the way disturbed CRF receptor signalling in the amygdala could initiate neuropathic pain.

Behavioral effects of peripheral corticotropin-releasing factor during maternal separation may be mediated by proinflammatory activity

When guinea pig pups are separated from their mothers in a novel environment, an initial period of active behavior (vocalizing, locomotor activity) wanes after an hour or so and is replaced by a second, passive stage characterized by a crouched stance, closed eyes, and extensive piloerection. If pups are given a peripheral injection of 7-14μg of corticotropin-releasing factor (CRF) prior to testing, the passive behaviors occur immediately upon separation. We found that intracerebroventricular infusion of 1-10μg of CRF did not increase passive behavior relative to vehicle infusion, but that peripheral injection of the anti-inflammatory cytokine, interleukin-10, attenuated the passive behavior induced by peripheral CRF injection. These results together with previous findings suggest that peripheral CRF administration affects behavior of separated guinea pig pups through a mechanism that involves peripheral proinflammatory activity. The possible role of endogenous peripheral CRF in the behavioral response of untreated pups during maternal separation is considered.

Neuroendocrine control of thyroid‐stimulating hormone and adrenocorticotropic hormone in amphibians

Event Abstract Back to Event Neuroendocrine control of thyroid‐stimulating hormone and adrenocorticotropic hormone in amphibians Reiko Okada1*, Kazutoshi Yamamoto2, Itaru Hasunuma3, Shigeyasu Tanaka1 and Sakae Kikuyama2 1 Shizuoka University, Integrated Bioscience Section, Graduate School of Science and Technology, Japan 2 Waseda University, Department of Biology, Faculty of Education and Integrated Arts and Science, Japan 3 Toho University, Department of Biology, Faculty of Science, Japan In non-mammalian vertebrates, pituitary thyrotropin (TSH) secretion is considered to be regulated by multiple hypothalamic neuropeptides such as TSH-releasing hormone (TRH), corticotropin-releasing factor (CRF), gonadotropin-releasing hormone, pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and somatostatin. The main TSH-releasing factor varies according to the animal classes and the developmental stages. By performing in vitro experiments combined with specific radioimmunoassay for bullfrog TSH, we demonstrated that the frog CRF potently stimulates the release of TSH from both adult and larval bullfrog pituitary cells, whereas TRH moderately stimulates the TSH release from adult pituitary cells but not from larval ones and that the action of CRF is mediated by the CRF receptor 2. It was also shown that TSH-releasing activity in the bullfrog hypothalamic extract is profoundly diminished by a CRF receptor antagonist, suggesting that endogenous CRF contributes as a main TSH-releasing factor. On the other hand, both CRF and arginine-vasotocin (AVT)/arginine-vasopressin (AVP) have been reported to stimulate the release of adrenocorticotropic hormone (ACTH) from the pituitary of various vertebrates. In order to compare the potency of both peptides in terms of stimulating the ACTH release, experiments were conducted using dispersed bullfrog pituitary cells. The amount of ACTH released into the culture medium, as measured by a newly developed time-resolved fluoroimmunoassay for frog ACTH, was much higher when the pituitary cells were incubated in the presence of AVT than when they were incubated with CRF. This raised possibility that in amphibians, AVT rather than CRF is the main ACTH-releasing factor. Keywords: ACTH, amphibian, AVT, CRF, TSH Conference: ISAREN 2011: 7th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology, Ann Arbor, United States, 11 Jul - 13 Jul, 2011. Presentation Type: Invited Symposium Topic: Abstracts Citation: Okada R, Yamamoto K, Hasunuma I, Tanaka S and Kikuyama S (2011). Neuroendocrine control of thyroid‐stimulating hormone and adrenocorticotropic hormone in amphibians. Front. Endocrinol. Conference Abstract: ISAREN 2011: 7th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology. doi: 10.3389/conf.fendo.2011.03.00036 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jul 2011; Published Online: 09 Aug 2011. * Correspondence: Dr. Reiko Okada, Shizuoka University, Integrated Bioscience Section, Graduate School of Science and Technology, Shizuoka, 422-8529, Japan, drokada@ipc.shizuoka.ac.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama Google Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama Google Scholar Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama PubMed Reiko Okada Kazutoshi Yamamoto Itaru Hasunuma Shigeyasu Tanaka Sakae Kikuyama Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Corticotropin-Releasing Factor in the Rat Amygdala Differentially Influences Sensory-Discriminative and Emotional-like Pain Response in Peripheral Neuropathy

The central nucleus of the amygdala (CeA) is involved in processing and regulation of pain. We determined whether amygdaloid corticotropin-releasing factor (CRF) contributes to pain modulation in the neuropathic rat. Emotional aspect of pain was assessed by an aversive place-conditioning test and sensory aspect of pain by determining monofilament-induced limb-withdrawal threshold. CRF₆₋₃₃ (an inhibitor of CRF-binding protein) or CRF₉₋₄₁, a nonselective CRF receptor antagonist, was microinjected to the left or right CeA or a control site in rats with spared nerve injury (SNI) or sham operation of the left hind limb. In SNI animals, CRF₆₋₃₃ in the left or right CeA, but not in a control site, attenuated emotional painlike behavior and increased sensory pain. In sham controls, CRF₆₋₃₃ in the right but not left CeA increased sensory aspect of pain, without influence on place-avoidance behavior. The effects induced by CRF₆₋₃₃ were reversed by CRF₉₋₄₁. The results indicate that endogenous CRF in the CeA, through action on CRF receptors, may differentially influence emotional and sensory aspects of pain in neuropathy. While the right CeA had a dominant role in modulation of pain-related responses in sham controls, left as well as right CeA contributed to pain modulation in neuropathic animals. An increase in free endogenous corticotropin-releasing factor in the central nucleus of the amygdala was accompanied by increased cutaneous hypersensitivity and decreased emotional painlike behavior in neuropathic animals. This finding indicates that CRF in the amygdala may have differential effects on sensory and emotional aspects of neuropathic pain.

The Serotonergic Projection from the Median Raphe Nucleus to the Ventral Hippocampus is Involved in the Retrieval of Fear Memory Through the Corticotropin-Releasing Factor Type 2 Receptor

Several different studies have separately established that serotonin, corticotropin-releasing factor (CRF) receptors, and the hippocampus are involved in fear memory retrieval. The main aim of this study is to connect these separate studies. To assess the levels of anxiety/fear, we used the contextual fear-conditioning test and the elevated plus maze test as memory-dependent and memory-independent tasks, respectively. We injected CRF receptor antagonists or vehicle into the median raphe nucleus (MRN) 10 min before behavioral tests. As a result, 1000 ng of astressin 2B (CRF(2) receptor antagonist), but not 250 ng of antalarmin (CRF(1) receptor antagonist), significantly suppressed the expression rate of freezing behavior in the contextual fear-conditioning test. However, in the elevated plus maze test, there was no difference between astressin 2B-injected rats and saline-injected rats in the time spent in open arms. Neither the amount of exploratory behavior nor the moving distance in the EPM of astressin 2B-injected rats differed from that of vehicle-injected rats. Moreover, when we assessed the extracellular serotonin release in the ventral hippocampus in freely moving rats through in vivo microdialysis, it was shown that the blockade of the CRF(2) receptor in the MRN suppressed serotonin release in the ventral hippocampus during fear memory retrieval. These results indicated that endogenous CRF and/or related ligands that were released in the MRN could activate the CRF(2) receptor and stimulate serotonin release in the ventral hippocampus, thereby inducing fear memory retrieval.

Postnatal developmental profile of urocortin 1 and cocaine- and amphetamine-regulated transcript in the perioculomotor region of C57BL/6J mice

Urocortin 1 (Ucn 1) is an endogenous corticotropin releasing factor (CRF)-related peptide. Ucn 1 is most highly expressed in the perioculomotor urocortin containing neurons (pIIIu), previously known as the non-preganglionic Edinger-Westphal nucleus (npEW). Various studies indicate that these cells are involved in stress adaptation and the regulation of ethanol (EtOH) intake. However, the developmental trajectory of these neurons remained unexamined. Expression of the cocaine- and amphetamine-regulated transcript (CART), which co-localizes with Ucn 1 in the perioculomotor area (pIII) has been examined prenatally, but not postnatally. The goal of the current study was to characterize the ontogenetic profile of Ucn 1 and CART during postnatal development in C57BL/6J (B6) mice. B6 mice were bred, and brains were collected at postnatal days (PND) 1, 4, 8, 12, 16, 24 and 45. Brightfield immunohistochemical staining for Ucn 1 and CART showed that Ucn 1-immunoreactivity (ir) was absent at PND 1, while CART-ir was already apparent in pIIIu at birth, a finding indicating that although the pIIIu neurons have already migrated to their adult position, Ucn 1 expression is triggered in them at later postnatal stages. Ucn 1-ir gradually increased with age, approaching adult levels at PND 16. This developmental profile was confirmed by double-immunofluorescence, which showed that Ucn 1 was absent in CART-positive cells of pIII at PND 4 and that Ucn 1 and CART are strongly but not completely co-localized in pIII at PND 24. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis confirmed that Ucn 1 mRNA levels are significantly lower at PND 4 and PND 12 than in adult animals. The lack of brain Ucn 1 immunoreactivity at birth and the gradual postnatal increase in Ucn 1 in pIIIu suggests that this peptide plays a greater behavioral role in adulthood than during the early postnatal development of an organism.

Urocortin Prevents Indomethacin-Induced Small Intestinal Lesions in Rats Through Activation of CRF2 Receptors

The role of corticotropin-releasing factor (CRF) in the pathogenesis of indomethacin-induced small intestinal lesions was examined in rats. Animals were given indomethacin (10 mg/kg) subcutaneously and killed 24 h later. Urocortin I [a nonselective CRF receptor (CRFR) agonist], astressin (a nonselective CRFR antagonist), NBI-27914 (a CRFR1 antagonist), or astressin-2B (a CRFR2 antagonist) was given intravenously 10 min before the administration of indomethacin. Indomethacin caused hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility, mucosal invasion of enterobacteria, up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of mucosal myeloperoxidase (MPO) activity. Pretreatment of the animals with astressin, a non-selective CRFR antagonist, aggravated the lesions in a dose-dependent manner. Likewise, astressin-2B also exacerbated the intestinal ulcerogenic response induced by indomethacin, while NBI-27914 did not. Urocortin I prevented indomethacin-induced intestinal lesions, together with the suppression of bacterial invasion and an increase in mucosal MPO activity and iNOS expression; these effects were significantly reversed by co-administration of astressin-2B but not NBI-27914. Urocortin I suppressed the hypermotility response to indomethacin, and this effect was also abrogated by astressin-2B but not NBI-27914. These results suggest that urocortin 1 prevents indomethacin-induced small intestinal lesions, and that this action is mediated by the activation of CRFR2 and is functionally associated with the suppression of the intestinal hypermotility response caused by indomethacin. It is assumed that endogenous CRF contributes to the maintenance of the mucosal defensive ability of the small intestine against indomethacin through the activation of CRFR2.