astressin-2b and Disease-Models--Animal

Ischemic stroke is the second leading cause of death worldwide. Therefore, exploring effective and emerging molecular targets for ischemic stroke is a primary task of basic and clinical research. The aim of the present study was to investigate the function of corticotropin-releasing factor (CRF) in ischemic stroke and its related mechanisms, to provide a reference for the treatment of ischemic stroke. CRF, antalarmin, or astressin-2B were used to activate or block the CRF1 (CRF receptor 1) or CRF2 (CRF receptor 2) in BV2 cells and adult male mice, thus constructing a distal middle cerebral artery occlusion (dMCAO) model. CRF not only accelerated microglial activity by promoting transcription and production of inflammatory factors, but also promoted the transformation of activated BV2 cells from a neuroprotective phenotype (M2) to cytotoxic phenotype (M1), and these effects were mediated by the TLR4/NF-κB signaling pathway. These effects can be blocked by antalarmin but not by astressin-2B. CRF significantly aggravated the neurological deficit, increased infarction volume, and exacerbated neuronal injuries. Additionally, CRF significantly improved the levels of TNF-α and phospho-NF-κB in the ischemia penumbra. Finally, CRF significantly increased the number of CD16/Iba-1-positive cells and decreased the number of CD206/Iba-1-positive cells in the ischemia penumbra. These results provide evidence of the proinflammatory role of CRF in an ischemic stroke model and a possible underlying mechanism, which may facilitate the elucidation of potential treatment approaches for ischemic stroke.

Topics: Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Inflammation; Ischemic Stroke; Male; Mice; Microglia; Neurons; NF-kappa B; Peptide Fragments; Peptides, Cyclic; Phosphorylation; Pyrimidines; Pyrroles; Receptors, Corticotropin-Releasing Hormone

Stress is antinociceptive in some models of pain, but enhances musculoskeletal nociceptive responses in mice and muscle pain in patients with fibromyalgia syndrome. To test the hypothesis that urocortins are stress hormones that are sufficient to enhance tactile and musculoskeletal hyperalgesia, von Frey fibre sensitivity and grip force after injection of corticotropin-releasing factor (CRF), urocortin I and urocortin II were measured in mice. Urocortin I (a CRF1 and CRF2 receptor ligand) produced hyperalgesia in both assays when injected intrathecally (i.t.) but not intracerebroventricularly, and only at a large dose when injected peripherally, suggesting a spinal action. Morphine inhibited urocortin I-induced changes in nociceptive responses in a dose-related fashion, confirming that changes in behaviour reflect hyperalgesia rather than weakness. No tolerance developed to the effect of urocortin I (i.t.) when injected repeatedly, consistent with a potential to enhance pain chronically. Tactile hyperalgesia was inhibited by NBI-35965, a CRF1 receptor antagonist, but not astressin 2B, a CRF2 receptor antagonist. However, while urocortin I-induced decreases in grip force were not observed when co-administered i.t. with either NBI-35965 or astressin 2B, they were even more sensitive to inhibition by astressin, a non-selective CRF receptor antagonist. Together these data indicate that urocortin I acts at CRF receptors in the mouse spinal cord to elicit a reproducible and persistent tactile (von Frey) and musculoskeletal (grip force) hyperalgesia. Urocortin I-induced hyperalgesia may serve as a screen for drugs that alleviate painful conditions that are exacerbated by stress.

Topics: Acenaphthenes; Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hand Strength; Hyperalgesia; Injections, Spinal; Mice; Nociception; Pain Measurement; Peptide Fragments; Peptides, Cyclic; Receptors, Corticotropin-Releasing Hormone; Spinal Cord; Stress, Psychological; Urocortins

Nesfatin-1 is produced in the periphery and in the brain where it has been demonstrated to regulate appetite, stress hormone secretion, and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally projecting oxytocin (OT) and corticotropin-releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent on activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist astressin2B abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist ornithine vasotocin (OVT), indicating that the hypertensive effect of nesfatin-1 may require activation of oxytocinergic (OTergic) neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of α-melanocyte stimulating hormone (α-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while α-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, α-MSH can signal independently from this circuit to increase MAP.

Topics: alpha-MSH; Animals; Blood Pressure; Calcium-Binding Proteins; Corticotropin-Releasing Hormone; Disease Models, Animal; DNA-Binding Proteins; Hormones; Hypertension; Male; Melanocortins; Melanocyte-Stimulating Hormones; Nerve Net; Nerve Tissue Proteins; Nucleobindins; Oxytocin; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Receptors, Oxytocin; Vasotocin

The exacerbation of musculoskeletal pain by stress in humans is modeled by the musculoskeletal hyperalgesia in rodents following a forced swim. We hypothesized that stress-sensitive corticotropin releasing factor (CRF) receptors and transient receptor vanilloid 1 (TRPV1) receptors are responsible for the swim stress-induced musculoskeletal hyperalgesia. We confirmed that a cold swim (26 °C) caused a transient, morphine-sensitive decrease in grip force responses reflecting musculoskeletal hyperalgesia in mice. Pretreatment with the CRF2 receptor antagonist astressin 2B, but not the CRF1 receptor antagonist NBI-35965, attenuated this hyperalgesia. Desensitizing the TRPV1 receptor centrally or peripherally using desensitizing doses of resiniferatoxin (RTX) failed to prevent the musculoskeletal hyperalgesia produced by cold swim. SB-366791, a TRPV1 antagonist, also failed to influence swim-induced hyperalgesia. Together these data indicate that swim stress-induced musculoskeletal hyperalgesia is mediated, in part, by CRF2 receptors but is independent of the TRPV1 receptor.

Topics: Acenaphthenes; Analgesics; Analysis of Variance; Animals; Body Weight; Cold Temperature; Disease Models, Animal; Diterpenes; Female; Hyperalgesia; Mice; Morphine; Muscle Strength; Musculoskeletal Pain; Pain Measurement; Peptide Fragments; Peptides, Cyclic; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Swimming; TRPV Cation Channels

Recent studies have provided convincing evidences for co-morbidity between opioid addiction and obsessive-compulsive disorder (OCD), and the involvement of the corticotrophin-releasing factor (CRF) in the effects of morphine-withdrawal. Some scanty evidences also point towards the role of CRF in OCD and related disorders. But, no evidence indicated the role of CRF in morphine withdrawal associated obsessive-compulsive behavior (OCB). Therefore, the present study investigated the role of CRF in morphine-withdrawal induced OCB in mice. Marble-burying behavior in mice was used to assess OCB as this model has good predictive and face validity. The results revealed that acute morphine dose dependently attenuated the marble burying behavior, whereas withdrawal of chronic morphine was associated with significant rise in marble burying behavior. This indicates the differential effect of acute morphine and chronic morphine-withdrawal on OCB. Further, acute treatment with CRF receptor antagonists like antalarmin (2 and 4 μg/mouse, i.c.v.) or astressin-2B (3 and 10 nmol/mouse, i.c.v.) dose dependently attenuated the peak morphine-withdrawal induced increase in marble burying behavior. Moreover, concomitant treatment with antalarmin (4 μg/mouse, i.c.v.) or astressin-2B (10 nmol/mouse, i.c.v.) along with morphine blocked the morphine-withdrawal associated exacerbation of OCB. These results indicate that OCB associated with morphine withdrawal state is partly mediated by the activation of central CRF receptors.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Morphine; Motor Activity; Narcotics; Obsessive-Compulsive Disorder; Peptide Fragments; Peptides, Cyclic; Pyrimidines; Pyrroles; Receptors, Corticotropin-Releasing Hormone; Substance Withdrawal Syndrome

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.

Topics: Aniline Compounds; Animals; Bacterial Translocation; Corticotropin-Releasing Hormone; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Agents; Gastrointestinal Motility; Indomethacin; Injections, Intravenous; Intestine, Small; Male; Nitric Oxide Synthase Type II; Peptic Ulcer; Peptide Fragments; Peptides, Cyclic; Peroxidase; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Time Factors; Urocortins