Dexamethasone attenuation of the cortisol response to nicotine in smokers

The effect of corticosteroids upon the cortisol response to nicotine from smoking was investigated in five heavy smokers. Corticosteroid activity was manipulated by administering dexamethasone, a synthetic glucocortoicoid (1 mg orally, 14 h before), in a doubleblind, placebo-controlled procedure. Testing took place in the middle of the day and involved the smoking of two high-nicotine (2.87 mg) research cigarettes over a 15-min period. The dexamethasone condition was characterized by a pronounced suppression of baseline plasma cortisol, as expected, and by a significant dampening of the cortisol response to nicotine, indicating diminished sensitivity to nicotine under conditions of enhanced corticosteroid activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46333/1/213_2005_Article_BF02244142.pd

Plasma Hormones Facilitated the Hypermotility of the Colon in a Chronic Stress Rat Model

Objective: To study the relationship between brain-gut peptides, gastrointestinal hormones and altered motility in a rat model of repetitive water avoidance stress (WAS), which mimics the irritable bowel syndrome (IBS). Methods: Male Wistar rats were submitted daily to 1-h of water avoidance stress (WAS) or sham WAS (SWAS) for 10 consecutive days. Plasma hormones were determined using Enzyme Immunoassay Kits. Proximal colonic smooth muscle (PCSM) contractions were studied in an organ bath system. PCSM cells were isolated by enzymatic digestion and IKv and IBKca were recorded by the patch-clamp technique. Results: The number of fecal pellets during 1 h of acute restraint stress and the plasma hormones levels of substance P (SP), thyrotropin-releasing hormone (TRH), motilin (MTL), and cholecystokinin (CCK) in WAS rats were significantly increased compared with SWAS rats, whereas vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and corticotropin releasing hormone (CRH) in WAS rats were not significantly changed and peptide YY (PYY) in WAS rats was significantly decreased. Likewise, the amplitudes of spontaneous contractions of PCSM in WAS rats were significantly increased comparing with SWAS rats. The plasma of WAS rats (100 ml) decreased the amplitude of spontaneous contractions of controls. The IKv and IBKCa of PCSMs were significantly decreased in WAS rats compared with SWAS rats and the plasma of WAS rats (100 ml) increased the amplitude of IKv and IBKCa in normal rats

Corticotropin-releasing hormone, its binding protein and receptors in human cervical tissue at preterm and term labor in comparison to non-pregnant state

BACKGROUND: Preterm birth is still the leading cause of neonatal morbidity and mortality. The level of corticotropin-releasing hormone (CRH) is known to be significantly elevated in the maternal plasma at preterm birth. Although, CRH, CRH-binding protein (CRH-BP), CRH-receptor 1 (CRH-R1) and CRH-R2 have been identified both at mRNA and protein level in human placenta, deciduas, fetal membranes, endometrium and myometrium, no corresponding information is yet available on cervix. Thus, the aim of this study was to compare the levels of the mRNA species coding for CRH, CRH-BP, CRH-R1 and CRH-R2 in human cervical tissue and myometrium at preterm and term labor and not in labor as well as in the non-pregnant state, and to localize the corresponding proteins employing immunohistochemical analysis. METHODS: Cervical, isthmic and fundal (from non-pregnant subjects only) biopsies were taken from 67 women. Subjects were divided in 5 groups: preterm labor (14), preterm not in labor (7), term labor (18), term not in labor (21) and non-pregnant (7). Real-time RT-PCR was employed for quantification of mRNA levels and the corresponding proteins were localized by immunohistochemical analysis. RESULTS: The levels of CRH-BP, CRH-R1 and CRH-R2 mRNA in the pregnant tissues were lower than those in non-pregnant subjects. No significant differences were observed between preterm and term groups. CRH-BP and CRH-R2 mRNA and the corresponding proteins were present at lower levels in the laboring cervix than in the non-laboring cervix, irrespective of gestational age. In most of the samples, with the exception of four myometrial biopsies the level of CRH mRNA was below the limit of detection. All of these proteins could be detected and localized in the cervix and the myometrium by immunohistochemical analysis. CONCLUSION: Expression of CRH-BP, CRH-R1 and CRH-R2 in uterine tissues is down-regulated during pregnancy. The most pronounced down-regulation of CRH-BP and CRH-R2 occurred in laboring cervix, irrespective the length of gestation. The detection of substantial expression of the CRH and its receptor proteins, as well as receptor mRNA in the cervix suggests that the cervix may be a target for CRH action. Further studies are required to elucidate the role of CRH in cervical ripening

Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA

Corticotropin Releasing Factor-Induced CREB Activation in Striatal Neurons Occurs via a Novel Gβγ Signaling Pathway

The peptide corticotropin-releasing factor (CRF) was initially identified as a critical component of the stress response. CRF exerts its cellular effects by binding to one of two cognate G-protein coupled receptors (GPCRs), CRF receptor 1 (CRFR1) or 2 (CRFR2). While these GPCRs were originally characterized as being coupled to Gαs, leading to downstream activation of adenylyl cyclase (AC) and subsequent increases in cAMP, it has since become clear that CRFRs couple to and activate numerous other downstream signaling cascades. In addition, CRF signaling influences the activity of many diverse brain regions, affecting a variety of behaviors. One of these regions is the striatum, including the nucleus accumbens (NAc). CRF exerts profound effects on striatal-dependent behaviors such as drug addiction, pair-bonding, and natural reward. Recent data indicate that at least some of these behaviors regulated by CRF are mediated through CRF activation of the transcription factor CREB. Thus, we aimed to elucidate the signaling pathway by which CRF activates CREB in striatal neurons. Here we describe a novel neuronal signaling pathway whereby CRF leads to a rapid Gβγ- and MEK-dependent increase in CREB phosphorylation. These data are the first descriptions of CRF leading to activation of a Gβγ-dependent signaling pathway in neurons, as well as the first description of Gβγ activation leading to downstream CREB phosphorylation in any cellular system. Additionally, these data provide additional insight into the mechanisms by which CRF can regulate neuronal function