Ghrelin receptor antagonist attenuated sickness behavior and activation of HPA-axis induced by immunological challenge in male rats

Abstract Stress is widely believed to play a major role in the pathogenesis of many diseases. Central neuropeptide Y (NPY) counteracts the biological actions of corticotropin-releasing factor (CRF), and in turn attenuates stress responses. Administration (intracerebroventricular, ICV) of NPY, significantly antagonized the inhibitory effects of chronic complicated stress (CCS) on gastrointestinal (GI) dysmotility in rats. However, ICV administration is an invasive technique. The effect of intranasal administration of NPY on the hypothalamus-pituitary-adrenal (HPA) axis and GI motility in CCS conditions have not been studied, and the inhibitory mechanism of NPY on CRF through the gamma-aminobutyric acid (GABA)A receptor needs to be further investigated. A CCS rat model was set up, NPY was intranasal administered every day prior to the stress loading. Further, a GABAA receptor antagonist was ICV injected daily. Central CRF and NPY expression were evaluated, serum corticosterone and NPY levels were analyzed, and colonic motor functions was assessed. CCS rats showed significantly increased CRF expression and corticosterone levels, which resulted in enhanced colonic motor functions. Intranasal NPY significantly increased central NPY mRNA expression and reduced central CRF mRNA expression as well as the plasma corticosterone level, helping to restore colonic motor functions. However, ICV administration of the GABAA receptor antagonist significantly abolished these effects. Intranasal administration of NPY upregulates the hypothalamic NPY system. NPY may, through the GABAA receptor, significantly antagonize the overexpressed central CRF and attenuate the HPA axis activities in CCS conditions, exerting influences and helping to restore colonic motor function.

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Increased plasma ghrelin suppresses insulin release in wethers fed with a high-protein diet

Journal of Endocrinology ◽

10.1530/joe-13-0501 ◽

2014 ◽

Vol 221 (3) ◽

pp. 371-380 ◽

Cited By ~ 1

Author(s):

T Takahashi ◽

K Sato ◽

S Kato ◽

T Yonezawa ◽

Y Kobayashi ◽

...

Keyword(s):

Receptor Antagonist ◽

High Protein Diet ◽

Diet Group ◽

High Protein ◽

Acylated Ghrelin ◽

Mrna Levels ◽

Ghrelin Receptor ◽

Gh Secretion ◽

Ghrelin Receptor Antagonist ◽

Ghrelin Secretion

Ghrelin is a multifunctional peptide that promotes an increase of food intake and stimulates GH secretion. Ghrelin secretion is regulated by nutritional status and nutrients. Although a high-protein (HP) diet increases plasma ghrelin secretion in mammals, the mechanisms and the roles of the elevated ghrelin concentrations due to a HP diet have not been fully established. To clarify the roles of elevated acylated ghrelin upon intake of a HP diet, we investigated the regulation of ghrelin concentrations in plasma and tissues in wethers fed with either the HP diet or the control (CNT) diet for 14 days, and examined the action of the elevated plasma ghrelin by using a ghrelin-receptor antagonist. The HP diet gradually increased the plasma acylated-ghrelin concentrations, but the CNT diet did not. Although the GH concentrations did not vary significantly across the groups, an injection of ghrelin-receptor antagonist enhanced insulin levels in circulation in the HP diet group. In the fundus region of the stomach, the ghrelin levels did not differ between the HP and CNT diet groups, whereas ghrelinO-acyltransferase mRNA levels were higher in the group fed with HP diet than those of the CNT diet group were. These results indicate that the HP diet elevated the plasma ghrelin levels by increasing its synthesis; this elevation strongly suppresses the appearance of insulin in the circulation of wethers, but it is not involved in GH secretion. Overall, our findings indicate a role of endogenous ghrelin action in secretion of insulin, which acts as a regulator after the consumption of a HP diet.

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A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.174039 ◽

2021 ◽

Vol 899 ◽

pp. 174039

Author(s):

Christian E. Edvardsson ◽

Jesper Vestlund ◽

Elisabet Jerlhag

Keyword(s):

Nucleus Accumbens ◽

Receptor Antagonist ◽

Ventral Tegmental Area ◽

Dopamine Release ◽

Nucleus Accumbens Shell ◽

Ghrelin Receptor ◽

Ventral Tegmental ◽

Ghrelin Receptor Antagonist

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Brainstem Thyrotropin-Releasing Hormone Regulates Food Intake through Vagal-Dependent Cholinergic Stimulation of Ghrelin Secretion

Endocrinology ◽

10.1210/en.2006-0820 ◽

2006 ◽

Vol 147 (12) ◽

pp. 6004-6010 ◽

Cited By ~ 30

Author(s):

Yan Ao ◽

Vay Liang W. Go ◽

Natalie Toy ◽

Tei Li ◽

Yu Wang ◽

...

Keyword(s):

Food Intake ◽

Receptor Antagonist ◽

Brain Stem ◽

Motor Neurons ◽

Physiological Role ◽

Natural Food ◽

Ghrelin Receptor ◽

Ghrelin Receptor Antagonist ◽

Fasted Rats ◽

Stimulation Of

The brainstem is essential for mediating energetic response to starvation. Brain stem TRH is synthesized in caudal raphe nuclei innervating brainstem and spinal vagal and sympathetic motor neurons. Intracisternal injection (ic) of a stable TRH analog RX77368 (7.5–25 ng) dose-dependently stimulated solid food intake by 2.4- to 3-fold in freely fed rats, an effect that lasted for 3 h. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. In pentobarbital-anesthetized rats, RX77368 (50 ng) ic induced a significant bipeak increase in serum total ghrelin levels from the basal of 8.7 ± 1.7 ng/ml to 13.4 ± 2.4 ng/ml at 30 min and 14.5 ± 2.0 ng/ml at 90 min, which was prevented by either bilateral vagotomy (−60 min) or atropine pretreatment (2 mg/kg, −30 min) but magnified by bilateral adrenalectomy (−60 min). TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (d-Lys-3)-GHRP-6 (10 μmol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 μl). Brain stem TRH mRNA and TRH receptor 1 mRNA increased by 57–58 and 33–35% in 24- and 48-h fasted rats and returned to the fed levels after a 3-h refeeding. Natural food intake in overnight fasted rats was significantly reduced by ic TRH antibody, ic Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors.

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