Ghrelin is secreted in the stomach during fasting and targets the growth hormone secretagogue receptor (GHSR1a) in the hypothalamus and brainstem to exert its orexigenic effect. Recently, liver enriched antimicrobial peptide-2 (LEAP2) was identified as an endogenous high-affinity GHSR1a antagonist. LEAP2 is a 40-amino acid peptide with two disulfide bridges and GHRS1a affinity in the N-terminal hydrophobic part. In this study, we tested modified truncated N-terminal peptide LEAP2 (1-14), along with its myristoylated, palmitoylated, and stearoylated analogs, to determine their affinity to and activation of GHSR1a and their anorexigenic effects after acute peripheral administration. The lipidized analogs bound GHSR1a with affinity similar to that of natural LEAP2, and lipidization significantly enhanced the affinity of LEAP2(1-14) to GHSR1a. According to the beta-lactamase reporter gene response, the natural GHSR1a agonist ghrelin activated the receptor with nanomolar EC50 LEAP2(1-14) analogs behaved as inverse agonists of GHSR1a and suppressed internal activity of the receptor with EC50 values in the 10-8 M range. LEAP2(1-14) analogs significantly lowered acute food intake in overnight fasted mice, and palmitoylated LEAP2(1-14) was the most potent. In free-fed mice, all LEAP2(1-14) analogs significantly decreased the orexigenic effect of the stable ghrelin analog [Dpr3]Ghrelin. Moreover, palmitoylated LEAP2(1-14) inhibited the growth hormone (GH) release induced by [Dpr3] Ghrelin and exhibited an increased stability in rat plasma compared with LEAP2(1-14). In conclusion, palmitoylated LEAP2(1-14) had the most pronounced affinity for GHSR1a, had an anorexigenic effect, exhibited stability in rat plasma, and attenuated [Dpr3]Ghrelin-induced GH release. Such properties render palmitoylated LEAP2(1-14) a promising substance for antiobesity treatment. SIGNIFICANCE STATEMENT: The agonist and antagonist of one receptor are rarely found in one organism. For ghrelin receptor (growth hormone secretagogue receptor, GHSR), endogenous agonist ghrelin and endogenous antagonist/inverse agonist liver enriched antimicrobial peptide-2 (LEAP2) co-exist and differently control GHSR signaling. As ghrelin has a unique role in food intake regulation, energy homeostasis, and cytoprotection, lipidized truncated LEAP2 analogs presented in this study could serve not only to reveal the relationship between ghrelin and LEAP2 but also for development of potential anti-obesity agents.

• MeSH
• aminokyseliny metabolismus   MeSH
• antimikrobiální peptidy MeSH
• disulfidy metabolismus   MeSH
• ghrelin * farmakologie   MeSH
• játra metabolismus   MeSH
• krysa rodu rattus MeSH
• látky proti obezitě * farmakologie   MeSH
• myši MeSH
• receptory ghrelinu metabolismus   MeSH
• růstový hormon metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin's/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin's/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

• MeSH
• biologické markery MeSH
• genetická predispozice k nemoci MeSH
• ghrelin metabolismus   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• náchylnost k nemoci MeSH
• nikotin škodlivé účinky   MeSH
• poruchy spojené s užíváním psychoaktivních látek etiologie   metabolismus   MeSH
• posilování (psychologie) MeSH
• receptory ghrelinu metabolismus   MeSH
• signální transdukce * MeSH
• stimulanty centrálního nervového systému škodlivé účinky   MeSH
• užívání tabáku škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Methamphetamine abuse imposes a significant burden on individuals and society worldwide, and an effective therapy of methamphetamine addiction would provide distinguished social benefits. Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; thus, ghrelin antagonism is proposed as a promising addiction treatment. The aim of our study was to elucidate whether the pretreatment with growth hormone secretagogue receptor (GHS-R1A) antagonist, substance JMV2959, could reduce the methamphetamine intravenous self-administration (IVSA) and the tendency to relapse, and whether JMV2959 could reduce or prevent methamphetamine-induced conditioned place preference (CPP) in rats. Following an adequate maintenance period, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 180 min sessions of methamphetamine IVSA under a fixed ratio FR1, which significantly reduced the number of active lever-pressings, the number of infusions, and the amount of the consumed methamphetamine dose. Pretreatment with JMV2959 also reduced or prevented relapse-like behavior tested in rats on the 12th day of the abstinence period. Pretreatment with JMV2959 significantly reduced the expression of methamphetamine-induced CPP. Simultaneous administration of JMV2959 with methamphetamine during the conditioning period significantly reduced the methamphetamine-CPP. Our results encourage further research of the ghrelin antagonism as a potential new pharmacological tool for methamphetamine addiction treatment.

• MeSH
• analýza rozptylu MeSH
• autoaplikace MeSH
• časové faktory MeSH
• glycin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• intravenózní podání MeSH
• methamfetamin aplikace a dávkování   farmakologie   MeSH
• podmiňování (psychologie) účinky léků   MeSH
• potkani Wistar MeSH
• prostorové chování účinky léků   MeSH
• receptory ghrelinu antagonisté a inhibitory   metabolismus   MeSH
• stimulanty centrálního nervového systému aplikace a dávkování   farmakologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• triazoly aplikace a dávkování   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.

• MeSH
• beta-laktamasy metabolismus   MeSH
• ghrelin analogy a deriváty   metabolismus   farmakokinetika   farmakologie   MeSH
• kompetitivní vazba MeSH
• lipopolysacharidy škodlivé účinky   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nechutenství chemicky indukované   farmakoterapie   metabolismus   patofyziologie   MeSH
• přijímání potravy účinky léků   MeSH
• receptory ghrelinu metabolismus   MeSH
• růstový hormon metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální transdukce účinky léků   MeSH
• stabilita proteinů MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The opioid-induced rise of extracellular dopamine, endocannabinoid anandamide and γ-aminobutyric acid (GABA) concentrations triggered by opioids in the nucleus accumbens shell (NACSh) most likely participate in opioid reward. We have previously demonstrated that systemic administration of ghrelin antagonist (JMV2959) significantly decreased morphine-induced dopamine and anandamide (N-arachidonoylethanolamine, AEA) increase in the NACSh. Fentanyl is considered as a µ-receptor-selective agonist. The aim of this study was to test whether JMV2959, a growth hormone secretagogue receptor (GHS-R1A) antagonist, can influence the fentanyl-induced effects on anandamide, 2-arachidonoylglycerol (2-AG) and GABA in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and nucleus accumbens (NAC). Using in vivo microdialysis in rats, we have found that pre-treatment with JMV2959 reversed dose dependently fentanyl-induced anandamide increases in the NACSh, resulting in a significant AEA decrease and intensified fentanyl-induced decreases in accumbens 2-AG levels, with both JMV2959 effects more expressed when administered into the NACSh in comparison to the VTA. JMV2959 pre-treatment significantly decreased the fentanyl-evoked accumbens GABA efflux and reduced concurrently monitored fentanyl-induced behavioural stimulation. Our current data encourage further investigation to assess if substances affecting GABA or endocannabinoid concentrations and action, such as GHS-R1A antagonists, can be used to prevent opioid-seeking behaviour.

• MeSH
• chování zvířat MeSH
• endokanabinoidy metabolismus   MeSH
• extracelulární prostor metabolismus   MeSH
• fentanyl farmakologie   MeSH
• GABA metabolismus   MeSH
• ghrelin farmakologie   MeSH
• glycin analogy a deriváty   farmakologie   MeSH
• krysa rodu rattus MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• receptory ghrelinu metabolismus   MeSH
• tegmentum mesencephali - area ventralis účinky léků   metabolismus   MeSH
• triazoly farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats. In the place preference model, the rats were conditioned for 8 days with morphine (10 mg/kg s.c.). On the experimental day, JMV2959 (3 and 6 mg/kg i.p.) or saline were administered before testing. We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens in rats following challenge-morphine dose (5 mg/kg s.c.) with or without JMV2959 (3 and 6 mg/kg i.p.) pretreatment, administered on the 12th day of spontaneous abstinence from morphine repeated treatment (5 days, 10-40 mg/kg). Induced behavioral changes were simultaneously monitored. Pretreatment with JMV2959 significantly and dose dependently reduced the morphine-induced conditioned place preference and significantly and dose dependently reduced the challenge-morphine-induced dopaminergic sensitization and affected concentration of by-products associated with dopamine metabolism in the nucleus accumbens. JMV2959 pretreatment also significantly reduced challenge-morphine-induced behavioral sensitization. Our present data suggest that GHS-R1A antagonists deserve to be further investigated as a novel treatment strategy for opioid addiction.

• MeSH
• dopamin * metabolismus   MeSH
• glycin analogy a deriváty   farmakologie   MeSH
• krysa rodu rattus MeSH
• mikrodialýza metody   MeSH
• morfin aplikace a dávkování   antagonisté a inhibitory   MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• operantní podmiňování účinky léků   fyziologie   MeSH
• opioidní analgetika aplikace a dávkování   antagonisté a inhibitory   MeSH
• potkani Wistar MeSH
• receptory ghrelinu antagonisté a inhibitory   metabolismus   MeSH
• triazoly farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• ghrelin metabolismus   MeSH
• hypothalamus fyziologie   MeSH
• lidé MeSH
• neurony fyziologie   MeSH
• receptory ghrelinu metabolismus   MeSH
• vápníkové kanály - typ N metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem MeSH

RATIONALE AND OBJECTIVES: Ghrelin, an orexigenic (appetite stimulating) peptide activates binding sites in the ventral tegmental area (a structure linked with the neural reward system) allowing it to participate in reward-seeking behavior. An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine, and nicotine abuse. However, the role of ghrelin, in opioid effects, has rarely been examined. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit markers of morphine-induced activation of the neural reward system, namely morphine-induced increase of dopamine in the nucleus accumbens and behavioral changes in rats. METHODS: We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens shell in rats following morphine (MO, 5, 10 mg/kg s.c.) administration with and without ghrelin antagonist pretreatment (JMV2959, 3, 6 mg/kg i.p., 20 min before MO). Induced behavioral changes were simultaneously monitored. RESULTS: JMV2959 significantly and dose dependently reduced MO-induced dopamine release in the nucleus accumbens shell and affected concentration of by-products associated with dopamine metabolism: 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). JMV2959 pretreatment also significantly reduced MO-induced behavioral stimulation, especially stereotyped behavior. CONCLUSIONS: Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.

• MeSH
• chování zvířat účinky léků   MeSH
• dopamin analogy a deriváty   metabolismus   farmakologie   MeSH
• ghrelin metabolismus   MeSH
• glycin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• krysa rodu rattus MeSH
• kyselina 3,4-dihydroxyfenyloctová metabolismus   MeSH
• kyselina homovanilová farmakologie   MeSH
• mikrodialýza MeSH
• morfin aplikace a dávkování   farmakologie   MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• odměna MeSH
• opioidní analgetika aplikace a dávkování   farmakologie   MeSH
• potkani Wistar MeSH
• receptory ghrelinu antagonisté a inhibitory   metabolismus   MeSH
• stereotypní chování účinky léků   MeSH
• triazoly aplikace a dávkování   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ghrelin and agonists of its receptor GHS-R1a are potential substances for the treatment of cachexia. In the present study, we investigated the acute and long term effects of the GHS R1a agonist JMV 1843 (H Aib-DTrp-D-gTrp-CHO) on food intake, body weight and metabolic parameters in lean C57BL/6 male mice. Additionally, we examined stability of JMV 1843 in mouse blood serum. A single subcutaneous injection of JMV 1843 (0.01-10 mg/kg) increased food intake in fed mice in a dose-dependent manner, up to 5-times relative to the saline-treated group (ED(50)=1.94 mg/kg at 250 min). JMV 1843 was stable in mouse serum in vitro for 24 h, but was mostly eliminated from mouse blood after 2 h in vivo. Ten days of treatment with JMV 1843 (subcutaneous administration, 10 or 20 mg/kg/day) significantly increased food intake, body weight and mRNA expression of the orexigenic neuropeptide Y and agouti-related peptide in the medial basal hypothalamus and decreased the expression of uncoupling protein 1 in brown adipose tissue. Our data suggest that JMV 1843 could have possible future uses in the treatment of cachexia.

• MeSH
• AGRP protein genetika   metabolismus   MeSH
• chuťová stimulancia aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• ghrelin agonisté   metabolismus   MeSH
• hmotnostní přírůstek účinky léků   MeSH
• hnědá tuková tkáň účinky léků   metabolismus   MeSH
• hypothalamus účinky léků   metabolismus   MeSH
• injekce subkutánní MeSH
• iontové kanály metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• mitochondriální proteiny metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuropeptid Y genetika   metabolismus   MeSH
• oligopeptidy aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• přijímání potravy účinky léků   MeSH
• receptory ghrelinu agonisté   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• upregulace MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.

• MeSH
• ghrelin analogy a deriváty   chemická syntéza   metabolismus   MeSH
• molekulární sekvence - údaje MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• přijímání potravy účinky léků   MeSH
• receptory ghrelinu metabolismus   MeSH
• růstový hormon krev   MeSH
• sekvence aminokyselin MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH