ghrelin/GHS-R1A
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Recent data suggest that the orexigenic peptide ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) have opposing effects on food intake regulation. Although circulating ghrelin is decreased in obesity, peripheral ghrelin administration does not induce food intake in obese mice. Limited information is available on ghrelin resistance in relation to LEAP2. In this study, the interplay between ghrelin and LEAP2 in obesity induced by a high-fat (HF) diet in mice was studied. First, the progression of obesity and intolerance to glucose together with plasma levels of active and total ghrelin, leptin, as well as liver LEAP2 mRNA expression at different time points of HF diet feeding was examined. In addition, the impact of switch from a HF diet to a standard diet on plasma ghrelin and LEAP2 production was studied. Second, sensitivity to the stable ghrelin analogue [Dpr3]Ghrelin or our novel LEAP2 analogue palm-LEAP2(1-14) during the progression of HF diet-induced obesity and after the switch for standard diet was investigated. Food intake was monitored after acute subcutaneous administration. HF diet feeding decreased both active and total plasma ghrelin and increased liver LEAP2 mRNA expression along with intolerance to glucose and the switch to a standard diet normalized liver LEAP2 mRNA expression and plasma level of active ghrelin, but not of total ghrelin. Additionally, our study demonstrates that a HF diet causes resistance to [Dpr3]Ghrelin, reversible by switch to St diet, followed by resistance to palm-LEAP2(1-14). Further studies are needed to determine the long-term effects of LEAP2 analogues on obesity-related ghrelin resistance.
- MeSH
- dieta s vysokým obsahem tuků * MeSH
- ghrelin * farmakologie MeSH
- glukosa MeSH
- messenger RNA MeSH
- myši MeSH
- obezita farmakoterapie MeSH
- receptory ghrelinu MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Central ghrelin signaling seems to play important role in addiction as well as memory processing. Antagonism of the growth hormone secretagogue receptor (GHS-R1A) has been recently proposed as a promising tool for the unsatisfactory drug addiction therapy. However, molecular aspects of GHS-R1A involvement in specific brain regions remain unclear. The present study demonstrated for the first time that acute as well as subchronic (4 days) administration of the experimental GHS-R1A antagonist JMV2959 in usual intraperitoneal doses including 3 mg/kg, had no influence on memory functions tested in the Morris Water Maze in rats as well as no significant effects on the molecular markers linked with memory processing in selected brain areas in rats, specifically on the β-actin, c-Fos, two forms of the calcium/calmodulin-dependent protein kinase II (CaMKII, p-CaMKII) and the cAMP-response element binding protein (CREB, p-CREB), within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum, and hippocampus (HIPP). Furthermore, following the methamphetamine intravenous self-administration in rats, the 3 mg/kg JMV2959 pretreatment significantly reduced or prevented the methamphetamine-induced significant decrease of hippocampal β-actin and c-Fos as well as it prevented the significant decrease of CREB in the NAC and mPFC. These results imply, that the GHS-R1A antagonist/JMV2959 might reduce/prevent some of the memory-linked molecular changes elicited by methamphetamine addiction within brain structures associated with memory (HIPP), reward (NAc), and motivation (mPFC), which may contribute to the previously observed significant JMV2959-induced reduction of the methamphetamine self-administration and drug-seeking behavior in the same animals. Further research is necessary to corroborate these results.
- MeSH
- aktiny MeSH
- ghrelin farmakologie MeSH
- krysa rodu rattus MeSH
- methamfetamin * farmakologie MeSH
- proteinkinasa závislá na vápníku a kalmodulinu typ 2 MeSH
- receptory ghrelinu * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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
Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.
- MeSH
- autoaplikace MeSH
- chování zvířat účinky léků MeSH
- glycin analogy a deriváty farmakologie MeSH
- intravenózní podání MeSH
- kanabinoidy aplikace a dávkování farmakologie MeSH
- krysa rodu rattus MeSH
- operantní podmiňování účinky léků MeSH
- podmiňování (psychologie) účinky léků MeSH
- posilování (psychologie) MeSH
- potkani Wistar MeSH
- receptory ghrelinu antagonisté a inhibitory MeSH
- triazoly farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.
- MeSH
- benzoxaziny aplikace a dávkování MeSH
- dopamin metabolismus MeSH
- endokanabinoidy metabolismus MeSH
- GABA metabolismus MeSH
- ghrelin metabolismus MeSH
- glyceridy metabolismus MeSH
- glycin aplikace a dávkování analogy a deriváty MeSH
- kyseliny arachidonové metabolismus MeSH
- morfoliny aplikace a dávkování MeSH
- naftaleny aplikace a dávkování MeSH
- nucleus accumbens účinky léků metabolismus MeSH
- polynenasycené alkamidy metabolismus MeSH
- potkani Wistar MeSH
- preklinické hodnocení léčiv MeSH
- triazoly aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The extended occurrence of fentanils abuse associated with the dramatic increase in opioid fatal overdoses and dependence strongly emphasizes insufficiencies in opioid addiction treatment. Recently, the growth hormone secretagogue receptor (GHS-R1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in opioid abuse is still unclear. Therefore, the aim of our study was to clarify whether the GHS-R1A antagonist JMV2959 could reduce the fentanyl-induced conditioned place preference (CPP), the fentanyl intravenous self-administration (IVSA), and the tendency to relapse, but also whether JMV2959 could significantly influence the fentanyl-induced dopamine efflux in the nucleus accumbens (NAC) in rats, that importantly participates in opioids' reinforcing effects. Following an ongoing fentanyl self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 minutes before three consequent daily 360-minute IVSA sessions under a fixed ratio FR1, which significantly reduced the number of active lever-pressing, the number of infusions, and the fentanyl intake. Pretreatment with JMV2959 also reduced the fentanyl-seeking/relapse-like behaviour tested in rats on the 12th day of the forced abstinence period. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of fentanyl-CPP. The fentanyl-CPP development was reduced after the simultaneous administration of JMV2959 with fentanyl during conditioning. The JMV2959 significantly reduced the accumbens dopamine release induced by subcutaneous and intravenous fentanyl. Simultaneously, it affected the concentration of byproducts associated with dopamine metabolism in the NAC. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of fentanyl.
- MeSH
- autoaplikace MeSH
- dopamin metabolismus MeSH
- fentanyl aplikace a dávkování škodlivé účinky MeSH
- ghrelin metabolismus MeSH
- glycin analogy a deriváty farmakologie MeSH
- intravenózní podání MeSH
- krysa rodu rattus MeSH
- narkotika aplikace a dávkování škodlivé účinky MeSH
- nucleus accumbens účinky léků MeSH
- operantní podmiňování účinky léků MeSH
- potkani Wistar MeSH
- receptory ghrelinu antagonisté a inhibitory MeSH
- triazoly farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
