Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanolinduced Neuroinflammation in Rats

Flores-Bastías, Osvaldo; Gómez, Gonzalo I.; Orellana, Juan A.; Karahanian, Eduardo

doi:10.2174/1381612825666191216145153

Cited by 11 publications

(6 citation statements)

References 66 publications

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“…Thus, 18 rats (62% of the starting group of rats) preferred morphine for the complete extension of the study. These rejection rates are in concordance to what was previously reported for other drugs since a diversity in the willingness to consume a drug is observed when outbred animals, i.e., not selectively bred to self-administer a drug, are used as a model for the study of consumption of ethanol [ 30 , 31 ].…”

Section: Discussionsupporting

confidence: 88%

A Novel Morphine Drinking Model of Opioid Dependence in Rats

Berríos-Cárcamo

Quezada

Santapau

et al. 2022

IJMS

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An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

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Section: Discussionsupporting

confidence: 88%

A Novel Morphine Drinking Model of Opioid Dependence in Rats

Berríos-Cárcamo

Quezada

Santapau

et al. 2022

IJMS

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“…Although we hypothesized that the activation of MC4R in the brain inhibits NF-κB activity and neuroinflammation induced by ethanol (Flores-Bastías and Karahanian, 2018;Flores-Bastías et al, 2019), MC4R elicits additional mechanisms that would help explain the effects of α-MSH or its synthetic analogs in reducing alcohol intake. After the pioneering work of Xu et al (2003) who reported that the activation of MC4R induces brain-derived neurotrophic factor (BDNF) expression in the hypothalamus, it was determined that BDNF is a downstream effector of MC4R signaling in food intake control (Nicholson et al, 2007;Bariohay et al, 2009).…”

mentioning

confidence: 99%

Activation of Melanocortin-4 Receptor Inhibits Both Neuroinflammation Induced by Early Exposure to Ethanol and Subsequent Voluntary Alcohol Intake in Adulthood in Animal Models: Is BDNF the Key Mediator?

Flores-Bastías

Adriasola-Carrasco

Karahanian

2020

Front. Cell. Neurosci.

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The concept that neuroinflammation induced by excessive alcohol intake in adolescence triggers brain mechanisms that perpetuate consumption has strengthened in recent years. The melanocortin system, composed of the melanocortin 4 receptor (MC4R) and its ligand α-melanocyte-stimulating hormone (α-MSH), has been implicated both in modulation of alcohol consumption and in ethanol-induced neuroinflammation decrease. Chronic alcohol consumption in adolescent rats causes a decrease in an α-MSH release by the hypothalamus, while the administration of synthetic agonists of MC4R causes a decrease in neuroinflammation and a decrease in voluntary alcohol consumption. However, the mechanism that connects the activation of MC4R with the decrease of both neuroinflammation and voluntary alcohol consumption has not been elucidated. Brainderived neurotrophic factor (BDNF) has been implicated in alcohol drinking motivation, dependence and withdrawal, and its levels are reduced in alcoholics. Deficiencies in BDNF levels increased ethanol self-administration in rats. Further, BDNF triggers important anti-inflammatory effects in the brain, and this could be one of the mechanisms by which BDNF reduces chronic alcohol intake. Interestingly, MC4R signaling induces BDNF expression through the activation of the cAMP-responsive element-binding protein (CREB). We hypothesize that ethanol exposure during adolescence decreases the expression of α-MSH and hence MC4R signaling in the hippocampus, leading to a lower BDNF activity that causes dramatic changes in the brain (e.g., neuroinflammation and decreased neurogenesis) that predispose to maintain alcohol abuse until adulthood. The activation of MC4R either by α-MSH or by synthetic agonist peptides can induce the expression of BDNF, which would trigger several processes that lead to lower alcohol consumption.

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“…MC4R functions to regulate food intake and energy expenditure, and regulate insulin secretion, lipid metabolism, bone mineral density, and body length [[11]]. The deficiency of MC4R influences eating behaviors in humans and animals (Table 2) [[54]]. Experiments using MC4R-inactivated mice develop a maturity-onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia [[55]].…”

Section: Role Of α-Msh In Appetite Regulationmentioning

confidence: 99%

Alpha-Melanocyte-Stimulating Hormone-Mediated Appetite Regulation in the Central Nervous System

Wu¹,

Jing-mei²,

Hua³

et al. 2023

Neuroendocrinology

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Understanding the complex action mechanism of appetite regulation peptides can significantly impact therapeutic options in the treatment of obesity and other metabolic diseases. Hypothalamic α-melanocyte-stimulating hormone (α-MSH) is an anorexigenic peptide, closely related to the occurrence of obesity, playing a central role in food intake and energy expenditure. In the central nervous system (CNS), α-MSH is cleaved from proopiomelanocortin (POMC) and then released into different hypothalamic regions to act on melanocortin 3/4 receptor (MC3/4R)-expressing neurons, lowering food intake and raising energy expenditure via appetite suppression and sympathetic nervous system. Furthermore, it can increase the transmission of some anorexigenic hormones (e.g., dopamine) and interact with other orexigenic factors (e.g., agouti-related protein, neuropeptide Y) to influence food reward rather than merely feeding behavior. Therefore, α-MSH is a critical node of the hypothalamus in transmitting appetite suppression signals and is a key component of the central appetite-regulating circuits. Herein, we describe the role of α-MSH in appetite suppression in terms of specific receptors, effector neurons, sites of action, and the interaction with other appetite-relative peptides, respectively. We focus on the role of α-MSH in obesity. The status of research on α-MSH-related drugs is also discussed. With the intention of illuminating a new approach for targeting α-MSH in the hypothalamus as a strategy to manage obesity, we hope to further understand the direct or indirect mechanisms by which α-MSH exerts its appetite-regulating effects.

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Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanolinduced Neuroinflammation in Rats

Cited by 11 publications

References 66 publications

A Novel Morphine Drinking Model of Opioid Dependence in Rats

A Novel Morphine Drinking Model of Opioid Dependence in Rats

Activation of Melanocortin-4 Receptor Inhibits Both Neuroinflammation Induced by Early Exposure to Ethanol and Subsequent Voluntary Alcohol Intake in Adulthood in Animal Models: Is BDNF the Key Mediator?

Alpha-Melanocyte-Stimulating Hormone-Mediated Appetite Regulation in the Central Nervous System

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