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1.
Nat Commun ; 12(1): 5249, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475397

RESUMO

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.


Assuntos
Glucose/metabolismo , Obesidade/metabolismo , Receptores de Orexina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Homeostase , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Resistência à Insulina , Fígado/metabolismo , Camundongos , Fibras Nervosas/metabolismo , Obesidade/etiologia , Receptores de Orexina/genética , Orexinas/metabolismo , Núcleos da Rafe/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais
2.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443437

RESUMO

Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.


Assuntos
Terapia de Alvo Molecular , Neoplasias/metabolismo , Orexinas/metabolismo , Animais , Humanos , Modelos Biológicos , Receptores de Orexina/química , Receptores de Orexina/metabolismo , Orexinas/química , Transdução de Sinais
3.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443622

RESUMO

Orexins are two neuropeptides synthesised mainly in the brain lateral hypothalamic area. The orexinergic system provides arousal-dependent cues for a plethora of brain centres, playing a vital role in feeding behaviour, regulation of the sleep-wake cycle and circadian rhythms. Recently, orexins were found to be produced in the retina of an eye; however, their content in the vitreous body and possible daily pattern of expression have not yet been explored. In this manuscript, we describe the development and validation of a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method designed for quantitative bioanalysis of orexin in the rat vitreous body. Orexin was extracted from vitreous body samples with a water:acetonitrile:formic acid (80:20:0.1; v/v/v) mixture followed by vortexing and centrifuging. Separation was performed on a reverse-phase HPLC column under gradient conditions. Orexin was analysed via multiple-reaction monitoring (MRM) in the positive electrospray mode. The total analysis time for each sample was less than 5.0 min. Once the method was fully optimised, it was then validated, following the 2018 FDA guidance on bioanalytical method validations. The calibration curves for orexin (1-500 ng/mL) were constructed using a linear regression with a 1/x2 weighting. The lower limit of quantitation for orexin was 1.0 pg/mL for the vitreous body. Intra-day and inter-day estimates of accuracy and precision were within 10% of their nominal values, indicating that the method is reliable for quantitation of orexin in the rat vitreous body. From the physiological perspective, our results are the first to show daily rhythm of orexin synthesis by the retina with possible implications on the circadian regulation of vision.


Assuntos
Cromatografia Líquida , Ritmo Circadiano , Orexinas/metabolismo , Retina/metabolismo , Espectrometria de Massas em Tandem , Corpo Vítreo/metabolismo , Animais , Calibragem , Modelos Lineares , Masculino , Ratos
4.
Biomolecules ; 11(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34439801

RESUMO

The potential, multifaceted therapeutic profile of cannabidiol (CBD), a major constituent derived from the Cannabis sativa plant, covers a wide range of neurological and psychiatric disorders, ranging from anxiety to pediatric epilepsy and drug addiction. However, the molecular targets responsible for these effects have been only partially identified. In this view, the involvement of the orexin system, the key regulator in arousal and the sleep/wake cycle, and in motivation and reward processes, including drug addiction, prompted us to explore, using computational and experimental approaches, the possibility that CBD could act as a ligand of orexin receptors, orexin 1 receptor of type 1 (OX1R) and type 2 (OX2R). Ligand-binding assays showed that CBD is a selective ligand of OX1R in the low micromolar range (Ki 1.58 ± 0.2 µM) while in vitro functional assays, carried out by intracellular calcium imaging and mobilization assays, showed that CBD acts as an antagonist at this receptor. Finally, the putative binding mode of CBD has been inferred by molecular docking and molecular dynamics simulations and its selectivity toward the OX1R subtype rationalized at the molecular level. This study provides the first evidence that CBD acts as an OX1R antagonist, supporting its potential use in addictive disorders and/or body weight regulation.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Canabidiol/farmacologia , Receptores de Orexina/química , Orexinas/química , Animais , Ansiolíticos/química , Ansiolíticos/metabolismo , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Sítios de Ligação , Células CHO , Cálcio/metabolismo , Canabidiol/química , Canabidiol/metabolismo , Cricetulus , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Imagem Molecular , Antagonistas dos Receptores de Orexina , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Ensaio Radioligante , Transgenes
5.
Life Sci ; 283: 119851, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34324916

RESUMO

Sleep disorders frequently comorbid with several cardiovascular diseases (CVDs), attracting increasing scientific attention and interest. Sleep disorders include insomnia, sleep-disordered breathing, restless legs syndrome, etc. It is well known that inflammation, sympathetic activation, and endothelial dysfunction play critical roles in sleep disorders, all of which are predisposing factors for CVDs. The comorbidity of sleep disorders and CVDs may have a bidirectional relationship. Patients with CVDs may have a high incidence of sleep disorders and vice versa. This review focused on the comorbidity of sleep disorders and CVDs and discussed the potential pathophysiological mechanisms and therapeutic strategies. In addition to the existing mechanisms, this review summarized novel potential mechanisms underlying comorbidities, such as gut microbiota, orexin, and extracellular vesicles, which may provide a theoretical basis for further basic research and clinical investigations on improving therapeutic outcomes.


Assuntos
Doenças Cardiovasculares , Microbioma Gastrointestinal , Transtornos do Sono-Vigília , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/terapia , Vesículas Extracelulares/metabolismo , Humanos , Orexinas/metabolismo , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/microbiologia , Transtornos do Sono-Vigília/terapia
6.
Handb Clin Neurol ; 180: 359-374, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225941

RESUMO

The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons containing these peptides. Further work demonstrated that these neurons were not simply linked to waking. Rather these neurons were active during pleasurable behaviors in waking and were silenced by aversive stimulation. This was seen in wild-type mice, rats, cats, and dogs. It was also evident in humans, with increased Hcrt release during pleasurable activities and decreased release, to the levels seen in sleep, during pain. We found that human heroin addicts have, on average, an increase of 54% in the number of detectable Hcrt neurons compared to "control" human brains and that these Hcrt neurons are substantially smaller than those in control brains. We found that in mice, chronic morphine administration induced the same changes in Hcrt neuron number and size. Our studies in the mouse allowed us to determine the specificity, dose response relations, time course of the change in the number of Hcrt neurons, and that the increased number of Hcrt neurons after opiates was not due to neurogenesis. Furthermore, we found that it took a month or longer for these anatomical changes in the mouse brain to return to baseline. Human narcoleptics, despite their prescribed use of several commonly addictive drugs, do not show significant evidence of dose escalation or substance use disorder. Similarly, mice in which the peptide has been eliminated are resistant to addiction. These findings are consistent with the concept that an increased number of Hcrt neurons may underlie and maintain opioid or cocaine use disorders.


Assuntos
Narcolepsia , Prazer , Animais , Gatos , Cães , Humanos , Hipotálamo/metabolismo , Camundongos , Neurônios/metabolismo , Orexinas/metabolismo , Ratos
7.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068146

RESUMO

Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX1 and OX2, Gq-coupled GPCRs. We examined the effect of a selective OX1 agonist, OXA (17-33) on cytosolic calcium concentration, [Ca2+]i, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca2+]i in a dose-dependent manner; the effect was prevented by SB-334867, a selective OX1 receptors antagonist. In Ca2+-free saline, the OXA (17-33)-induced increase in [Ca2+]i was not affected by pretreatment with bafilomycin A1, an endo-lysosomal calcium disrupter, but was blocked by 2-APB and xestospongin C, antagonists of inositol-1,4,5-trisphosphate (IP3) receptors. Pretreatment with VU0155056, PLD inhibitor, or BD-1047 and NE-100, Sigma-1R antagonists, reduced the [Ca2+]i response elicited by OXA (17-33). Cocaine potentiated the increase in [Ca2+]i by OXA (17-33); the potentiation was abolished by Sigma-1R antagonists. Our results support an additional signaling mechanism for orexin A-OX1 via choline-Sigma-1R and a critical role for Sigma-1R in the cocaine-orexin A interaction in nucleus accumbens neurons.


Assuntos
Colina/metabolismo , Cocaína/farmacologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Receptores sigma/metabolismo , Animais , Animais Recém-Nascidos , Regulação da Expressão Gênica , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptores de Orexina/genética , Orexinas/genética , Ratos , Ratos Sprague-Dawley , Receptores sigma/genética , Vasoconstritores/farmacologia
8.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073933

RESUMO

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.


Assuntos
Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/metabolismo , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/metabolismo , Tronco Encefálico/fisiopatologia , Córtex Cerebral/fisiopatologia , Dopamina/metabolismo , Humanos , Hipotálamo/fisiopatologia , Melatonina/metabolismo , Transtornos de Enxaqueca/patologia , Transtornos de Enxaqueca/fisiopatologia , Orexinas/metabolismo , Serotonina/metabolismo , Sono/fisiologia , Transtornos do Sono-Vigília/patologia , Transtornos do Sono-Vigília/fisiopatologia , Tálamo/fisiopatologia
9.
Neuroscience ; 468: 158-167, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126185

RESUMO

The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. We investigated the role of orexin receptors type 1 (OX1R) and type 2 (OX2R) in the PL in such processes upon confrontation with an erratically moving robo-beetle in mice. The selective blockade of OX1R and OX2R in the PL with SB 334867 (3, 30, 300 nM) and TCS OX2 29 (3, 30, 300 nM), respectively, did not affect general exploratory behavior or reactive fear such as avoidance, jumping or freezing, but significantly enhances tolerance and approach behavior at the highest dose of each antagonist tested (300 nM). We interpret these findings as evidence for an altered cognitive appraisal of the potential threatening stimulus. Consequently, the orexin system seems to bias the perception of stimuli towards danger or threat via OX1R and OX2R in the PL.


Assuntos
Córtex Cerebral , Antagonistas dos Receptores de Orexina , Animais , Córtex Cerebral/metabolismo , Hipotálamo/metabolismo , Camundongos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo
10.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925368

RESUMO

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic-pituitary-adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.


Assuntos
Orexinas/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem Celular , Corticotrofos/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Camundongos , Orexinas/fisiologia , Fosforilação , Hipófise/metabolismo , Pró-Opiomelanocortina/genética , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
FASEB J ; 35(5): e21532, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33817828

RESUMO

TWIK-related acid-sensitive potassium channels (TASKs)-like current was recorded in orexin neurons in the lateral hypothalamus (LH), which are essential in respiratory chemoreflex. However, the specific mechanism responsible for the pH-sensitivity remains elusive. Thus, we hypothesized that TASKs contribute to respiratory chemoreflex. In the present study, we found that TASK1 and TASK3 were expressed in orexin neurons. Blocking TASKs or microinjecting acid artificial cerebrospinal fluid (ACSF) in the LH stimulated breathing. In contrast, alkaline ACSF inhibited breathing, which was attenuated by blocking TASK1. Damage of orexin neurons attenuated the stimulatory effect on respiration caused by microinjection of acid ACSF (at a pH of 6.5) or TASKs antagonists. The orexinA-positive fiber and orexin type 1 receptor (OX1R) neurons were located in the nucleus tractus solitarius (NTS). The exciting effect of acidosis in the LH on respiration was inhibited by blocking OX1R of the NTS. Taken together, we conclude that orexin neurons sense the extracellular pH change through TASKs and regulate respiration by projecting to the NTS.


Assuntos
Região Hipotalâmica Lateral/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Orexinas/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Reflexo/fisiologia , Respiração , Núcleo Solitário/fisiologia , Animais , Células Quimiorreceptoras/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Orexinas/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Ratos , Ratos Sprague-Dawley
12.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672695

RESUMO

Circadian desynchrony induced by a long period of irregular feeding leads to metabolic diseases, such as obesity and diabetes mellitus. The recently identified neurosecretory protein GL (NPGL) and neurosecretory protein GM (NPGM) are hypothalamic small proteins that stimulate food intake and fat accumulation in several animals. To clarify the mechanisms that evoke feeding behavior and induce energy metabolism at the appropriate times in accordance with a circadian rhythm, diurnal fluctuations in Npgl and Npgm mRNA expression were investigated in mice. Quantitative RT-PCR analysis revealed that the mRNAs of these two genes were highly expressed in the mediobasal hypothalamus during the active dark phase under ad libitum feeding. In mice restricted to 3 h of feeding during the inactive light phase, the Npgl mRNA level was augmented in the moment prior to the feeding period and the midnight peak of Npgm mRNA was attenuated. Moreover, the mRNA expression levels of clock genes, feeding regulatory neuropeptides, and lipid metabolic enzymes in the central and peripheral tissues were comparable to those of central Npgl and Npgm. These data suggest that Npgl and Npgm transcription fluctuates daily and likely mediates feeding behavior and/or energy metabolism at an appropriate time according to the meal timing.


Assuntos
Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Análise de Variância , Animais , Anorexia/sangue , Anorexia/genética , Glicemia/metabolismo , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Perfilação da Expressão Gênica , Insulina/sangue , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Orexinas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo
13.
FASEB J ; 35(4): e21345, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715219

RESUMO

Obesity is common in the middle aged population and it increases the risks of diabetes, cardiovascular diseases, certain cancers, and dementia. Yet, its etiology remains incompletely understood. Here, we show that ectopic expression of HB-EGF, an important regulator of neurogenesis, in Nestin+ neuroepithelial progenitors with the Cre-LoxP system leads to development of spontaneous middle age obesity in male mice accompanied by hyperglycemia and insulin resistance. The Nestin-HB-EGF mice show decreases in food uptake, energy expenditure, and physical activity, suggesting that reduced energy expenditure underlies the pathogenesis of this obesity model. However, HB-EGF expression in appetite-controlling POMC or AgRP neurons or adipocytes fails to induce obesity. Mechanistically, HB-EGF suppresses expression of Hypocretin/Orexin, an orexigenic neuropeptide hormone, in the hypothalamus of middle aged Nestin-HB-EGF mice. Hypothalamus Orexin administration alleviates the obese and hyperglycemic phenotypes in Nestin-HB-EGF mice. This study uncovers an important role for HB-EGF in regulating Orexin expression and energy expenditure and establishes a midlife obesity model whose pathogenesis involves age-dependent changes in hypothalamus neurons.


Assuntos
Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Nestina/metabolismo , Células-Tronco Neurais/metabolismo , Obesidade/metabolismo , Orexinas/metabolismo , Adiponectina/sangue , Envelhecimento , Animais , Composição Corporal , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Insulina/sangue , Leptina/sangue , Camundongos , Nestina/genética , Orexinas/genética
14.
Commun Biol ; 4(1): 165, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547399

RESUMO

Cataplexy is triggered by laughter in humans and palatable food in mice. To further evaluate mice's cataplexy, we examined courtship behavior in orexin neuron-ablated mice (ORX-AB), one of the animal models of narcolepsy/cataplexy. Wild-type female mice were placed into the home cage of male ORX-AB and cataplexy-like behavior was observed along with ultrasonic vocalizations (USVs), also known as the "love song". ORX-AB with a female encounter showed cataplexy-like behavior both during the dark and light periods, whereas ORX-AB with chocolate predominantly showed it during the dark period. During the light period observation, more than 85% of cataplexy-like bouts were preceded by USVs. A strong positive correlation was observed between the number of USVs and cataplexy-like bouts. Cataplexy-like behavior in narcoleptic mice is a good behavioral measure to study the brain mechanisms behind positive emotion because they can be induced by different kinds of positive stimuli, including chocolate and female courtship.


Assuntos
Cataplexia/patologia , Corte , Neurônios/patologia , Excitação Sexual , Vocalização Animal/fisiologia , Animais , Comportamento Animal/fisiologia , Cataplexia/genética , Cataplexia/fisiopatologia , Cataplexia/psicologia , Corte/psicologia , Genes Transgênicos Suicidas , Masculino , Camundongos , Camundongos Transgênicos , Narcolepsia/genética , Narcolepsia/patologia , Narcolepsia/fisiopatologia , Narcolepsia/psicologia , Neurônios/metabolismo , Orexinas/deficiência , Orexinas/genética , Orexinas/metabolismo
15.
Sci Rep ; 11(1): 113, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420284

RESUMO

The role of central orexin in the sympathetic control of interscapular brown adipose tissue (iBAT) thermogenesis has been established in rodents. Stimulatory doses of caffeine activate orexin positive neurons in the lateral hypothalamus, a region of the brain implicated in stimulating BAT thermogenesis. This study tests the hypothesis that central administration of caffeine is sufficient to activate BAT. Low doses of caffeine administered either systemically (intravenous [IV]; 10 mg/kg) and centrally (intracerebroventricular [ICV]; 5-10 µg) increases BAT thermogenesis, in anaesthetised (1.5 g/kg urethane, IV) free breathing male rats. Cardiovascular function was monitored via an indwelling intra-arterial cannula and exhibited no response to the caffeine. Core temperature did not significantly differ after administration of caffeine via either route of administration. Caffeine administered both IV and ICV increased neuronal activity, as measured by c-Fos-immunoreactivity within subregions of the hypothalamic area, previously implicated in regulating BAT thermogenesis. Significantly, there appears to be no neural anxiety response to the low dose of caffeine as indicated by no change in activity in the basolateral amygdala. Having measured the physiological correlate of thermogenesis (heat production) we have not measured indirect molecular correlates of BAT activation. Nevertheless, our results demonstrate that caffeine, at stimulatory doses, acting via the central nervous system can increase thermogenesis, without adverse cardio-dynamic impact.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Cafeína/administração & dosagem , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/fisiologia , Animais , Estimulantes do Sistema Nervoso Central , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Orexinas/metabolismo , Ratos , Ratos Sprague-Dawley
16.
Expert Opin Drug Metab Toxicol ; 17(2): 179-199, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33470852

RESUMO

Introduction: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder. Areas covered: Based on the aforementioned findings, the present review: (i) summarizes the current knowledge on the role of the above neuropeptides in the trigeminovascular system, and migraine pathophysiology; and (ii) discusses some issues related with the mechanisms of action and side effects concerns that could be elicited when targeting the CGRPergic, PACAPergic, oxytocinergic and orexinergic systems. Expert opinion: Specific antimigraine pharmacotherapies have evolved from the enhancement of serotonergic 5-HT1B/1D/1F transmission to the use of compounds interacting with neuropeptidergic systems. Canonically, neuropeptides cause an array of complex intracellular mechanisms that, after modifying neuronal and/or vascular transmission, result in antimigraine action and also potential side effects. Furthermore, due to the chemical nature of some molecules targeting the above neuropeptidergic transmission (e.g., monoclonal antibodies, peptides), there are some limiting pharmacokinetics issues.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Neuropeptídeos/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Humanos , Transtornos de Enxaqueca/fisiopatologia , Orexinas/metabolismo , Ocitocina/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Serotonina/metabolismo
17.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466831

RESUMO

Aside from the classical motor symptoms, Parkinson's disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson's. In this study, we hypothesized that Parkinson's-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson's, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson's disease pathology. This study implicates the involvement of orexin in early Parkinson's-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson's disease symptomology.


Assuntos
Modelos Animais de Doenças , Metabolismo Energético/genética , Atividade Motora/genética , Neurônios/metabolismo , Orexinas/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , Animais , Composição Corporal/genética , Gliose/genética , Gliose/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Orexinas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/metabolismo
18.
J Physiol ; 599(1): 231-252, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997815

RESUMO

KEY POINTS: Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase. Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non-image forming visual structures. We provide evidence for the high nocturnal levels of orexins with stable circadian expression of predominant orexin receptor 2 in the LGN. Our data additionally establish the convergence of orexinergic and pituitary adenylate cyclase (PAC)-activating peptide/PAC1 receptor systems (used by melanopsin-expressing retinal ganglion cells), which directly regulates responses to the retinal input. These results help us better understand circadian orexinergic control over the non-image forming subcortical visual system, forming the animal's preparedness for the behaviourally active night. ABSTRACT: The orexinergic system of the lateral hypothalamus is tightly interlinked with the master circadian clock and displays daily variation in activity to provide arousal-related excitation for the plethora of brain structures in a circadian manner. Here, using a combination of electrophysiological, optogenetic, histological, molecular and neuronal tracing methods, we explore a particular link between orexinergic and visual systems in rat. The results of the present study demonstrate that orexinergic fibre density at the area of subcortical visual system exerts a clear day to night variability, reaching a maximum at behaviourally active night. We also show pronounced electrophysiological activations of neurons in the lateral geniculate nucleus by orexin A through 24 h, via identified distinct orexin receptors, with the ventrolateral geniculate displaying a daily cycle of responsiveness. In addition, for the first time, we provide a direct evidence for orexins to act on retinorecipient neurons with a high convergence of orexinergic and putatively retinal pituitary adenylate cyclase (PAC)-activating peptide/PAC1 receptor systems. Altogether, the present study ties orexins to non-image forming visual structures with implications for circadian orexinergic modulation of neurons, which process information on ambient light levels.


Assuntos
Corpos Geniculados , Neurônios , Animais , Ritmo Circadiano , Região Hipotalâmica Lateral/metabolismo , Neurônios/metabolismo , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ratos
19.
Br J Anaesth ; 126(1): 279-292, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33131759

RESUMO

BACKGROUND: The neuropeptide orexin promotes arousal from general anaesthesia, however the neuronal circuits that mediate this effect have not been defined. We investigated whether orexinergic neurones modulate the basal forebrain (BF) and locus coeruleus (LC) in emergence from anaesthesia. METHODS: Hcrtcre rats were generated using a CRISPR/Cas9-based approach. Viruses encoding optogenetic probes were injected into the perifornical lateral hypothalamic (PeFLH) area, optogenetic fibres were embedded in the PeFLH, BF, or LC, and changes in anaesthesia state under 1.4 vol% or 0.8 vol% isoflurane were determined. RESULTS: In the PeFLH, 98.8% (0.4%) of orexin-A-positive cells expressed tdTomato, and 91.9% (2.2%) of tdTomato cells were orexin-A-positive. Under 1.4 vol% isoflurane anaesthesia, compared with control groups, burst suppression ratio was less, and emergence time was shorter in groups with optogenetic activation of orexinergic cell bodies in the PeFLH (923 [162] vs 493 [68] s, P=0.0003) or orexinergic terminals in the BF (937 (122) vs 674 (108) s, P=0.0049) or LC (913 [128] vs 742 [76] s, P=0.022). Optical stimulation of orexinergic terminals in the BF and LC also improved the movement scores of rats under 0.8 vol% isoflurane anaesthesia. CONCLUSIONS: Activation of orexinergic terminals in the FB or LC mediates facilitation of emergence from anaesthesia by orexinergic neurones during isoflurane anaesthesia.


Assuntos
Período de Recuperação da Anestesia , Prosencéfalo Basal/efeitos dos fármacos , Isoflurano/farmacologia , Locus Cerúleo/efeitos dos fármacos , Optogenética/métodos , Orexinas/fisiologia , Anestésicos Inalatórios/farmacologia , Animais , Prosencéfalo Basal/metabolismo , Eletroencefalografia/métodos , Locus Cerúleo/metabolismo , Modelos Animais , Orexinas/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Gen Comp Endocrinol ; 300: 113637, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017583

RESUMO

Allatotropin is a pleiotropic peptide originally characterized in insects. The existence of AT neuropeptide signaling was proposed in other invertebrates. In fact, we previously proposed the presence of an AT-like system regulating feeding behavior in Hydra sp. Even in insects, the information about the AT signaling pathway is incomplete. The aim of this study is to analyze the signaling cascade activated by AT in Hydra plagiodesmica using a pharmacological approach. The results show the involvement of Ca2+ and IP3 signaling in the transduction pathway of the peptide. Furthermore, we confirm the existence of a GPCR system involved in this pathway, that would be coupled to a Gq subfamily of Gα protein, which activates a PLC, inducing an increase in IP3 and cytosolic Ca2+. To the best of our knowledge, this work represents the first in vivo approach to study the overall signaling pathway and intracellular events involved in the myoregulatory effect of AT in Hydra sp.


Assuntos
Sinalização do Cálcio , Hydra/metabolismo , Hormônios de Inseto/metabolismo , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Indóis/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Maleimidas/farmacologia , Meliteno/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Pirrolidinonas/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismo
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