RESUMO
The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.
Assuntos
Fármacos Antiobesidade , Aprendizagem da Esquiva , Receptor do Peptídeo Semelhante ao Glucagon 1 , Vias Neurais , Rombencéfalo , Resposta de Saciedade , Animais , Feminino , Masculino , Camundongos , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacologia , Área Postrema/metabolismo , Área Postrema/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios/efeitos dos fármacos , Obesidade/metabolismo , Rombencéfalo/citologia , Rombencéfalo/efeitos dos fármacos , Rombencéfalo/metabolismo , Rombencéfalo/fisiologia , Resposta de Saciedade/efeitos dos fármacos , Resposta de Saciedade/fisiologia , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiologia , AlimentosRESUMO
Postoperative nausea and vomiting (PONV) are the second most frequent adverse events after surgery second only to postoperative pain. Despite the advances in antiemetics and implementation of multimodal prophylactic interventions, the clinical management of PONV remains problematic. Neurokinin-1 (NK-1) receptor is a tachykinin receptor found throughout the central and peripheral nervous systems, with a particular affinity towards substance P. NK-1 receptors interact with several parts of the neuronal pathway for nausea and vomiting. This includes the chemoreceptor trigger zone, the gastrointestinal tract, and dorsal motor nucleus of the vagus. NK-1 antagonists are thought to prevent nausea and vomiting by downregulating the emetogenic signals at those points. As more head-to-head trials are conducted between the various anti-emetics, there is emerging evidence that NK-1 antagonists may be more effective in preventing PONV than several other antiemetics currently in use. In this review, we will discuss the pharmacology of NK-1 antagonists, their efficacy in clinical practice, and how they could fit into the framework of PONV management.
Assuntos
Antieméticos/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Animais , Área Postrema/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Nervo Vago/efeitos dos fármacosRESUMO
The discovery of neural stem cells (NSCs) in the adult mammalian brain has provided insights into an extra level of brain plasticity. The proliferation and differentiation of NSCs is modulated by various physiological, pathological, and pharmacological stimuli. NSCs were recently detected in the medulla oblongata of adult rodents and humans; however, their functional significance currently remains unknown. In the present study, we examined the effects of chronic wheel-running and a corticosterone (CORT) treatment on the proliferation of astrocyte-like NSCs in the area postrema (AP) and dentate gyrus (DG). Chronic running significantly decreased the number of bromodeoxyuridine (BrdU)-labeled astrocyte-like NSCs in the AP of adult mice, but markedly increased that of BrdU+ NSCs/neural progenitor cells in the DG. The chronic CORT treatment markedly reduced the number of BrdU+ astrocyte-like NSCs in the AP, but not in the DG. These results demonstrate that the proliferation of astrocyte-like NSCs in the medulla oblongata is decreased by chronic running and a CORT treatment.
Assuntos
Área Postrema/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Corticosterona/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologiaRESUMO
Central administration of fibroblast growth factor-1 (FGF1) results in long-lasting resolution of hyperglycemia in various rodent models, but the pre- and postsynaptic mechanisms mediating the central effects of FGF1 are unknown. Here we utilize electrophysiology recordings from neuronal populations in the arcuate nucleus of the hypothalamus (ARH), nucleus of the solitary tract (NTS), and area postrema (AP) to investigate the mechanisms underlying FGF1 actions. While FGF1 did not alter membrane potential in ARH-NPY-GFP neurons, it reversibly depolarized 83% of ARH-POMC-EGFP neurons and decreased the frequency of inhibitory inputs onto ARH-POMC-EGFP neurons. This depolarizing effect persisted in the presence of FGF receptor (R) blocker FIIN1, but was blocked by pretreatment with the voltage-gated sodium channel (VGSC) blocker tetrodotoxin (TTX). Non-FGF1 subfamilies can activate vascular endothelial growth factor receptors (VEGFR). Surprisingly, the VEGFR inhibitors axitinib and BMS605541 blocked FGF1 effects on ARH-POMC-EGFP neurons. We also demonstrate that FGF1 induces c-Fos in the dorsal vagal complex, activates NTS-NPY-GFP neurons through a FGFR mediated pathway, and requires VGSCs to activate AP neurons. We conclude that FGF1 acts in multiple brain regions independent of FGFRs. These studies present anatomical and mechanistic pathways for the future investigation of the pharmacological and physiological role of FGF1 in metabolic processes.
Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Área Postrema/efeitos dos fármacos , Fator 1 de Crescimento de Fibroblastos/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Área Postrema/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleo Solitário/metabolismoRESUMO
INTRODUCTION: Volatile anesthetics are speculated to cause postoperative nausea and vomiting via stimulation of the chemoreceptor trigger zone (CTZ). However, the precise mechanism underlying the emetic action of these drugs is not well understood. In this study, we assessed whether isoflurane induced the expression of c-Fos, a neuronal activation marker, in the area postrema (AP), the locus of the CTZ, in rats, which do not have vomiting action. MATERIALS AND METHODS: Male rats were exposed to 1.3% isoflurane for 0-240 min, or to various concentrations of isoflurane (0, 1.3%, or 2.6%) for 120 min. Finally, the rats were exposed to 1.3% isoflurane for 120 min after ondansetron administration. After the treatments, immunohistochemistry of the rat AP was performed using c-Fos antibody staining. RESULTS: One-way analysis of variance showed that isoflurane exposure significantly increased c-Fos expression in the AP; however, the rats pretreated with 4 mg/kg ondansetron showed significantly decreased c-Fos expression. Moreover, we evaluated the effect of the anesthetic on inducing pica in the rats, and found that kaolin intake was not influenced by isoflurane exposure. CONCLUSION: Overall, these results suggest that isoflurane activates AP neurons and may be involved in the emetic mechanism of isoflurane. This study further suggests the feasibility of using rats as a model for studying emetic mechanisms of drugs, despite their lack of vomit action.
Assuntos
Anestésicos Inalatórios/farmacologia , Área Postrema/efeitos dos fármacos , Isoflurano/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Masculino , Neurônios/metabolismo , Ondansetron/farmacologia , Ratos , Ratos Wistar , Vômito/induzido quimicamenteRESUMO
AIMS: Neuroinflammation is a common feature in renovascular, obesity-related, and angiotensin II mediated hypertension. There is evidence that increased release of the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) contributes to the development of the hypertension, but the underlying neural mechanisms are unclear. Here, we investigated whether TNF-α stimulates neurons in the area postrema (AP), a circumventricular organ, to elicit sympathetic excitation, and increases in blood pressure (BP). METHODS AND RESULTS: In rats with renovascular hypertension, AP neurons that expressed TNF-α type-1 receptor (TNFR1) remained constantly activated (expressed c-Fos) and injection of TNFR1 neutralizing antibody into the AP returned BP (systolic: â¼151 mmHg) to normotensive levels (systolic: â¼108 mmHg). Nanoinjection of TNF-α (100 pg/50 nL) into the AP of anaesthetized normotensive rats increased BP (â¼16 mmHg) and sympathetic nerve activity, predominantly to the heart (â¼53%), but also to the kidneys (â¼35%). These responses were abolished by prior injection of a TNFR1 neutralizing antibody (1 ng/50 nL) within the same site. TNFR1 were expressed in the somata of neurons activated by TNF-α that were retrogradely labelled from the rostral ventrolateral medulla (RVLM). CONCLUSION: These findings indicate that in renovascular hypertension, blocking TNFR1 receptors in the AP significantly reduces BP, while activation of TNFR1 expressing neurons in the AP by TNF-α increases BP in normotensive rats. This is mediated, in part, by projections to the RVLM and an increase in both cardiac and renal sympathetic nerve activity. These findings support the notion that proinflammatory cytokines and neuroinflammation are important pathological mechanisms in the development and maintenance of hypertension.
Assuntos
Área Postrema/metabolismo , Pressão Arterial , Frequência Cardíaca , Coração/inervação , Hipertensão Renovascular/metabolismo , Rim/inervação , Neurônios/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Área Postrema/efeitos dos fármacos , Área Postrema/fisiopatologia , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores Tipo I de Fatores de Necrose Tumoral/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagemRESUMO
The pancreatic hormone amylin is released from beta cells following nutrient ingestion and contributes to the control of body weight and glucose homeostasis. Amylin reduces food intake by activating neurons in the area postrema (AP). Amylin was also shown to synergize with the adipokine leptin, with combination therapy producing greater weight loss and food intake reduction than either hormone alone. Although amylin and leptin were initially thought to interact downstream of the AP in the hypothalamus, recent findings show that the two hormones can act on the same AP neurons, suggesting a more direct relationship. The objective of this study was to determine whether amylin action depends on functional leptin signaling. We tested the ability of amylin to induce satiation and to activate its primary target neurons in the AP in two rodent models of LepR deficiency, the db/db mouse and the Zucker diabetic fatty (ZDF) rat. When compared with wild-type (WT) mice, db/db mice exhibited reduced amylin-induced satiation, reduced amylin-induced Fos in the AP, and a lower expression of calcitonin receptor (CTR) protein, the core component of all amylin receptors. ZDF rats also showed no reduction in food intake following amylin treatment; however, unlike the db/db mice, levels of amylin-induced Fos and CTR in the AP were no different than WT rats. Our results suggest that LepR expression is required for the full anorexic effect of amylin; however, the neuronal activation in the AP seems to depend on the type of LepR mutation.
Assuntos
Agonistas dos Receptores da Amilina/farmacologia , Depressores do Apetite/farmacologia , Área Postrema/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Leptina/metabolismo , Receptores para Leptina/metabolismo , Resposta de Saciedade/efeitos dos fármacos , Animais , Área Postrema/metabolismo , Genótipo , Masculino , Mutação , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Zucker , Receptores da Calcitonina/agonistas , Receptores da Calcitonina/metabolismo , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/efeitos dos fármacos , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Receptores para Leptina/deficiência , Receptores para Leptina/efeitos dos fármacos , Receptores para Leptina/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: Prolactin-releasing peptide (PrRP) is a neuropeptide that suppresses food intake and increases body temperature when delivered to the forebrain ventricularly or parenchymally. However, PrRP's receptor GPR10 is widely distributed throughout the brain with particularly high levels found in the dorsomedial hindbrain. Thus, we hypothesized that hindbrain-directed PrRP administration would affect energy balance and motivated feeding behavior. METHODS: To address this hypothesis, a range of behavioral and physiologic variables were measured in Sprague-Dawley rats that received PrRP delivered to the fourth ventricle (4V) or the nucleus of the solitary tract (NTS) at the level of the area postrema (AP). RESULTS: 4V PrRP delivery decreased chow intake and body weight, in part, through decreasing meal size in ad libitum maintained rats tested at dark onset. PrRP inhibited feeding when delivered to the nucleus tractus solitarius (NTS), but not to more ventral hindbrain structures. In addition, 4V as well as direct NTS administration of PrRP increased core temperature. By contrast, 4V PrRP did not reduce ad libitum intake of highly palatable food or the motivation to work for or seek palatable foods. CONCLUSIONS: The dorsomedial hindbrain and NTS/AP, in particular, are sites of action in PrRP/GPR10-mediated control of chow intake, core temperature, and body weight.
Assuntos
Área Postrema/metabolismo , Temperatura Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Hormônio Liberador de Prolactina/administração & dosagem , Receptores Acoplados a Proteínas G/metabolismo , Núcleo Solitário/metabolismo , Animais , Área Postrema/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Microinjeções/métodos , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Núcleo Solitário/efeitos dos fármacosRESUMO
The aim of the present study was to determine whether arcuate nucleus (ARC) lesions affect the ghrelin level in the plasma and the stomach in monosodium glutamate (MSG)treated mice. The aim of the present study was to investigate whether the ARC was destroyed in mice treated neonatally with MSG, and whether the ARC lesions affect the ghrelin level in the plasma and lipid mobilization in MSGtreated mice. The results revealed that MSG led to a marked reduction in ARC cresyl violet staining, tyrosine hydroxylase-immunoreactive (IR) neurons and neuropeptide YIR fibers, compared with saline controls. MSGtreated mice exhibited significantly increased body mass compared with saline controls, and MSG treatment did not prevent food deprivationinduced decrease in white adipose tissue mass compared with controls. Plasma ghrelin levels were significantly increased in MSGtreated mice that were fasted for 48 h, compared with the levels prior to fasting and refeeding, and the preprandial peak of plasma ghrelin persisted in MSGtreated mice. In summary, the ARC was not found to be essential for food deprivationinduced lipid mobilization and preprandial peak in MSGtreated mice. However, this finding does not mean that ARC neurons do not contribute to food sensing and lipid mobilization under normal conditions, as compensatory mechanisms may have emerged after the ablation of ARC neurons.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Grelina/sangue , Glutamato de Sódio/administração & dosagem , Tecido Adiposo Branco/anatomia & histologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Peso Corporal/efeitos dos fármacos , Contagem de Células , Comportamento Alimentar/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Grelina/genética , Grelina/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glutamato de Sódio/farmacologia , Estômago/efeitos dos fármacosRESUMO
During cancer chemotherapy, drugs such as 5-HT3 receptor antagonists have typically been used to control vomiting and anorexia. We examined the effects of oxytocin (OXT), which has been linked to appetite, on cisplatin-induced anorexia in rats. Fos-like immunoreactivity (Fos-LI) expressed in the supraoptic nucleus (SON), the paraventricular nucleus (PVN), the area postrema and the nucleus of the solitary tract (NTS) after intraperitoneal (ip) administration of cisplatin. We also examined the fluorescence intensity of OXT-mRFP1 after ip administration of cisplatin in OXT-mRFP1 transgenic rats. The mRFP1 fluorescence intensity was significantly increased in the SON, the PVN, and the NTS after administration of cisplatin. The cisplatin-induced anorexia was abolished by OXT receptor antagonist (OXTR-A) pretreatment. In the OXT-LI cells, cisplatin-induced Fos expression in the SON and the PVN was also suppressed by OXTR-A pretreatment. These results suggested that central OXT may be involved in cisplatin-induced anorexia in rats.
Assuntos
Anorexia/metabolismo , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Supraóptico/metabolismo , Animais , Anorexia/induzido quimicamente , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Transgênicos , Ratos Wistar , Receptores de Ocitocina/antagonistas & inibidores , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Supraóptico/efeitos dos fármacosRESUMO
OBJECTIVE: Fos protein expression in catecholamine-synthesizing neurons of the substantia nigra (SN) pars compacta (SNC, A8), pars reticulata (SNR, A9), and pars lateralis (SNL), the ventral tegmental area (VTA, A10), the locus coeruleus (LC, A6) and subcoeruleus (sLC), the ventrolateral pons (PON-A5), the nucleus of the solitary tract (NTS-A2), the area postrema (AP), and the ventrolateral medulla (VLM-A1) was quantitatively evaluated aft er a single administration of asenapine (ASE) (designated for schizophrenia treatment) in male Wistar rats preconditioned with a chronic unpredictable variable mild stress (CMS) for 21 days. Th e aim of the present study was to reveal whether a single ASE treatment may 1) activate Fos expression in the brain areas selected; 2) activate tyrosine hydroxylase (TH)-synthesizing cells displaying Fos presence; and 3) be modulated by CMS preconditioning. METHODS: Control (CON), ASE, CMS, and CMS+ASE groups were used. CMS included restraint, social isolation, crowding, swimming, and cold. Th e ASE and CMS+ASE groups received a single dose of ASE (0.3 mg/kg, s.c.) and CON and CMS saline (300 µl/rat, s.c.). The animals were sacrificed 90 min aft er the treatments. Fos protein and TH-labeled immunoreactive perikarya were analyzed on double labeled histological sections and enumerated on captured pictures using combined light and fluorescence microscope illumination. RESULTS: Saline or CMS alone did not promote Fos expression in any of the structures investigated. ASE alone or in combination with CMS elicited Fos expression in two parts of the SN (SNC, SNR) and the VTA. Aside from some cells in the central gray tegmental nuclei adjacent to LC, where a small number of Fos profiles occurred, none or negligible Fos occurrence was detected in the other structures investigated including the LC and sLC, PON-A5, NTS-A2, AP, and VLM-A1. CMS preconditioning did not infl uence the level of Fos induction in the SN and VTA elicited by ASE administration. Similarly, the ratio between the amount of free Fos and Fos colocalized with TH was not aff ected by stress preconditioning in the SNC, SNR, and the VTA. CONCLUSIONS: Th e present study provides an anatomical/functional knowledge about the nature of the acute ASE treatment on the catecholamine-synthesizing neurons activity in certain brain structures and their missing interplay with the CMS preconditioning.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Condicionamento Psicológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Estresse Psicológico/metabolismo , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Animais , Área Postrema/citologia , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Catecolaminas/biossíntese , Dibenzocicloeptenos , Imuno-Histoquímica , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Bulbo/citologia , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Microscopia de Fluorescência , Neurônios/metabolismo , Parte Compacta da Substância Negra/citologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Parte Reticular da Substância Negra/citologia , Parte Reticular da Substância Negra/efeitos dos fármacos , Parte Reticular da Substância Negra/metabolismo , Ponte/citologia , Ponte/efeitos dos fármacos , Ponte/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Estresse Psicológico/psicologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg-1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA's behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA's central effects that sustain its pro-satiety action.
Assuntos
Área Postrema/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides/farmacologia , Hipotálamo/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Animais , Área Postrema/fisiologia , Tronco Encefálico/fisiologia , Dopamina beta-Hidroxilase/análise , Dopamina beta-Hidroxilase/metabolismo , Hipotálamo/fisiologia , Masculino , Ocitocina/análise , Ocitocina/metabolismo , PPAR alfa/análise , PPAR alfa/metabolismo , Proteínas Proto-Oncogênicas c-fos/análise , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos WistarRESUMO
BACKGROUND: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome. PURPOSE: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers. METHODS: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management. RESULTS: All 13 patients experienced symptom relief after administration of capsaicin cream. CONCLUSION: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.
Assuntos
Dor Abdominal/tratamento farmacológico , Antieméticos/administração & dosagem , Capsaicina/administração & dosagem , Serviço Hospitalar de Emergência , Abuso de Maconha/complicações , Fumar Maconha/efeitos adversos , Náusea/tratamento farmacológico , Fármacos do Sistema Sensorial/administração & dosagem , Vômito/tratamento farmacológico , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Adulto , Antieméticos/efeitos adversos , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Capsaicina/efeitos adversos , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Massachusetts , Pessoa de Meia-Idade , Missouri , Náusea/diagnóstico , Náusea/etiologia , Náusea/metabolismo , Estudos Retrospectivos , Fármacos do Sistema Sensorial/efeitos adversos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Síndrome , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Resultado do Tratamento , Vômito/diagnóstico , Vômito/etiologia , Vômito/metabolismo , Adulto JovemRESUMO
The pancreatic hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic 'reward' pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN. To determine whether and how peripheral amylin or sCT affect mesolimbic reward circuitry we utilized fast scan cyclic voltammetry under anesthesia to measure phasic DA release in the NAc evoked by electrical stimulation of the VTA in intact, AP lesioned and bilaterally PBN lesioned rats. Amylin (50µg/kg i.p.) did not change phasic DA responses compared to saline control rats. However, sCT (50µg/kg i.p.) decreased evoked DA release to VTA-stimulation over 1h compared to saline treated control rats. Further investigations determined that AP and bilateral PBN lesions abolished the ability of sCT to suppress evoked phasic DA responses to VTA-stimulation. These findings implicate the AP and the PBN as important sites for peripheral sCT to decrease evoked DA release in the NAc and suggest that these nuclei may influence hedonic and motivational processes to modulate food intake.
Assuntos
Área Postrema/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Calcitonina/farmacologia , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Núcleos Parabraquiais/efeitos dos fármacos , Animais , Eletrólise/efeitos adversos , Masculino , Núcleos Parabraquiais/lesões , Ratos , Ratos Wistar , Salmão/metabolismoRESUMO
Ghrelin is known to act on the area postrema (AP), a sensory circumventricular organ located in the medulla oblongata that regulates a variety of important physiological functions. However, the neuronal targets of ghrelin in the AP and their potential role are currently unknown. In this study, we used wild-type and genetically modified mice to gain insights into the neurons of the AP expressing the ghrelin receptor [growth hormone secretagogue receptor (GHSR)] and their role. We show that circulating ghrelin mainly accesses the AP but not to the adjacent nucleus of the solitary tract. Also, we show that both peripheral administration of ghrelin and fasting induce an increase of c-Fos, a marker of neuronal activation, in GHSR-expressing neurons of the AP, and that GHSR expression is necessary for the fasting-induced activation of AP neurons. Additionally, we show that ghrelin-sensitive neurons of the AP are mainly γ-aminobutyric acid (GABA)ergic, and that an intact AP is required for ghrelin-induced gastric emptying. Overall, we show that the capacity of circulating ghrelin to acutely induce gastric emptying in mice requires the integrity of the AP, which contains a population of GABA neurons that are a target of plasma ghrelin.
Assuntos
Área Postrema/fisiologia , Neurônios GABAérgicos/fisiologia , Grelina/sangue , Animais , Área Postrema/efeitos dos fármacos , Jejum , Neurônios GABAérgicos/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Grelina/administração & dosagem , Grelina/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/genética , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
To evaluate relative factors for anorectic effects of L-histidine, we performed behavioral experiments for measuring food and fluid intake, conditioned taste aversion (CTA), taste disturbance, and c-Fos immunoreactive (Fos-ir) cells before and after i.p. injection with L-histidine in rats. Animals were injected with saline (9 ml/kg, i.p.) for a control group, and saline (9 ml/kg, i.p.) containing L-histidine (0.75, 1.5, 2.0 g/kg) for a L-histidine group. Injection of L-histidine decreased the average value of food intake, and statistically significant anorectic effects were found in animals injected with 1.5 or 2.0 g/kg L-histidine but not with 0.75 g/kg L-histidine. Taste abnormalities were not detected in any of the groups. Animals injected with 2.0 g/kg L-histidine were revealed to present with nausea by the measurement of CTA. In this group, a significant increase in the number of Fos-ir cells was detected both in the area postrema and the nucleus tractus solitarius (NTS). In the 0.75 g/kg L-histidine group, a significant increase in the number of Fos-ir cells was detected only in the NTS. When the ventral gastric branch vagotomy was performed, recovery from anorexia became faster than the sham-operated group, however, vagotomized rats injected with 2.0 g/kg L-histidine still acquired CTA. These data indicate that acute anorectic effects induced by highly concentrated L-histidine are partly caused by induction of nausea and/or visceral discomfort accompanied by neuronal activities in the NTS and the area postrema. We suggest that acute and potent effects of L-histidine on food intake require substantial amount of L-histidine in the diet.
Assuntos
Depressores do Apetite/administração & dosagem , Encéfalo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Histidina/administração & dosagem , Paladar/efeitos dos fármacos , Dor Visceral/induzido quimicamente , Animais , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Área Postrema/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Injeções Intraperitoneais , Náusea/induzido quimicamente , Náusea/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia , Fatores de Tempo , Vagotomia , Dor Visceral/fisiopatologia , Dor Visceral/psicologiaRESUMO
The area postrema (AP) is a circumventricular organ with important roles in central autonomic regulation. This medullary structure has been shown to express the leptin receptor and has been suggested to have a role in modulating peripheral signals, indicating energy status. Using RT-PCR, we have confirmed the presence of mRNA for the leptin receptor, ObRb, in AP, and whole cell current-clamp recordings from dissociated AP neurons demonstrated that leptin influenced the excitability of 51% (42/82) of AP neurons. The majority of responsive neurons (62%) exhibited a depolarization (5.3 ± 0.7 mV), while the remaining affected cells (16/42) demonstrated hyperpolarizing effects (-5.96 ± 0.95 mV). Amylin was found to influence the same population of AP neurons. To elucidate the mechanism(s) of leptin and amylin actions in the AP, we used fluorescence resonance energy transfer (FRET) to determine the effect of these peptides on cAMP levels in single AP neurons. Leptin and amylin were found to elevate cAMP levels in the same dissociated AP neurons (leptin: % total FRET response 25.3 ± 4.9, n = 14; amylin: % total FRET response 21.7 ± 3.1, n = 13). When leptin and amylin were coapplied, % total FRET response rose to 53.0 ± 8.3 (n = 6). The demonstration that leptin and amylin influence a subpopulation of AP neurons and that these two signaling molecules have additive effects on single AP neurons to increase cAMP, supports a role for the AP as a central nervous system location at which these circulating signals may act through common intracellular signaling pathways to influence central control of energy balance.
Assuntos
Área Postrema/efeitos dos fármacos , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Receptores para Leptina/agonistas , Potenciais de Ação , Animais , Área Postrema/citologia , Área Postrema/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Metabolismo Energético/efeitos dos fármacos , Técnicas In Vitro , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Masculino , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Fatores de TempoRESUMO
We report a noteworthy case of a 7-month-old infant who suddenly and unexpectedly died during her sleep. After a complete postmortem examination, review of the clinical history, and detailed death scene investigation, the death remained unexplained, leading to a diagnosis of sudden infant death syndrome. However, an extensive review of the brainstem neuropathology revealed a severe alteration in the area postrema (a highly vascular structure lying at the base of the fourth ventricle outside of the blood-brain barrier). The alteration was likely due to massive and repeated to a common household insecticide in the last few weeks of life. These results provide an explanation for this sudden infant death, allowing a differential diagnosis from sudden infant death syndrome.
Assuntos
Área Postrema/efeitos dos fármacos , Inseticidas/intoxicação , Nitrofenóis/intoxicação , Morte Súbita do Lactente/etiologia , Área Postrema/patologia , Feminino , Humanos , Lactente , Morte Súbita do Lactente/diagnósticoRESUMO
A 65-year old patient suffering from severe psychotic depression obtained quetiapine for roughly one year. Several attempts to discontinue quetiapine by tapering the dose provoked severe withdrawal symptoms with nausea and vomitus. Pretreatment with domperidone largely prevented withdrawal so that he finally could successfully discontinue quetiapine administration.
Assuntos
Transtornos Psicóticos Afetivos/tratamento farmacológico , Antieméticos/uso terapêutico , Antipsicóticos/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Domperidona/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Náusea/induzido quimicamente , Fumarato de Quetiapina/efeitos adversos , Síndrome de Abstinência a Substâncias/etiologia , Vômito/induzido quimicamente , Idoso , Antidepressivos/uso terapêutico , Antieméticos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Área Postrema/efeitos dos fármacos , Domperidona/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Humanos , Compostos de Lítio/uso terapêutico , Masculino , Náusea/tratamento farmacológico , Náusea/fisiopatologia , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/uso terapêutico , Receptores de Dopamina D2/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Cloridrato de Venlafaxina/uso terapêutico , Vômito/tratamento farmacológico , Vômito/fisiopatologiaRESUMO
Previous studies from our laboratory have shown that methysergide, a serotonergic antagonist, injected into the lateral parabrachial nucleus (LPBN) combined with a pre-load of 2 M NaCl, given by gavage, induces 0.3 M NaCl intake. The mechanisms involved in this paradoxical behavior are still unknown. In the present work, we investigated the effect of serotonergic blockade into the LPBN on hindbrain and hypothalamic activity, gastric emptying and arterial blood pressure in cell-dehydrated rats. Methysergide plus 2 M NaCl infused intragastrically or intravenously promoted 0.3 M NaCl intake in two-bottle tests. In cell-dehydrated rats with no access to fluids, methysergide compared to vehicle increased Fos immunoreactivity in the medial nucleus of the solitary tract, area postrema and non-oxytocinergic cells of the ventral portion of the hypothalamic paraventricular nucleus (PVN). There was no alteration in the number of neurons double-labeled for Fos-ir and oxytocin in the PVN and supraoptic nuclei. There was also no alteration in plasma oxytocin and vasopressin, or arterial pressure. In rats cell-dehydrated by i.v. 2 M NaCl, methysergide also did not change the amount of an intragastric load of 0.3 M NaCl retained in the stomach or intestine. The results suggest that methysergide injected into the LPBN of cell-dehydrated rat does not alter primary inhibitory signals that control sodium intake. The inhibitory signals blocked by methysergide in the LPBN possibly originated from activation of brain osmoreceptors, second order visceral/hormonal signals or a combination of both.