RESUMO
Hypocretin/orexin is produced exclusively in the dorsal and lateral hypothalamus but its projection is widespread within the brain and plays important roles. In this paper, we review the independent discoveries of the hypocretin/orexin peptides, the neuroanatomy of this system, and the link to the sleep disorder narcolepsy that has led to the idea that this system plays a crucial role in the regulation of sleep and wakefulness.
Assuntos
Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Narcolepsia/veterinária , Neuropeptídeos/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Homeostase/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Narcolepsia/metabolismo , OrexinasRESUMO
Narcolepsy is a chronic sleep disorder that affects human beings and animals. Up to 17 breeds of dogs are affected sporadically, and familial forms occur in dobermanns, labrador retrievers and dachshunds. These dogs display characteristics strikingly similar to those of human narcolepsy, including cataplexy (a sudden loss of muscle tone in response to emotional stimulation) and a shorter sleep latency. It has recently been shown that the aetiology of both the familial form (receptor null mutation) and the sporadic form (loss of ligand production) of canine narcolepsy is associated with a deficit in hypocretin/orexin neurotransmission. Hypocretin deficiency can be detected by the measurement of hypocretin-1 in cerebrospinal fluid, and this could be used to diagnose hypocretin ligand deficient cases in clinical practice. Narcolepsy is neither progressive nor life-threatening, but the clinical signs persist throughout life, and lifelong treatment and care are required. This article reviews the recent progress in narcolepsy research in dogs, and describes the diagnosis and treatment of the disease.
Assuntos
Doenças do Cão/patologia , Hipotálamo/fisiopatologia , Narcolepsia/veterinária , Neuropeptídeos/metabolismo , Animais , Doença Crônica , Diagnóstico Diferencial , Doenças do Cão/tratamento farmacológico , Doenças do Cão/fisiopatologia , Cães , Predisposição Genética para Doença , Narcolepsia/tratamento farmacológico , Narcolepsia/patologia , Narcolepsia/fisiopatologia , Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/metabolismoRESUMO
Since the discovery of an almost 100 p. cent association of human narcolepsy with the HLA gene DQB1*0602, research has been focused on autoimmune mechanisms. Epidemiological data (age of onset, triggering factors, association with multiple sclerosis) would lend support to this hypothesis. However it has remained largely impossible to demonstrate immune abnormalities in blood or CSF by means of usual techniques. The canine form of the disease was supposed to be also immunologically mediated, since a linkage with a human immunoglobulin-related gene had been demonstrated. This was eventually demonstrated to be a pseudo-linkage, the real cause being a mutation in the closely related hypocretin receptor gene. This recently discovered neuropeptide is clearly involved in some aspects of sleep regulation. Soon thereafter, hypocretin deficiency was found in human narcoleptics, due to a severe neuronal loss in the hypothalamus; gliosis having been evidenced, it may be considered as the evidence of a prior inflammatory reaction, possibly due to an immune attack.
Assuntos
Doenças Autoimunes/imunologia , Narcolepsia/imunologia , Animais , Doenças Autoimunes/genética , Doenças do Cão/genética , Doenças do Cão/imunologia , Cães , Marcadores Genéticos/genética , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Humanos , Hipotálamo/imunologia , Hipotálamo/patologia , Narcolepsia/genética , Narcolepsia/veterináriaAssuntos
Proteínas de Transporte/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular , Narcolepsia/metabolismo , Neuropeptídeos/fisiologia , Receptores de Neuropeptídeos/deficiência , Animais , Apetite/fisiologia , Nível de Alerta/fisiologia , Sinalização do Cálcio , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cataplexia/genética , Cataplexia/metabolismo , Cromossomos Humanos Par 17/genética , Doenças do Cão/genética , Cães , Genes Recessivos , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiopatologia , Sistema Límbico/fisiopatologia , Locus Cerúleo/fisiopatologia , Camundongos , Camundongos Knockout , Narcolepsia/genética , Narcolepsia/veterinária , Degeneração Neural/genética , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Receptores de Orexina , Orexinas , Ratos , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/fisiologia , Deleção de Sequência , Sono/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.
Assuntos
Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular , Narcolepsia/genética , Neuropeptídeos/deficiência , Neuropeptídeos/metabolismo , Precursores de Proteínas/deficiência , Idade de Início , Animais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Doenças do Cão/genética , Cães , Eletroencefalografia , Eletromiografia , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modafinila , Narcolepsia/tratamento farmacológico , Narcolepsia/metabolismo , Narcolepsia/fisiopatologia , Narcolepsia/veterinária , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Receptores de Orexina , Orexinas , Fenótipo , Postura , Precursores de Proteínas/genética , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/genética , Sono/fisiologia , Sono REM/fisiologia , Especificidade da Espécie , Comportamento EstereotipadoRESUMO
Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.