RESUMEN
The Tyr-MIF-1 family of small peptides has served a prototypic role in the introduction of several novel concepts into the peptide field of research. MIF-1 (Pro-Leu-Gly-NH(2)) was the first hypothalamic peptide shown to act "up" on the brain, not just "down" on the pituitary. In several situations, including clinical depression, MIF-1 exhibits an inverted U-shaped dose-response relationship in which increasing doses can result in decreasing effects. This tripeptide also can antagonize opiate actions, and the first report of such activity also correctly predicted the discovery of other endogenous antiopiate peptides. The tetrapeptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH(2)) not only shows antiopiate activity, but also considerable selectivity for the mu-opiate binding site. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH(2)) is an even more selective ligand for the mu receptor, leading to the discovery of two more Tyr-Pro tetrapeptides that have the highest specificity and affinity for this site. These are the endomorphins: endomorphin-1 is Tyr-Pro-Trp-Phe-NH(2) and endomorphin-2 is Tyr-Pro-Phe-Phe-NH(2). Tyr-MIF-1 proved, contrary to the then prevailing dogma, that peptides can be saturably transported across the blood-brain barrier by a quantifiable transport system. Unexpectedly, the Tyr-MIF-1 transporter is shared with Met-enkephalin. In the era in which it was doubtful whether a peripheral peptide could exert CNS effects, the Tyr-MIF-1 family of peptides also explicitly showed that they can exert more than one central action that persists longer than their half-lives in blood. These peptides clearly illustrate that the name of a peptide restricts neither its actions nor its conceptual implications.
Asunto(s)
Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Hormona Inhibidora de la Liberación de MSH/fisiología , Oligopéptidos/fisiología , Analgésicos/farmacología , Animales , Sitios de Unión , Barrera Hematoencefálica , Depresión/tratamiento farmacológico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Humanos , Hormona Inhibidora de la Liberación de MSH/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Ratas , Receptores Opioides/metabolismoRESUMEN
Neurons immunoreactive to an antiserum specifically directed against the Prolyl-Leucyl-Glycinamide peptide (PLGamide: Melanocyte Inhibiting Factor: MIF) were detected in the brain of the leech Theromyzon tessulatum. Radioimmunoassay titrations of the PLGamide-like material at different physiological stages of the life cycle indicated a maximal amount at stage 3B, which is correlated to phase of both maximal water uptake and coelomic vitellogenin accumulation. In vivo experiments demonstrate that this cerebral PLGamide-like material is an anti-diuretic factor that would act at stage 3B in order to permit a water uptake leading to water retention allowing coelomic yolk protein accumulation. In brains of the Gnatobdellid leech Hirudo medicinalis and the Pharyngobdellid leech Erpobdella octoculata, anti-PLGamide material was also detected with an amount not differing with the degree of sex maturation of the animals, confirming the link between osmoregulation and ovogenesis in rhynchobdellid leeches. Using a combination of biochemical techniques including high-pressure gel permeation chromatography followed by reversed-phase HPLC on brain extracts and Edman degradation, we demonstrated the presence of an authentic MIF-1 peptide in leech brain. Finally, since in vertebrates MIF-1 belongs to the non-classical opioid peptide family, we studied its binding displacement, in contrast to morphine, on mu-receptors and on nitric oxide (NO) release experiments in leech brain. PLGamide did not bind to mu-alkaloid opioid receptors and did not stimulate NO release.
Asunto(s)
Encéfalo/metabolismo , Hormona Inhibidora de la Liberación de MSH/fisiología , Equilibrio Hidroelectrolítico , Animales , Unión Competitiva , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Inmunoensayo , Sanguijuelas , Estadios del Ciclo de Vida , Hormona Inhibidora de la Liberación de MSH/aislamiento & purificación , Hormona Inhibidora de la Liberación de MSH/metabolismo , Hormona Inhibidora de la Liberación de MSH/farmacología , Óxido Nítrico/metabolismo , Receptores Opioides mu/metabolismoRESUMEN
Hypocretin has been identified as a regulator of metabolic and endocrine systems. Several brain regions involved in the central regulation of autonomic and endocrine processes or attention are targets of extensive hypocretin projections. The most dense arborization of hypocretin axons in the brainstem was detected in the locus coeruleus (LC). Multiple labeling immunocytochemistry revealed a massive synaptic innervation of catecholaminergic LC cells by hypocretin axon terminals in rats and monkeys. In both species, all tyrosine hydroxylase-immunopositive cells in the LC examined by electron microscopy were found to receive asymmetrical (excitatory) synaptic contacts from multiple axons containing hypocretin. In parallel electrophysiological studies with slices of rat brain, all LC cells showed excitatory responses to the hypocretin-2 peptide. Hypocretin-2 uniformly increased the frequency of action potentials in these cells, even in the presence of tetrodotoxin, indicating that receptors responding to hypocretin were expressed in LC neurons. Two mechanisms for the increased firing rate appeared to be a reduction in the slow component of the afterhyperpolarization (AHP) and a modest depolarization. Catecholamine systems in other parts of the brain, including those found in the medulla, zona incerta, substantia nigra or olfactory bulb, received significantly less hypocretin input. Comparative analysis of lateral hypothalamic input to the LC revealed that hypocretin-containing axon terminals were substantially more abundant than those containing melanin-concentrating hormone. The present results provide evidence for direct action of hypothalamic hypocretin cells on the LC noradrenergic system in rats and monkeys. Our observations suggest a signaling pathway via which signals acting on the lateral hypothalamus may influence the activity of the LC and thereby a variety of CNSfunctions related to noradrenergic innervation, including vigilance, attention, learning, and memory. Thus, the hypocretin innervation of the LC may serve to focus cognitive processes to compliment hypocretin-mediated activation of autonomic centers already described.
Asunto(s)
Locus Coeruleus , Neuropéptidos , Neurotransmisores , Norepinefrina/análisis , Norepinefrina/fisiología , Terminales Presinápticos/química , Terminales Presinápticos/ultraestructura , Potenciales de Acción/fisiología , Animales , Chlorocebus aethiops , Femenino , Hipotálamo/química , Hipotálamo/fisiología , Hipotálamo/ultraestructura , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular , Locus Coeruleus/química , Locus Coeruleus/fisiología , Locus Coeruleus/ultraestructura , Hormona Inhibidora de la Liberación de MSH/análisis , Hormona Inhibidora de la Liberación de MSH/fisiología , Macaca fascicularis , Masculino , Microscopía Electrónica , Neurotransmisores/análisis , Neurotransmisores/farmacología , Neurotransmisores/fisiología , Orexinas , Terminales Presinápticos/fisiología , Ratas , Ratas Sprague-Dawley , Tetrodotoxina/farmacología , Tirosina 3-Monooxigenasa/análisisRESUMEN
A comparison of solution conformations of active, restricted-conformation analogues of two sequence-similar insect/vertebrate neuropeptide family pairs shed light on the potential existence of molecular evolutionary relationships. Analogues of the locustatachykinins and the mammalian tachykinin substance P, containing a sterically hindered Aib-NMePhe/Tyr residue block, share similar low-energy turn conformations incorporating a cis peptide bond. Conversely, restricted conformation analogues of the insect kinins and the mammalian opiate peptide Tyr-W-MIF-1, with near identical C-terminal tetrapeptide sequences, adopt different conformations. The insect kinins adopt a cisPro 1-4 beta-turn, in which the Phe1 is critical for bioactivity. Tyr-W-MIF-1 prefers a transPro 2-5 turn, and an additional N-terminal Phe severely inhibits mu-opiate receptor binding. Comparisons of the chemical/conformational requirements for receptor interaction are consistent with a distant evolutionary relationship between the insectatachykinins and tachykinins, but not between the insect kinins and Tyr-W-MIF-1. Therefore, analogues of the insect kinins with pest control potential can be readily designed to avoid mammalian interactions.
Asunto(s)
Insectos , Neuropéptidos/química , Taquicininas/química , Secuencia de Aminoácidos , Animales , Humanos , Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Hormona Inhibidora de la Liberación de MSH/química , Hormona Inhibidora de la Liberación de MSH/fisiología , Mamíferos , Modelos Moleculares , Antagonistas de Narcóticos/química , Neuropéptidos/fisiología , Conformación Proteica , Taquicininas/fisiologíaRESUMEN
Tyr-MIF-1 is a representative of the MIF's family of endogenous peptides. It has been isolated from bovine hypothalamus and human parietal cortex that suggests its involvement in nociception. Tyr-MIF-1 can bind to the mu-receptors as well as to its specific non-opiate receptors in the brain. Data in the literature rise the idea that histamine (HA), a well known nociceptive agent, and Tyr-MIF-1 might have a common pathway in their effects on nociception. We tested that possibility by investigation of the combined action of diphenhydramine (DPH, an H (1) -antagonist) and Tyr-MIF-1 on nociception. The changes in the nociceptive effects were examined in the male Wistar rats by the Randall-Sellito paw-pressure (PP) and the tail-flick (TF) tests. Tyr-MIF-1 in a dose of 1 mg/kg exerted strong naloxone-reversible analgesic effects. DPH (100 microg/kg, i.p.) had an antinociceptive action, too. The co-administration of Tyr-MIF-1 and DPH enhanced the antinociceptive effect, as compared to DPH (PP) and to TYR-MIF-1 alone (TF). These effects were reversed when methylene blue (MB, 500 microg/rat) was applied 1h before the combination. However, naloxone (1 mg/kg, i.p.) only slightly affected the antinociceptive effect of DPH and TYR-MIF-1, compared to that of MB. The results obtained confirmed the hypothesis that cyclic nucleotides are involved in the realization of nociceptive effects of both HA and Tyr-MIF-1.
Asunto(s)
Analgésicos/farmacología , Difenhidramina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Analgésicos/administración & dosificación , Animales , Difenhidramina/administración & dosificación , Combinación de Medicamentos , Miembro Posterior , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Calor , Inyecciones Intraperitoneales , Hormona Inhibidora de la Liberación de MSH/administración & dosificación , Hormona Inhibidora de la Liberación de MSH/fisiología , Masculino , Naloxona/administración & dosificación , Antagonistas de Narcóticos , Ratas , Ratas Wistar , Cola (estructura animal)Asunto(s)
Endorfinas/aislamiento & purificación , Oligopéptidos/aislamiento & purificación , Receptores Opioides mu/agonistas , Secuencia de Aminoácidos , Analgésicos Opioides/aislamiento & purificación , Analgésicos Opioides/farmacología , Animales , Unión Competitiva , Encéfalo/metabolismo , Bovinos , Endorfinas/fisiología , Humanos , Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Hormona Inhibidora de la Liberación de MSH/fisiología , Mamíferos , Datos de Secuencia Molecular , Oligopéptidos/fisiología , Médula Espinal/metabolismoRESUMEN
A ventrally localized melanization-inhibiting factor (MIF) may play an important role in the expression of dorsal-ventral pigment patterns of amphibians. In efforts to purify this putative MIF, ventral skin conditioned medium (VCM) from Rana forreri was partially fractionated and used to immunize mice. A monoclonal antibody that has the ability to block the activity of MIF was isolated, and an immunoaffinity matrix was prepared by cross-linking the antibody to protein G-Sepharose. The fraction of VCM that bound to the affinity matrix decreased the number of melanized cells in the Xenopus laevis neural tube explant assay, but did not reduce significantly the number of cells that emigrated. The monoclonal antibody was used for immunohistochemical studies on R. pipiens skin. Strong staining with the antibody was observed beneath the basement membrane, in mucous glands, and in the subcutaneous tissue of the ventral skin. A weak staining was also observed in the ground substances of both ventral and dorsal skin. These results confirm that a monoclonal antibody has been secured against at least one of the MIF constituents and that it is useful as a probe in detecting the distribution of MIF in tissues. The results of its use in this study support the hypothesis that MIF plays a role in the expression, development, and maintenance of the dorsal-ventral pigmentation patterns of frogs.
Asunto(s)
Hormona Inhibidora de la Liberación de MSH/fisiología , Melanocitos/química , Pigmentación , Piel/química , Animales , Anticuerpos Monoclonales/inmunología , Cromatografía de Afinidad , Hormona Inhibidora de la Liberación de MSH/aislamiento & purificación , Melanocitos/fisiología , RanidaeAsunto(s)
Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Barrera Hematoencefálica , Bovinos , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/fisiología , Corteza Cerebral/metabolismo , Semivida , Humanos , Aprendizaje/efectos de los fármacos , Hormona Inhibidora de la Liberación de MSH/aislamiento & purificación , Hormona Inhibidora de la Liberación de MSH/farmacología , Hormona Inhibidora de la Liberación de MSH/fisiología , Datos de Secuencia Molecular , Homología de Secuencia de AminoácidoRESUMEN
A review of research on the Tyr-MIF-1 family of peptides is presented with emphasis on Tyr-MIF-1 and its structure, passage through the blood-brain barrier, and both opiate antagonist and agonist properties. Family members MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1 are also included.
Asunto(s)
Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Neuropéptidos/fisiología , Animales , Barrera Hematoencefálica/fisiología , Humanos , Hormona Inhibidora de la Liberación de MSH/metabolismo , Hormona Inhibidora de la Liberación de MSH/farmacología , Hormona Inhibidora de la Liberación de MSH/fisiología , Neuropéptidos/metabolismo , Neuropéptidos/farmacologíaRESUMEN
The concentrations in plasma of the biologically active endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) have not been measured during development or in female rats. By radioimmunoassay, we found that Tyr-MIF-1-like immunoreactivity (Tyr-MIF-1-LI) was first consistently detectable in plasma when the rat was 5 days old, and then gradually increased to adult concentrations by day 15. In male rats, the levels remained relatively constant for the next 21 months. In female rats, plasma concentrations of Tyr-MIF-1-LI at day 15 were about the same as in male rats. At 6 months of age, however, the concentrations in females decreased by half and by 21 months of life were only about a third of the concentrations found at day 15 or in age-matched males. The differences with age were not due to the length of time of storage of the samples, because another group of rats 1 month old was killed on the same day as 5-day-old rats and still showed several times more Tyr-MIF-1-LI in the plasma; again, no differences were found between male and female rats at either 5 days or 1 month. A single injection of estradiol followed by progesterone lowered the concentrations in 1-month-old male rats. In female rats that were either ovariectomized or sham-ovariectomized, the expected similarity in their plasma concentrations of Tyr-MIF-1-LI was found at 1 month of age.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Distribución por Edad , Factores de Edad , Animales , Animales Recién Nacidos , Estradiol/sangre , Femenino , Hormona Inhibidora de la Liberación de MSH/sangre , Hormona Inhibidora de la Liberación de MSH/inmunología , Hormona Inhibidora de la Liberación de MSH/fisiología , Masculino , Progesterona/sangre , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
Social investigatory behaviour was used as a measure of olfactory recognition in two experiments to assess social memory in adult male rats. In Experiment 1, time spent in social investigation of juvenile males by 3-month-old adults was significantly higher than time spent by 7- and 11-month-old animals. Furthermore, a reexposure to the same juvenile male 30 min after the initial exposure elicited significantly less social investigation in adult males aged 7 and 11 months but not in those aged 3 months. If the reexposure occurs 2 h later, the same juvenile is thoroughly investigated by adult males irrespective of the age. The age-related differences in social recognition are discussed in terms of the internal readiness of adult males. While the social recognition was confirmed in older adult males, it is suggested that an ability to recognize the same juvenile may be masked in young animals by a high sexual arousal. Behavioural phenomenon of the social recognition was used in Experiment 2. An administration of hypothalamic MIF-I or its synthetic derivative Alaptide to adult males 7 or 11 months old immediately after their 1st exposure to a juvenile male resulted in decreasing the time spent in social investigation of the same juvenile during a reexposure performed 120 min later. Both drugs were ineffective if adult males were reexposed to a novel juvenile. The results suggest that both MIF-I and Alaptide improved an animal's capacity to store information received through olfactory cues.
Asunto(s)
Envejecimiento/fisiología , Hormona Inhibidora de la Liberación de MSH/fisiología , Neuropéptidos/fisiología , Péptidos Cíclicos/fisiología , Olfato/fisiología , Conducta Social , Animales , Hipotálamo/fisiología , Masculino , Ratas , Ratas EndogámicasRESUMEN
Evidence is presented that the small peptides MIF-1/Tyr-MIF-1 are part of an endogenous antiopiate system that may function to balance the opiate system. We review the biological activity, behavioral activity, and functional effects of this proposed opiate antagonist system. In addition, we suggest, based on antinociceptive mechanisms, that the individual components of the antiopiate system might function differently from naloxone.
Asunto(s)
Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Hormona Inhibidora de la Liberación de MSH/fisiología , Antagonistas de Narcóticos , Analgesia , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hipotálamo/metabolismo , Cinética , Naloxona/farmacología , Receptores Opioides/metabolismoAsunto(s)
Conducta/efectos de los fármacos , Hormonas Hipotalámicas/fisiología , Proteínas del Tejido Nervioso/fisiología , Neurotensina/fisiología , Hormonas Hipofisarias/fisiología , Sustancia P/fisiología , Animales , Nivel de Alerta/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Regulación de la Temperatura Corporal/efectos de los fármacos , Bombesina/farmacología , Química Encefálica/efectos de los fármacos , Estimulantes del Sistema Nervioso Central , Hormona Liberadora de Corticotropina/fisiología , Conducta Alimentaria/efectos de los fármacos , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Aprendizaje/efectos de los fármacos , Hormona Inhibidora de la Liberación de MSH/fisiología , Actividad Motora/efectos de los fármacos , Nociceptores/efectos de los fármacos , Somatostatina/fisiología , Hormona Liberadora de Tirotropina/fisiologíaRESUMEN
By specialized cell types of the hypothalamus 6 peptides (liberins) acting stimulating on the synthesis and secretion of hormones of the pituitary gland and 3 peptides acting inhibiting (statins) were formed. The synthesis of the hypothalamus hormones apparently takes place from larger precursor molecules. Under influence of corticoliberin the pro-opiomelanocortin is formed in the pituitary gland, the breaking up of which produces in the anterior pituitary lobe the ACTH, the beta-lipotropin and the beta-endorphin as well as in the middle lobe above all melanotropins. The secretion of the growth hormone is furthered above all by the somatoliberin and inhibited by the somatostatin. The luliberin stimulates the secretion of follicle stimulating hormone (FSH) and the luteinising hormone (LH). In increased secretion of prolactin the supply of the FSH- and LH-synthetizing cells with receptors for the luliberin is decreased. The secretion of the prolactin is furthered by the prolactoliberin and inhibited by the prolactostatin. In the regulation of the release of the melanotropins also participate 2 peptides. In the adrenal cortex the melanotropins further the synthesis of glucocorticosteroids stimulated by ACTH.
Asunto(s)
Hormonas Hipotalámicas , Animales , Fenómenos Químicos , Química , Hormona Liberadora de Corticotropina/fisiología , Femenino , Hormona Liberadora de Gonadotropina/fisiología , Hormona Liberadora de Hormona del Crecimiento/fisiología , Humanos , Hormonas Hipotalámicas/fisiología , Sistema Hipotálamo-Hipofisario/embriología , Hormona Inhibidora de la Liberación de MSH/fisiología , Macaca mulatta , Masculino , Hormonas Estimuladoras de los Melanocitos/fisiología , Factores Inhibidores de la Liberación de Prolactina/fisiología , Somatostatina/fisiología , Hormona Liberadora de Tirotropina/fisiologíaAsunto(s)
Encéfalo/citología , Hormona Inhibidora de la Liberación de MSH/fisiología , Receptores Dopaminérgicos/fisiología , Antiparkinsonianos , Hormonas/uso terapéutico , Humanos , Hormona Inhibidora de la Liberación de MSH/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Receptores Dopaminérgicos/efectos de los fármacosAsunto(s)
Regulación de la Temperatura Corporal , Encéfalo/fisiología , Proteínas del Tejido Nervioso/fisiología , Hipófisis/fisiología , Hormonas Hipofisarias/fisiología , Hormona Adrenocorticotrópica/fisiología , Angiotensina II/fisiología , Animales , Bombesina/fisiología , Endorfinas/fisiología , Hormonas/fisiología , Humanos , Hormona Inhibidora de la Liberación de MSH/fisiología , Hormonas Estimuladoras de los Melanocitos/fisiología , Neurotensina/fisiología , Somatostatina/fisiología , Tirotropina/fisiología , Vasopresinas/fisiologíaAsunto(s)
Hormonas Hipotalámicas/fisiología , Péptidos/fisiología , Hormonas Hipofisarias/fisiología , Terapia por Acupuntura , Hormona Adrenocorticotrópica/fisiología , Animales , Endorfinas/fisiología , Encefalinas/fisiología , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Hormona Inhibidora de la Liberación de MSH/fisiología , Hormonas Estimuladoras de los Melanocitos/fisiología , Ratas , Esquizofrenia/etiología , Somatostatina/fisiología , Hormona Liberadora de Tirotropina/fisiología , Vasopresinas/fisiologíaAsunto(s)
Cuerpo Estriado/metabolismo , Dopamina/biosíntesis , Hormona Inhibidora de la Liberación de MSH/fisiología , Hormona Liberadora de Tirotropina/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Dextroanfetamina/farmacología , Dopamina/metabolismo , Técnicas In Vitro , Masculino , Ratas , Tiramina/farmacologíaRESUMEN
It is well known that the release of melanocyte-stimulating hormone (MSH) from the pituitary gland is mainly controlled by an inhibitory influence from the hypothalamus. In addition to this inhibitory control, there may also be a stimulatory influence. Most, but by no means all, of the evidence is compatible with the possibility that inhibition is mediated by dopaminergic and/or alpha-adrenergic receptors. Gamma-aminobutyric acid also has been shown to have an inhibitory role in some studies. beta-Adrenergic receptors, serotonin, and acetylcholine may be involved in the stimulation of MSH release. Interaction of hypothalamic peptides like Pro-Leu-Gly-NH2(MIF-I) with biogenic amines, however, has not been excluded as a factor in the control of the release of MSH from the pituitary. Just as the evidence for the involvement of amines in the control of MSH release is somewhat puzzling and contradictory, conflicting evidence concerning their involvement in mediating the specific effects of MSH and MIF-I on the CNS remains unresolved.