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1.
Neurochem Res ; 33(10): 2035-43, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18373195

ABSTRACT

The blood-brain barrier (BBB) is a structural and functional barrier that prevents free exchange of circulating substances with the brain, where the endothelial cells of microvessels are joined by tight junctions. The circumventricular organs (CVOs), by contrast, lack tight junctions and exhibit more direct communication with the circulating blood and cerebrospinal fluid. Despite many outstanding morphological studies at the electron microscopic level, there remain misconceptions that the CVOs provide direct passage of blood-borne substances to the rest of the brain. This study will show the structure of the anatomical borders of the dorsal vagal complex in the brainstem. A distinct diffusion barrier between the area postrema (AP, a CVO) and the nucleus tractus solitarius (NTS) was illustrated by immunohistochemistry at both the light and electron microscopic levels. The border zone between the AP and NTS was underlined by a continuous monolayer of columnar cells that were immunopositive for both the tight junction protein zona occludin-1 and the astrocyte marker glial fibrillary acidic protein. This observation of a diffusion barrier between the AP and NTS resolves a long-standing dispute about whether the NTS is a structural extension of the AP with a leaky BBB.


Subject(s)
Area Postrema/ultrastructure , Blood-Brain Barrier , Solitary Nucleus/ultrastructure , 2',3'-Cyclic-Nucleotide Phosphodiesterases/analysis , Animals , Diffusion , Male , Microscopy, Confocal , Microscopy, Immunoelectron , Rats , Rats, Wistar , Tight Junctions/ultrastructure
2.
Regul Pept ; 145(1-3): 122-7, 2008 Jan 10.
Article in English | MEDLINE | ID: mdl-17931715

ABSTRACT

Synaptic relationships between ghrelin-like immunoreactive axon terminals and other neurons in the hypothalamic arcuate nucleus (ARC) were studied using immunostaining methods at the light and electron microscope levels. Many ghrelin-like immunoreactive axon terminals were found to be in apposition to ghrelin-like immunoreactive neurons at the light microscopic level. At the electron microscopic level, ghrelin-like immunoreactive axon terminals were found to make synapses on ghrelin-like immunoreactive cell bodies and dendrites in the ARC. While the axo-dendritic synapses between ghrelin- and ghrelin-like immunoreactive neurons were mostly the asymmetric type, the axo-somatic synapses were both asymmetric and symmetric type of synapses. Ghrelin at 10(-10) M increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in the neurons isolated from the ARC, some of which were immunocytochemically identified as ghrelin-positive. Ghrelin at 10(-10) M also increased [Ca(2+)](i) in 12% of ghrelin-like immunoreactive neurons in the ARC. These findings suggest that ghrelin serves as a transmitter and/or modulator that stimulates [Ca(2+)](i) signaling in ghrelin neurons of the ARC, which may participate in the orexigenic action of ghrelin. Our data suggests a possibility of existing a novel circuit implicating regulation of feeding and/or energy metabolism.


Subject(s)
Ghrelin/metabolism , Hypothalamus/metabolism , Neurons/metabolism , Synapses/metabolism , Animals , Calcium/metabolism , Cell Shape , Hypothalamus/ultrastructure , Male , Microscopy, Immunoelectron , Neurons/ultrastructure , Rats , Rats, Wistar , Synapses/ultrastructure
3.
Regul Pept ; 145(1-3): 128-32, 2008 Jan 10.
Article in English | MEDLINE | ID: mdl-17936371

ABSTRACT

Both proopiomelanocortin (POMC) and ghrelin peptides are implicated in the feeding regulation. The synaptic relationships between POMC- and ghrelin-containing neurons in the hypothalamic arcuate nucleus were studied using double-immunostaining methods at the light and electron microscope levels. Many POMC-like immunoreactive axon terminals were found to be apposed to ghrelin-like immunoreactive neurons and also to make synapses with ghrelin-like immunoreactive neuronal perikarya and dendritic processes. Most of the synapses were symmetrical in shape. A small number of synapses made by ghrelin-like immunoreactive axon terminals on POMC-like immunoreactive neurons were also identified. Both the POMC- and ghrelin-like immunoreactive neurons were found to contain large dense granular vesicles. These data suggest that the POMC-producing neurons are modulated via synaptic communication with ghrelin-containing neurons. Moreover, ghrelin-containing neurons may also have a feedback effect on POMC-containing neurons through direct synaptic contacts.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Ghrelin/metabolism , Neurons/metabolism , Pro-Opiomelanocortin/metabolism , Synapses/metabolism , Animals , Arcuate Nucleus of Hypothalamus/ultrastructure , Male , Microscopy, Electron , Neurons/ultrastructure , Rats , Rats, Wistar , Synapses/ultrastructure
4.
Peptides ; 27(11): 2885-93, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16793173

ABSTRACT

Galanin-like peptide (GALP), commonly known as an appetite-regulating peptide, has been shown to increase plasma luteinizing hormone (LH) through luteinizing hormone-releasing hormone (LHRH). This led us to investigate, using both light and electron microscopy, whether GALP-containing neurons in the rat brain make direct inputs to LHRH-containing neurons. As LHRH-containing neurons are very difficult to demonstrate immunohistochemically with LHRH antiserum without colchicine treatment, we used a transgenic rat in which LHRH tagged with enhanced green fluorescence protein facilitated the precise detection of LHRH-producing neuronal cell bodies and processes. This is the first study to report on synaptic inputs to LHRH-containing neurons at the ultrastructural level using this transgenic model. We also used immunohistochemistry to investigate the neuronal interaction between GALP- and LHRH-containing neurons. The experiments revealed that GALP-containing nerve terminals lie in close apposition with LHRH-containing cell bodies and processes in the medial preoptic area and the bed nucleus of the stria terminalis. At the ultrastructural level, the GALP-positive nerve terminals were found to make axo-somatic and axo-dendritic synaptic contacts with the EGFP-positive neurons in these areas. These results strongly suggest that GALP-containing neurons provide direct input to LHRH-containing neurons and that GALP plays a crucial role in the regulation of LH secretion via LHRH.


Subject(s)
Galanin-Like Peptide/biosynthesis , Gonadotropin-Releasing Hormone/biosynthesis , Neurons/metabolism , Preoptic Area/metabolism , Septal Nuclei/metabolism , Synapses/ultrastructure , Animals , Animals, Genetically Modified , Fluorescent Dyes/analysis , Gonadotropin-Releasing Hormone/genetics , Green Fluorescent Proteins/genetics , Immunohistochemistry , Male , Neurons/ultrastructure , Preoptic Area/ultrastructure , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Septal Nuclei/ultrastructure
5.
Regul Pept ; 129(1-3): 17-23, 2005 Jul 15.
Article in English | MEDLINE | ID: mdl-15927693

ABSTRACT

The distribution of orexin A immunoreactivity and the synaptic relationships of orexin A-positive neurons in the rat area postrema were studied using both light and electron microscopy techniques. At the light microscope level, numerous orexin A-like immunoreactive fibers were found within the area postrema. Using electron microscopy, immunoreactivity within fibers was confined primarily to the axon terminals, most of which contained dense-cored vesicles. Both axo-somatic and axo-dendritic synapses made by orexin A-like immunoreactive axon terminals were found, with these synapses being both symmetric and asymmetric in form. Orexin A-like immunoreactive axon terminals could be found presynaptic to two different immunonegative profiles including the perikarya and dendrites. Occasionally, some orexin A-like immunoreactive profiles, most likely to be dendrites, could be seen receiving synaptic inputs from immunonegative or immunopositive axon terminals. The present results suggest that the physiological function of orexin A in the area postrema depends on synaptic relationships with other immunopositive and immunonegative neurons, with the action of orexin A mediated via a self-modulation feedback mechanism.


Subject(s)
Area Postrema/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Neuropeptides/metabolism , Secretory Vesicles/metabolism , Synapses/metabolism , Animals , Area Postrema/ultrastructure , Axons/metabolism , Axons/ultrastructure , Dendrites/metabolism , Dendrites/ultrastructure , Immunohistochemistry , Male , Microscopy, Electron, Transmission , Orexins , Rats , Secretory Vesicles/ultrastructure , Synapses/ultrastructure
6.
Regul Pept ; 126(1-2): 21-6, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15620409

ABSTRACT

The hypothalamus plays an important role in the regulation of feeding behavior, energy metabolism and reproduction. A novel peptide containing 60 amino acid peptide and a non-amidated C-terminus is produced in the hypothalamic arcuate nucleus (ARC) and has been named galanin-like peptide (GALP) on the basis of a portion of this peptide being homologous with galanin. It acts in the central nervous system (CNS), where it is involved in the regulation of feeding behavior. GALP-producing neurons make neuronal networks with several feeding related peptide-producing neurons. Since GALP is involved in the control of food intake and energy balance, it is possible that it plays an important role in the development of obesity. Furthermore, GALP regulates plasma lateral hypothalamus (LH) levels via the activation of gonadotropin-releasing hormone (GnRH)-producing neurons, suggesting that GALP is active in the reproductive system. Thus, interesting findings on the roles of GALP have made across a number of physiological systems. This review will attempt to summarize the research carried out to date on these areas. Because GALP may be involved in feeding behavior, energy metabolism and reproduction, further studies on the morphology and function of GALP-containing neurons in the CNS should increase our understanding of the role of GALP in brain function.


Subject(s)
Brain/physiology , Eating/physiology , Energy Metabolism/physiology , Galanin-Like Peptide/metabolism , Reproduction/physiology , Animals , Humans
7.
Regul Pept ; 126(1-2): 35-42, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15620411

ABSTRACT

Orexin/hypocretin has been well demonstrated to excite the serotonergic neurons in the dorsal raphe nucleus (DRN). We studied the morphological relationships between orexin-containing axon terminals and serotonin- as well as orexin-receptor-containing neurons in the dorsal raphe nucleus. Using immunohistochemical techniques at the light microscopic level, orexin A (OXA)-like immunoreactive neuronal fibers in the DRN were found to make close contact with serotonergic neurons, while some of the serotonergic neurons also expressed the orexin 1 receptor (OX1R). At the electron microscopic level, double-immunostaining experiments showed that the orexin A-like immunoreactive fibers were present mostly as axon terminals that made synapses on the serotonin- and orexin 1-receptor-containing neurons. While only axodendritic synapses between orexin A-containing axon terminals and serotonergic neurons were detected, the synapses made by orexin A-containing axon terminals on the orexin 1-receptor-containing neurons were both axodendritic and axosomatic. The present study suggests that excitation effect of orexin A on dorsal raphe serotonergic neurons is via synaptic communication through orexin 1 receptor.


Subject(s)
Axons/metabolism , Raphe Nuclei/metabolism , Receptors, Neuropeptide/biosynthesis , Serotonin/metabolism , Synapses/metabolism , Animals , Axons/ultrastructure , Cell Communication/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Male , Neuropeptides/metabolism , Orexin Receptors , Orexins , Raphe Nuclei/ultrastructure , Rats , Rats, Wistar , Receptors, G-Protein-Coupled , Synapses/ultrastructure
8.
Regul Pept ; 126(1-2): 43-7, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15620412

ABSTRACT

The serotonergic dorsal raphe (DR) neurons play an important role in sleep-wakefulness regulation. Orexinergic neurons in the lateral hypothalamus densely project to the brainstem sites including the DR. To test the effects of orexins on the serotonergic DR neurons, we applied orexin A (0.1 mM) by pressure to these neurons in unanesthetized and urethane anesthetized rats. Orexin A caused excitation in 10 of 15 neurons under unanesthetized condition. The excitation was characterized by slow onset (0-18 s), long lasting duration (15-150 s) and state-dependency. Orexin A applied during REM sleep or slow wave sleep induced significant excitation while during wakefulness, the similar amount of orexin A did not increase the firing rate any more. In the anesthetized animals, orexin A induced excitation in four of eight neurons. The excitation had slow onset and was long lasting. These results suggest that orexinergic neurons exert excitatory influence on the serotonergic DR neurons to maintain tonic activity of them, thereby participating in regulation of sleep-wakefulness cycles and other functions.


Subject(s)
Intracellular Signaling Peptides and Proteins/administration & dosage , Neurons/physiology , Neuropeptides/administration & dosage , Raphe Nuclei/physiology , Sleep Stages/physiology , Wakefulness/physiology , Animals , Male , Neurons/drug effects , Orexins , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Signal Transduction/drug effects , Sleep Stages/drug effects , Wakefulness/drug effects
9.
Regul Pept ; 126(1-2): 73-8, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15620417

ABSTRACT

Galanin-like peptide (GALP) is a novel peptide which is isolated from the porcine hypothalamus. GALP-containing neurons are present in the arcuate nucleus (ARC), being particularly densely concentrated in medial posterior regions. To observe the ultrastructure and synaptic relationships of GALP-containing neurons in the ARC, light and immunoelectron microscopy techniques were used. At the light microscope level, GALP-containing neurons were observed distributed rostrocaudally throughout the ARC, with the majority present in the posterior, periventricular zones. At the electron microscope level, many immunopositive dense-cored vesicles were evident in the perikarya, dendrites and axon terminals of the GALP-containing neurons. Furthermore, these neurons received synapses from immunonegative axon terminals that were symmetric in the case of synapses made on perikarya, and both asymmetric and symmetric for synapses made on dendrites. Axon terminals of GALP-containing neurons often made synapses on immunonegative dendrites. Such synapses were all symmetric. Synapses were also found between axon terminals and perikarya as well as dendrites of GALP-containing neurons. These findings suggest that the physiological role of the GALP-containing neurons in the ARC is based on complex synaptic relationships between GALP-containing neurons and either GALP-immunopositive or -immunonegative neurons.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Axons/metabolism , Dendrites/metabolism , Galanin-Like Peptide/biosynthesis , Animals , Arcuate Nucleus of Hypothalamus/ultrastructure , Axons/ultrastructure , Cell Communication/physiology , Dendrites/ultrastructure , Male , Microscopy, Electron, Transmission , Rats , Rats, Wistar , Secretory Vesicles/metabolism , Secretory Vesicles/ultrastructure , Synapses/metabolism , Synapses/ultrastructure
11.
Peptides ; 25(8): 1307-11, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15350698

ABSTRACT

The ultrastructural properties of orexin 1-receptor-like immunoreactive (OX1R-LI) neurons in the dorsal horn of the rat spinal cord were examined using light and electron microscopy techniques. At the light microscopy level, the most heavily immunostained OX1R-LI neurons were found in the ventral horn of the spinal cord, while some immunostained profiles, including nerve fibers and small neurons, were also found in the dorsal horn. At the electron microscopy level, OX1R-LI perikarya were identified containing numerous dense-cored vesicles which were more heavily immunostained than any other organelles. Similar vesicles were also found within the axon terminals of the OX1R-LI neurons. The perikarya and dendrites of some of the OX1R-LI neurons could be seen receiving synapses from immunonegative axon terminals. These synapses were found mostly asymmetric in shape. Occasionally, some OX1R-LI axon terminals were found making synapses on dendrites that were OX1R-LI in some cases and immunonegative in others. The synapses made by OX1R-LI axon terminals were found both asymmetric and symmetric in appearance. The results provide solid morphological evidence that OX1R is transported in the dense-cored vesicles from the perikarya to axon terminals and that OX1R-LI neurons in the dorsal horn of the spinal cord have complex synaptic relationships both with other OX1R-LI neurons as well as other neuron types.


Subject(s)
Posterior Horn Cells/chemistry , Posterior Horn Cells/ultrastructure , Receptors, Neuropeptide/analysis , Spinal Cord/chemistry , Spinal Cord/ultrastructure , Animals , Immunohistochemistry , Male , Microscopy, Electron , Orexin Receptors , Rats , Rats, Wistar , Receptors, G-Protein-Coupled
12.
Anat Sci Int ; 78(3): 123-38, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14527127

ABSTRACT

The hypothalamus is a region of the brain that plays a critical role in feeding regulation. It has been revealed by various physiological experiments that the feeding-regulating center is confined to the ventromedial hypothalamus, lateral hypothalamus (LH) and arcuate nucleus (ARC). Many kinds of neurons in these areas of the hypothalamus express factors such as melanin-concentrating hormone (MCH), neuropeptide Y (NPY), proopiomelanocortin (POMC), orexin (OX) and ghrelin, which have been implicated in feeding regulation. In tissues of the periphery, two critical factors involved in feeding regulation, leptin and ghrelin, have been identified. Both hormone peptides are secreted mainly from adipose and stomach tissue, respectively, and are considered to function via their receptors mainly through several hypothalamic nuclei that play important roles in the regulation of appetite. The present review looks mainly at the functional significance of feeding-regulation factors, such as those described above, and the humoral and neuronal interactions among these compounds in the hypothalamus by drawing on published reports of morphological and physiological analyses. Immunohistochemical and in situ hybridization experiments indicate that both leptin and ghrelin receptors are distributed in the hypothalamus and that there are reciprocal interactions between MCH and OX neurons in the LH. Morphological and physiological studies on single living cells isolated from fresh rat hypothalamus or with receptor agonist and antagonist combined with immunohistochemisry clearly demonstrate that both leptin and OX reciprocally regulate NPY- and POMC-containing neurons in the ARC and that ghrelin may regulate feeding status independently through direct OX and NPY pathways. In this way, cross-talking systems in the hypothalamus play a role in determining feeding states.


Subject(s)
Appetite Regulation/physiology , Feeding Behavior/physiology , Hypothalamus/metabolism , Intracellular Signaling Peptides and Proteins , Nerve Net/metabolism , Neuropeptides/metabolism , Animals , Carrier Proteins/metabolism , Ghrelin , Humans , Hypothalamus/cytology , Leptin/metabolism , Nerve Net/cytology , Orexins , Peptide Hormones/metabolism
13.
Brain Res ; 987(1): 86-92, 2003 Oct 10.
Article in English | MEDLINE | ID: mdl-14499949

ABSTRACT

The ultrastructure and synaptic relationships of orexin A-like immunoreactive neuronal fibers in the dorsal horn of the rat cervical spinal cord were examined at both the light and electron microscopic levels. At the light microscopic level, many intensely immunostained orexin A-like fibers were found, while at the electron microscopic level, immunoreactivity in these fibers was mostly confined to axon terminals. Most of the axon terminals contained dense-cored vesicles. Immunoreactive and immunonegative dense-cored vesicles were occasionally found within the same orexin A-like immunoreactive axon terminals, which were often found making synapses with immunonegative dendrites. These synapses were both asymmetric and symmetric, with the asymmetric ones predominant. Orexin A-like immunoreactive processes that contained no synaptic vesicles were also found with less frequency. These processes were also observed receiving synaptic inputs from immunonegative axon terminals, but the synapses were mostly asymmetric. Sometimes, such processes were found to receive multiple synaptic inputs for which the presynaptic immunonegative axon terminals could make synapses on other immunonegative dendrites simultaneously. Occasionally, synapses between the orexin A-like immunoreactive axon terminals and orexin A-like immunoreactive processes containing no synaptic vesicles were also found. The present results provide solid morphological evidence that orexin A may be involved in pain-inhibition mechanisms in the spinal cord and suggest that this function may be complex and occur in conjunction with the regulatory effects of other neurotransmitters.


Subject(s)
Carrier Proteins/analysis , Intracellular Signaling Peptides and Proteins , Neuropeptides/analysis , Posterior Horn Cells/chemistry , Animals , Male , Microscopy, Immunoelectron , Orexins , Posterior Horn Cells/ultrastructure , Rats , Rats, Wistar , Spinal Cord/chemistry
14.
Peptides ; 24(6): 925-30, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12948846

ABSTRACT

The ultrastructure and the synaptic relationships of the orexin-A-like immunoreactive fibers in the dorsal raphe nucleus were examined with an immunoelectron microscopic method. At the electron microscopic level, most of the immunoreactive fibers, a varicosity appearance at the light microscopic level, were found as axon terminals. The large dense-cored vesicles contained in the immunoreactive axon terminals were the most intensely immunostained organellae. These axon terminals were often found to make synapses. While the axo-dendritic synapses were usually asymmetric in appearance, the axo-somatic synapses were symmetric. Orexin-A-like immunoreactive processes with no synaptic vesicles were also found. These processes often received asymmetric synapses. With less frequency, the synapses were found between the orexin-like immunoreactive processes. The results suggest that the orexin peptides are stored in the large dense-cored vesicles; the orexin-containing fibers may have influences on the physiological activities of the dorsal raphe nucleus through direct synaptic relationships.


Subject(s)
Carrier Proteins/immunology , Carrier Proteins/ultrastructure , Intracellular Signaling Peptides and Proteins , Neuropeptides/immunology , Raphe Nuclei/metabolism , Raphe Nuclei/ultrastructure , Animals , Carrier Proteins/analysis , Male , Microscopy, Immunoelectron , Neuropeptides/analysis , Orexins , Raphe Nuclei/immunology , Rats , Rats, Wistar
15.
Peptides ; 24(5): 687-94, 2003 May.
Article in English | MEDLINE | ID: mdl-12895654

ABSTRACT

The arcuate nucleus (ARC) of the hypothalamus has been identified as a prime feeding regulating center in the brain. Several feeding regulating peptides, such as neuropeptide Y (NPY) and proopiomelanocortin (POMC), are present in neurons of the ARC, which also serves as a primary targeting site for leptin, a feeding inhibiting hormone secreted predominantly by adipose tissues, and for orexin (OX)-containing neurons. OX is expressed exclusively around the lateral hypothalamus, an area also established as a feeding regulating center. Some recent physiological analyses have shown that NPY- and POMC-containing neurons are activated or inactivated by leptin and OX. Moreover, we have already shown, using double immunohistochemical staining techniques, that NPY- and POMC-containing neurons express leptin receptors (LR) and orexin type 1 receptors (OX-1R). However, no morphological study has yet described the possibility of whether or not these arcuate neurons are influenced by both leptin and OX simultaneously. In order to address this issue, we performed histochemistry on ARC neurons using a triple immunofluorescence method. We found that 77 out of 213 NPY- and 99 out of 165 POMC-immunoreactive neurons co-localized with both LR- and OX-1R-immunoreactivities. These findings strongly suggest that both NPY- and POMC-containing neurons are regulated simultaneously by both leptin and OX.


Subject(s)
Arcuate Nucleus of Hypothalamus/chemistry , Neurons/chemistry , Neuropeptide Y/analysis , Pro-Opiomelanocortin/analysis , Receptors, Cell Surface/analysis , Receptors, Neuropeptide/analysis , Animals , Appetite Regulation , Arcuate Nucleus of Hypothalamus/cytology , Arcuate Nucleus of Hypothalamus/physiology , Fluorescent Antibody Technique , Male , Neuropeptide Y/immunology , Neuropeptide Y/metabolism , Orexin Receptors , Pro-Opiomelanocortin/immunology , Pro-Opiomelanocortin/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/immunology , Receptors, G-Protein-Coupled , Receptors, Leptin , Receptors, Neuropeptide/immunology
16.
Neurosci Lett ; 341(2): 107-10, 2003 May 01.
Article in English | MEDLINE | ID: mdl-12686377

ABSTRACT

Endomorphin 2 is a newly discovered peptide that has high affinity and specificity for the mu-opioid receptor. One criterion for establishing that endomorphin serves as an endogenous agonist for the mu receptor is that it be anatomically distributed in close proximity to that receptor. We tested this idea with a preembedding double immunostaining technique to study synaptic relationships between them. The distributions of both endomorphin 2 and the mu-opioid receptor were similar in the dorsal horn of the cervical spinal cord at the light microscopic level. At the electron microscopic level, axon terminals with dense-cored vesicles containing endomorphin 2-like immunoreactivity were observed making mostly asymmetrical synapses on profiles immunostained for the mu-opioid receptor. The immunostaining for the mu-opioid receptor was found mostly in postsynaptic membranes in profiles having dendrite-like appearance. The results support the idea that endomorphin 2 is an endogenous ligand for the mu-opioid receptor. Furthermore, the results indicate that such a role is mediated at least in part through synaptic relationships.


Subject(s)
Oligopeptides/pharmacology , Receptors, Opioid, mu/agonists , Spinal Cord/drug effects , Animals , Male , Microscopy, Immunoelectron/methods , Oligopeptides/metabolism , Posterior Horn Cells/metabolism , Posterior Horn Cells/ultrastructure , Rats , Rats, Wistar , Receptors, Opioid, mu/metabolism , Receptors, Opioid, mu/ultrastructure , Secretory Vesicles/metabolism , Secretory Vesicles/ultrastructure , Spinal Cord/metabolism , Synapses/drug effects , Synapses/metabolism , Synapses/ultrastructure
17.
Endocrinology ; 144(4): 1506-12, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12639935

ABSTRACT

The hypothalamus regulates energy intake by integrating the degree of starvation or satiation with the status of the environment through a variety of neuronal and blood-derived signals. Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates feeding and GH secretion. Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY) and agouti-related protein systems. The interaction between ghrelin and other hypothalamic orexigenic peptides, however, has not been clarified. Here, we investigated the anatomical interactions and functional relationship between ghrelin and two orexigenic peptides, orexin and melanin-concentrating hormone (MCH), present in the lateral hypothalamus. Ghrelin-immunoreactive axonal terminals made direct synaptic contacts with orexin-producing neurons. Intracerebroventricular administration of ghrelin induced Fos expression, a marker of neuronal activation, in orexin-producing neurons but not in MCH-producing neurons. Ghrelin remained competent to induce Fos expression in orexin-producing neurons following pretreatment with anti-NPY IgG. Pretreatment with anti-orexin-A IgG and anti-orexin-B IgG, but not anti-MCH IgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-IgGs. Ghrelin-induced feeding was also suppressed in orexin knockout mice. This study identifies a novel hypothalamic pathway that links ghrelin and orexin in the regulation of feeding behavior and energy homeostasis.


Subject(s)
Carrier Proteins/metabolism , Eating/drug effects , Intracellular Signaling Peptides and Proteins , Neuropeptides/metabolism , Peptide Hormones/pharmacology , Animals , Antibodies/pharmacology , Carrier Proteins/genetics , Carrier Proteins/immunology , Eating/physiology , Fluorescent Antibody Technique , Ghrelin , Hypothalamic Hormones/immunology , Hypothalamic Hormones/metabolism , Male , Melanins/immunology , Melanins/metabolism , Mice , Mice, Knockout , Microscopy, Immunoelectron , Neurons/chemistry , Neurons/metabolism , Neurons/ultrastructure , Neuropeptides/genetics , Neuropeptides/immunology , Orexins , Peptide Hormones/analysis , Pituitary Hormones/immunology , Pituitary Hormones/metabolism , Proto-Oncogene Proteins c-fos/biosynthesis , Rats , Rats, Wistar
18.
Peptides ; 24(12): 1921-8, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15127943

ABSTRACT

Morphological relationships between neuropeptide Y- (NPY) like and ghrelin-like immunoreactive neurons in the arcuate nucleus (ARC) were examined using light and electron microscopy techniques. At the light microscope level, both neuron types were found distributed in the ARC and could be observed making contact with each other. Using a preembedding double immunostaining technique, some NPY-immunoreactive axon terminals were observed at the electron microscope level to make synapses on ghrelin-immunoreactive cell bodies and dendrites. While the axo-somatic synapses were mostly symmetric in nature, the axo-dendritic synapses were both symmetric and asymmetric. In contrast, ghrelin-like immunoreactive (ghrelin-LI) axon terminals were found to make synapses on NPY-like immunoreactive (NPY-LI) dendrites although no NPY-like immunoreactive perikarya were identified receiving synapses from ghrelin-LI axon terminals. NPY-like axon terminals were also found making synapses on NPY-like neurons. Axo-axonic synapses were also identified between NPY- and ghrelin-like axon terminals. The present study shows that NPY- and ghrelin-LI neurons could influence each other by synaptic transmission through axo-somatic, axo-dendritic and even axo-axonic synapses, and suggests that they participate in a common effort to regulate the food-intake behavior through complex synaptic relationships.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Neurons/metabolism , Neuropeptide Y/metabolism , Peptide Hormones/metabolism , Synapses/metabolism , Animals , Arcuate Nucleus of Hypothalamus/ultrastructure , Ghrelin , Male , Microscopy, Electron , Neurons/ultrastructure , Rats , Rats, Wistar , Synapses/ultrastructure
19.
Jpn J Pharmacol ; 89(3): 209-15, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12184723

ABSTRACT

Endomorphins (EMs) are newly found endogenous opioid peptides. Both endomorphin-1 (EM-1) and -2 (EM-2) are composed of four amino acids. Their high affinity and specificity for mu-opioid receptors have been confirmed by many physiological and pharmacological studies. In the present minireview, we discuss the distribution and localization of these peptides. While EM-2 is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. We also discuss the possible coexistence of EM with other neurotransmitters. Finally, we introduce some new results regarding the ultrastructure and synaptic relationships of EM-2 obtained by the immunoelectron microscopic method.


Subject(s)
Central Nervous System/ultrastructure , Neurons/ultrastructure , Oligopeptides/analysis , Animals , Central Nervous System/chemistry , Central Nervous System/cytology , Humans , Neurons/chemistry , Neurons/cytology , Synapses/chemistry , Synapses/ultrastructure
20.
Neurosci Lett ; 329(2): 209-12, 2002 Aug 30.
Article in English | MEDLINE | ID: mdl-12165414

ABSTRACT

The distribution and ultrastructural localization of the orexin-1 receptor (OX(1)R) in the rat arcuate nucleus were studied using immunocytochemical techniques. OX(1)R-containing neurons were found throughout the nucleus, but were concentrated in its posterior region. Both OX(1)R-positive perikarya and dendrites were found to receive synapses from other unknown axon terminals. In addition, a small number of OX(1)R-positive axon terminals were observed. These OX(1)R-immunoreactive axon terminals were often found to make synapses on unidentified immunonegative dendritic processes. The present results indicate that orexin may act on food intake regulating neurons through both pre- and post-synaptic OX(1)R.


Subject(s)
Arcuate Nucleus of Hypothalamus/ultrastructure , Neurons/ultrastructure , Presynaptic Terminals/ultrastructure , Receptors, Neuropeptide/ultrastructure , Animals , Arcuate Nucleus of Hypothalamus/chemistry , Male , Neurons/chemistry , Orexin Receptors , Presynaptic Terminals/chemistry , Rats , Rats, Wistar , Receptors, G-Protein-Coupled , Receptors, Neuropeptide/analysis
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