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Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels.

Background: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS., Methods: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity., Results: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood., Conclusions: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.

The ultrastructure of the reproductive gland, dorsal body (DB), of Megalobulimus abbreviatus was analysed. Electron microscope immunohistochemistry was used to detect FMRFamide-like peptides in the nerve endings within this gland. Nerve backfilling was used in an attempt to identify the neurons involved in this innervation. In M. abbreviatus, the DB has a uniform appearance throughout their supraesophageal and subesophageal portions. Dorsal body cells have several features in common with steroid-secreting gland cells, such as the presence of many lipid droplets, numerous mitochondria with tubular cristae and a developed smooth endoplasmic reticulum cisternae. Throughout the DB in M. abbreviatus numerous axonal endings were seen to be in contact with the DB cells exhibiting a synaptic-like structure. The axon terminals contained numerous electron-dense and scanty electron-lucid vesicles. In addition, the DB nerve endings exhibited FMRFamide immunoreactive vesicles. Injection of neural tracer into the DB yielded retrograde labelling of neurons in the metacerebrum lobe of the cerebral ganglia and in the parietal ganglia of the subesophageal ganglia complex. The possibility that some of these retrograde-labelled neurons might be FMRFamide-like neurons that may represent a neural control to the DB in M. abbreviatus is discussed.

This review summarizes the data obtained with the aid of the recently introduced dual viral tracing technique, which uses isogenic recombinants of pseudorabies virus that express unique reporter gene. This approach made possible to explore simultaneously neural circuits of two organs. The results of these studies indicate: (1) there are neurons innervating exclusively a given organ; (2) left-sided predominance in the supraspinal innervation of the endocrine glands (adrenal, ovary) studied, so far; (3) viral co-infection of neurons, i.e., special neuronal populations coexist in different brain areas that are transsynaptically connected with both paired endocrine and non-endocrine organs, endocrine glands and non-endocrine organs, and organs of bodily systems other than the endocrine one. The number of common neurons seems to be related to the need of coordinating action of different systems. The data on co-infection of neurons suggest that the central nervous system has the capacity to coordinate different organ functions via common brain neurons providing supraspinal innervation of the organs.

A morpho-functional investigation of the sex pheromone-producing area was correlated with the pheromone release mechanism in the female gypsy moth Lymantria dispar. As assessed by male electroantennograms (EAG) and morphological observations, the pheromone gland consists of a single-layered epithelium both in the dorsal and ventral halves of the intersegmental membrane between the 8th and 9th abdominal segments. By using the male EAG as a biosensor of real-time release of sex pheromone from whole calling females, we found this process time coupled with extension movements of the ovipositor. Nevertheless, in females in which normal calling behavior was prevented, pheromone release was detected neither in absence nor in presence of electrical stimulation of the ventral nerve cord/terminal abdominal ganglion (TAG) complex. Tetramethylrhodamine-conjugated dextran amine stainings also confirm the lack of any innervation of the gland from nerves IV to VI emerging from the TAG. These findings indicate that the release of sex pheromone from the glands in female gypsy moths is independent of any neural control exerted by the TAG on the glands, at least by way of its three most caudally located pairs of nerves, and appears as a consequence of a squeezing mechanism in the pheromone-producing area.

This review summarizes our recent studies using the viral transneuronal tracing technique to identify sites in the central nervous system (CNS) that are connected with the ovary. A neurotropic virus (pseudorabies virus) was injected into the ovary and various times after the inoculation the spinal cord and brain were examined for virus-infected neurons identified by immunocytochemistry. Such neurons could be detected in well-defined cell groups of the spinal cord (intermediolateral cell column), brain stem (vagal nuclei, area postrema, parapyramidal nucleus, caudal raphe nuclei, A1, A5, A7 noradrenergic cell groups, locus coeruleus, Barrington's nucleus, periaqueductal gray), hypothalamus (paraventricular nucleus, anterior hypothalamus, arcuate nucleus, zona incerta), and, at longer survival time, in some telencephalic structures (amygdala, bed nucleus of the stria terminalis). These findings provided the first neuromorphological evidence for the existence of a multisynaptic neuronal pathway between the brain and the ovary presumably involved in the neuronal control of the organ. The observations indicate that there is a significant overlap of CNS structures connected with the ovary, the testis, other organs and organ systems, suggesting similar neuronal circuitries of the autonomic nervous system innervating the different organs. The known descending neuronal connections between the CNS structures labeled from the ovary by the viral transneuronal tracing technique and the findings suggesting a pituitary independent interplay between certain cerebral structures such as the hypothalamus, the amygdala, and the ovary are also summarized in this review., (Copyright 2002 Wiley-Liss, Inc.)

This review is a summary of recent neuromorphological observations on the existence of multisynaptic neural pathways between the endocrine glands and the central nervous system (CNS) and its structures involved in this pathway. Introduction of the viral transneuronal tracing technique has made possible investigations of multisynaptic connections. The utility of this approach is based on the ability of the neurotropic virus to invade and replicate in neurons, and then gradually infect synaptically linked second-order, third-order. etc. neurons. Injecting the virus into the endocrine glands, this technique was used to identify cell groups in the spinal cord and in the brain which are connected with the adrenal gland, the gonads and the pancreas. Injection of the virus into these organs resulted in viral labeling of neurons in practically identical structures of the CNS including the intermediolateral cell column of the spinal cord, the vagal nuclei and certain other cell groups in the brain stem. In the hypothalamus the most intensive labeling was in the parvocellular part of the paraventricular nucleus and in the telencephalon labeled nerve cells were detected in the amygdala, the bed nucleus of the stria terminalis and in the preoptic area. It is known that the labeled CNS structures are members of descending pathways arising from the hypothalamic paraventricular nucleus or from other cell groups and terminating on neurons of the vagal nuclei and the intermediolateral cell column of the spinal cord. Experimental data support the view that the CNS structures and pathways connected with the endocrine glands are involved in the neural control of these organs.

More than 30 years ago, Douglas (Douglas & Rubin, 1961; Douglas, 1968) proposed that intracellular Ca2+ controls stimulus-secretion coupling in endocrine cells, and Katz & Miledi (1967; Katz, 1969) proposed that intracellular Ca2+ ions control the rapid release of neurotransmitters from synapses. These related hypotheses have been amply confirmed in subsequent years and for students of excitable cells, they dominate our teaching and research. Calcium controls regulated exocytosis. On the other hand, many studies of epithelial and blood cell biology emphasize Ca2+-independent regulation of secretion of mucin, exocytotic delivery of transporters and degranulation. The evidence seems good. Are these contrasting conclusions somehow mistaken, or are the dominant factors controlling exocytosis actually different in different cell types? In this essay, we try to reconcile these ideas and consider classes of questions to ask and hypotheses to test in seeking a more integrated understanding of excitation-secretion coupling. Our review is conceptual and narrowly selective of a few examples rather than referring to a broader range of useful studies in the extensive literature. The examples are taken from mammals and are documented principally by citing other reviews and two of our own studies. The evidence shows that protein phosphorylation by kinases potentiates Ca2+-dependent exocytosis and often suffices to induce exocytosis by itself. Apparently, protein phosphorylation is the physiological trigger in a significant number of examples of regulated exocytosis. We conclude that although sharing many common properties, secretory processes in different cells are specialized and distinct from each other.

The hypothesis that neuroepithelial endocrine (NEE) cells control spontaneous tone in isolated guinea pig tracheal preparations was examined. Epithelium-denuded preparations were unable to develop a normal oscillating tone in 12% oxygen (corresponding to systemic arterial oxygen levels) and, instead, developed a strong, smooth tone, similar to the "classic" tone in 94% oxygen. Inhibition of the hydrogen peroxide-producing NADPH oxidase in the NEE cells by 20 microM diphenyleneiodonium chloride transformed, in intact preparations in 94% oxygen, the tone from a strong, smooth type to an oscillating tone of considerably less force. Similar experiments in denuded preparations showed no change of tone and no oscillations. After pretreatment with the catalase inhibitor 3-amino-1,2, 4-triazole (1 mM), addition of 2 mM hydrogen peroxide to intact preparations displaying the oscillating tone caused a transformation to a strong, smooth type. These findings support the hypothesis that the spontaneous tone in this preparation is largely controlled by the oxygen-sensing NEE cells. For the first time, previous findings on isolated cells can be linked to effects in intact tissue preparations. The results also suggest that the regulation by the NEE cells involves the release of powerful relaxing and contracting factors from the epithelium.

Skin conductance level (SCL) and spectral analysis of variations in heart rate (HR) and blood pressure (BP), in relation to plasma catecholamine concentrations, were used to evaluate autonomic nervous system activity during situations of supine rest within a period of 4 h after oral administration of 1 mg alprazolam and 2 mg lorazepam. Twelve healthy men received in a double-blind, randomized crossover design, either 1 mg alprazolam, or 2 mg lorazepam, or a placebo on different days. ECG, BP, respiration, and SCL were monitored continuously during each session. For HR, systolic and diastolic BP (SBP, DBP) time series, power spectra were calculated per 5 min for three 15-min periods at 30 min, 1 h and 45 min, and 3 h after dosing. Spectral power was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.50 Hz). Per time segment, the gain in the mid-frequency band between the systolic BP values and the RR interval times was computed as index of baroreflex sensitivity (BRS). Blood samples for assay of plasma catecholamines were obtained after each 15-min period. Alprazolam reduced DBP during the whole recording period; the effect was accompanied by an initial increase of mid-frequency band fluctuations of BP at 30 min, which subsequently decreased at 1 h 45 min and 3 h after dose administration, in comparison with placebo (suggesting an initial reflectory increase, followed by an attenuation of sympathetic tone). The BP effects were accompanied by a reduction of plasma noradrenaline concentrations. HR showed a time-dependent decrease after alprazolam and an increase in high-frequency band fluctuations of HR and BRS (suggesting a time-dependent increase in cardiac vagal tone). SCL was decreased after alprazolam administration. Lorazepam did not show a time-dependent reduction of HR and had no effect on BP, but increased low-frequency band power of HR and DBP and mildly reduced SCL. Alprazolam and lorazepam had no effect on respiratory frequency. Noninvasive indices of autonomic regulation revealed several small, but significant, time-dependent effects of 1 mg alprazolam on sympathetic and parasympathetic processes, whereas for 2 mg lorazepam, these effects were less clear. The reduction in noninvasive indices of sympathetic tone after alprazolam administration corresponded with the attenuation of plasma noradrenaline concentrations by alprazolam.

The development and functioning of the nervous system are known to be influenced in various ways by endocrine signals. In turn, neural tissue modulates internal homeostasis, not only by electrical signaling, but also by regulating the release of endocrine messengers. However, the mechanisms underlying these processes are not fully understood. Recent evidence indicates that glia may play a significant role in the link between the endocrine and nervous systems. Glial cells express nuclear receptors for both thyroid and steroid hormones and participate in the metabolism of these hormones, resulting in the production of neuroactive metabolites. Furthermore, glial cells synthesize endogenous neuroactive steroids, including pregnenolone and progesterone, from cholesterol. Thyroid hormones, glucocorticoids, gonadal steroids, and neurosteroids affect myelinization by acting on oligodendroglia and modulate astroglia morphology, differentiation, and gene expression in different brain areas. Under physiological conditions, hormonal effects on glia may have important consequences for neuronal development, metabolism, and activity and for the formation and plasticity of synaptic connections. In addition, glucocorticoids, gonadal steroids, and neurosteroids may affect regenerative processes in neurons by modulating glial responses after injury. These effects include the activation of microglia, which is regulated by glucocorticoids, and the proliferation of reactive astroglia, which is regulated by gonadal hormones and neurosteroids. Glial cells are also involved in the modulation of hormone release. Pituicytes and microglia in the neurohypophysis may influence hormonal secretion by regulating neurovascular contacts, while astroglia in the hypothalamus regulate the number of synaptic inputs to specific neuronal populations involved in pituitary hormone release, such as LHRH and oxytocinergic neurons. Furthermore, tanycytes and astrocytes in the arcuate nucleus and median eminence release trophic factors that regulate hormone secretion by hypothalamic neurons.

Three regulating systems, nervous, endocrine and immune, are involved in maintenance of homeostasis. They are regarded as interacting, with interaction between nervous and endocrine systems being well defined and giving rise to development of independent realm of knowledge--the neuroendocrinology. As concerns interaction between the neuroendocrine and immune systems it seems to be exciting and intensely developing trend of up-to-date investigation. A great deal of evidence is adduced bringing new sight into the mechanisms of bidirectional exchange of signals among the nervous, endocrine and immune systems. This paper provides analytical consideration of the vast information, that allowed the development of the new integrative area of biology--the neuro-immuno-endocrinology, with special reference being paid to some general regularities underlying integration of each regulatory constituents into the single operating system. Attention is also paid to up-date information concerning mechanisms of neurotransmition and immune response in terms of the problem under consideration.

The endocrine cells of rainbow trout pyloric ceca and intestine have been investigated immunocytochemically using the avidin-biotin method. Twenty-six antisera were tested and 13 endocrine cell types immunoreacted with antisera to serotonin, somatostatin-25, bombesin, C-flanking bombesin, substance P, salmon PP, NPY, PYY, PP, glucagon, GLP1, Met-enkephalin, and CCK/G. Glucagon and GLP1 immunoreactivities appear in the same cells. Nerves positive to serotonin, substance P, PHI, and VIP were also found. The presence of cells positive to somatostatin-25, C-flanking bombesin, and salmon PP are described for the first time in fish intestine.

To visualize the entire shape of the intraepithelial nerve fibers, whole mount preparations of the dog urethra were produced and immunostained with an antiserum against CGRP, one of the predominant substances contained in the nerves. The immunoreactive nerves in the lamina propria were smooth (non-beaded) in appearance and weak in immunoreaction. Within the epithelium, they displayed typical beaded profiles and were intense in immunoreaction. The intraepithelial fibers branched and wound into an extensive network with wide meshes ("reticular terminal"). The bead-like swellings included large ones resembling Herring bodies in hypophyseal neurosecretory fibers. Another type of nerve terminal, consisting of fine and weakly immunopositive fibers, was also found in the epithelium. These branched in dendritic or in dense bouquet-like fashion, occupying smaller areas ("bouquet-like terminals). Vesicular swellings often characterized these terminals, though they were smaller and more uniform in size and far less in their amount of immunoreactive substance than were the swellings in the reticular terminals. Both types of nerve terminals originated from the same nerve trunk. The connection between the reticular and bouquet-like terminals, which may presumably represent secretory and receptive parts, respectively, morphologically supports the possible occurrence of an axon reflex in the urethral CGRP neurons. Our whole mount preparations, when doubly stained with CGRP and serotonin antibodies, further revealed the CGRP-positive reticular terminals being closely associated with serotonin- or CGRP-immunoreactive paraneurons dispersed in the epithelium.

Female Heliothis moths normally produce their species-specific male attractant (sex pheromone blend) during scotophase, and this production is stimulated by pheromone biosynthesis activating neuropeptide (PBAN), presumably carried in the hemolymph. Several lines of evidence indicate that the central nervous system plays another critical role in this regulation. Pheromone biosynthesis was induced during photophase by electrical stimulation of the ventral nerve cord or the peripheral nerves projecting from the terminal abdominal ganglion to the pheromone gland in the tip of the abdomen. Electron microscopy further revealed that axonal branches innervate the gland tissue. Nerve branches associated with pheromone gland cells are enwrapped in glia and contain dense-core vesicles, suggesting that the innervation of the gland might be neurosecretory. Finally, the biogenic monoamine octopamine was nearly as effective as purified Heliothis zea PBAN in stimulating pheromone biosynthesis when injected into intact females during mid-photophase. Furthermore, both octopamine and PBAN stimulated significant increases in the pheromone content of the glands in isolated abdomens lacking a ventral nerve cord but only when abdomens were treated at the onset of scotophase. These data suggest that the regulation of sex pheromone production in Heliothis is more complex than previously thought. Activation of the gland appears to be governed by both neural and hormonal mechanisms, and these control mechanisms depend on photoperiodic cues.

Various peptide immunoreactivities in the respiratory system have been reported, indicating complex physiological mechanisms. There is only little information on the upper respiratory system of man. The present study was carried out to demonstrate regulatory peptides in the nasal mucosa, larynx (vocal cords and ventricular folds) and soft palate of man using highly efficient immunocytochemical methods. In addition, some peptide immunoreactivities were measured by use of radioimmunoassay (RIA). Using indirect immunofluorescence and immunogold-silver staining (IGSS) with silver acetate autometallography, a series of peptides could be detected, including vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), galanin, calcitonin gene-related peptide (CGRP), substance P, neuropeptide tyrosine (NPY), C-flanking peptide of NPY (CPON) and somatostatin. In addition, antibodies to protein gene-product (PGP) 9.5, neuron-specific enolase (NSE), S-100, PHE-5 and neurofilament proteins gave positive reactions in tissue sections. Using RIA, CGRP, substance P, and neurokinin A were measured. Our results demonstrate a complex network of regulatory peptide-containing nerve fibers and the possible existence of endocrine cells regulating various functions of the upper respiratory system, which need to be further investigated.

Iontophoretic application of enkephalins induced inhibitory effects on unit activity of endocrine and adjacent neurones in the preoptic-septal region. Antagonism or lack of antagonism of these effects by naloxone indicated an action of enkephalins through different opiate receptors. Inhibitory effects of enkephalins were obtained during iontophoretic application of Mg2+, showing that these opioid peptides acted postsynaptically. Because enkephalin acts on endocrine neurones, these opioid peptides might be involved in the control of gonadotrophic hormone release by acting on cell bodies of LH-RH neurones.

This article discusses current experimental evidence indicating a role for prostaglandins (PGs) in pineal and median eminence neuroendocrine junctions. Both tissues release PGs, particularly of the E series, upon exposure to norepinephrine (NE) and through alpha-adrenoceptors. Exposure of pineal and median eminence explants to nanomolar concentrations of PGE2 augments melatonin and GnRH release, respectively. In the pineal gland, this effect appears to be linked to the stimulation of adenylate cyclase. Both in vivo and in vitro PG synthesis inhibitors impair the hormone release elicited by NE. In the pineal gland, PGE2 also constitutes a trans-synaptic negative signal for NE release. PGs receptors are present in pineal and hypothalamic membranes.

Data from the current literature are used to demonstrate the structural-functional relationship of endocrine and nervous apparatuses of the kidneys which must be taken into consideration in the analysis of clinical manifestations and pathogenesis of many diseases, first of all those of the kidneys. Therefore it is recommended that in examinations of kidney biopsies the state of the endocrine apparatuses and nervous system be evaluated which requires deep kidney biopsy and special methods of morphological analysis.

Neurosecretory cells and retrocerebral endocrine glands of Amsacta collaris Hampson have been studied by using PF and PARF techniques in whole mounts and sections. On the basis of staining properties, three principal types of cells viz., A, B and C-types have been distinguished, which have been further classified into A-1, A-2, A-3, A-4, B-1, B-2 and C-1, C-2 subtypes respectively. The cells are arranged in 12-groups i.e. 2-medial, 2-lateral, 2-optic, 2-posterior, 2-ventral and 2-tritocerebral. The material elaborated in the medial, lateral, ventral and posterior groups of cells is stored in the outer part of the corpus allatum and that of the optic and tritocerebral, is stored in the corpus cardiacum. In addition to brain, distinct neurosecretory cells have been observed in the frontal and hypocerebral ganglia, and in the latter case they have been reported here probably for the first time in Lepidoptera. The corpora cardiaca are a pair of club-shaped or stellate bodies lying behind the brain, with which they are attached by NCC-I and NCC-II. The corpora cardiaca are composed of only a few intrinsic cells. Some nerves arise from the corpus cardiacum and innervate the gut dialator muscles, recurrent nerve, aorta and the adjacent organs. The corpora allata are oval in shape, attached to the corpora cardiaca via allatic nerve. In larval stages, each corpus allatum is a single lobed body which becomes many lobed in late pupa and adult stages. The gland is superficially innervated by the neurosecretory axons of cerebral origin which contain a large amount of NSM. Thus the outer part of the gland acts as a principal neurohaemal organ. The inner part of the corpus allatum is devoid of NSM.

Ultrastructural aspects of hormone release from the sinus gland of the crab Carcinus maenas, have been studied by incubation of glands in vitro (i) in high potassium-containing media to induce hormone release; (ii) in a high potassium-containing calcium-free medium in which depolarisation but no hormone release would be expected; and (iii) in control saline. Uptake of horseradish peroxidase into subcellular organelles was also studied. Many neurosecretory granules could be found in the nerve terminals but, in contrast to mammalian neurosecretory systems, structures resembling microvesicles were extremely scarce. High potassium stimulation in the presence of calcium caused an 18% loss of granules from the nerve terminals associated with images of single and multiple exocytosis. It further caused an increase in vacuoles which could have accounted fro 33% of the membrane of the granules exocytosed. After incubation in high potassium-containing, calcium-free media there was no evidence either of exocytosis of granules or of an increase in the vacuole population. The population of sparse microvesicle-like structures was not significantly altered by incubation in either high potassium medium. Horseradish peroxidase reaction product could be found only in vacuoles of tissues stimulated by high potassium concentrations in the presence of calcium. It is concluded that this depolarising stimulus produces, in the presence of calcium, the release by exocytosis of about one sixth of all the granules in the sinus gland, and that vacuoles are the organelle responsible for the recapture of membrane after the exocytosis.

Lateral segmental organs and a peritracheal gland in adult and immature Argas (Persicargas) arboreus are described and compared with similar organs in other arthropods. Four pairs of lateral segmental organs containing neuronal cell bodies and innervated by branches of hemal nerves from pedal nerve roots are present in nymphal instars and in the adult; 3 pairs are present in the larva. In each postembryonic developmental stage, the peritracheal gland consists of cell masses with neurosecretory granular activity and is associated with the tracheal plexus in the region of the central nerve mass and adjacent hypodermis. The glandular cells show cyclic changes in size and activity related to the molting process in immature stages and probably to other events in the adult.

There is a pair of corpuscles of Stannius in the hillstream catfish, Glyptothorax pectinopterus. They are rounded or oval bodies visible to the naked eye, and situated ventrolaterally in the posterior mesonephros. Each CS is enclosed in a connective tissue capsule. Histologically, the CS have granulated secretory cells which stain positively with AF, PAS and CAH. They have oval or spherical nucleus with one or two nucleoli. Neural structures are present in the capsule as well as in the substance of the corpuscle.

Distribution of calcitonin gene-related peptide-like immunoreactive (CGRPI) nerve fibers and their fine structure were examined in the skin of rat foot pads using immunocytochemistry. The CGRPI fibers formed bundles in the dermis and subcutaneous tissue. Two types of single-stranded CGRPI fibers were seen to leave the fiber bundles: one was located along the blood vessels or around the eccrine sweat glands, while the other entered the epidermis directly or through the Meissner's corpuscles in the dermal papillae. CGRPI fibers in the epidermis were distributed widely and were occasionally associated with Merkel cells. Immunoelectron microscopic study revealed that CGRPI fibers located around blood vessels, sweat glands, epidermal keratinocytes and Merkel cells, or in the Meissner's corpuscles did not form typical synaptic contacts with underlying cells, despite being varicose and filled with vesicles resembling synaptic ones. These findings suggested that the CGRP is released non-synaptically from these terminals to influence diffusely the organs surrounding the terminals. These cutaneous fibers seemed to originate from CGRPI neurons (both small type B cells and large type A cells) in the dorsal root ganglia (DRG), because injection of fast blue dye into the cutaneous nerve resulted in labeling of these CGRPI cells in the DRG and excision of the L3-L6 DRG resulted in the non-detection of cutaneous CGRPI fibers in the foot pads. Analysis of the composition of CGRPI fibers found in the rat skin has revealed that these are mostly unmyelinated. C-type fibers with some of them being thin myelinated fibers. This was true even of CGRPI fibers at the proximal end of peripheral neurites of the DRG.(ABSTRACT TRUNCATED AT 250 WORDS)

The pancreatic islet is one of the well-studied endocrine tissues in regard to innervation. This neuro-insular complex has been known since the 1920's. The direct contact of the nervous element to the gastro-enteric endocrine cells has recently been reported in the proventricular mucosa of the finch. Here, the majority of the endocrine cells lie in the lamina propria and form a neuro-endocrine complex with unmyelinated nerve fibers. A similar neuro-endocrine complex was also reported in the rat stomach and in the duodenum of the human fetus. The occurrence of the neuro-endocrine complexes in the gastro-entero-pancreatic endocrine system might provide supportive data to the neuro-ectodermal theory on the origin of the endocrine cells proposed by Professors A. G. E. PEARSE and T. FUJITA.

A recently developed pharmacologic means for suppressing acquired immunity by drugs acting on neuroendocrine regulation has been applied to transplantation immune reactions. A number of drugs have been tested singly and in combination for their capacity to suppress the immune response of mice grafted with allogeneic skin. Another model involved newborn F1 hybrid recipients inoculated with spleen cells from donors of parental strains that had been made specifically "unresponsive" by drug and alloantigen treatment. These procedures led to the identification of a combination of four drugs that induced a remarkable delay in allograft rejection and a prolonged unresponsiveness to alloantigens. This combination of drugs also abrogated the graft-vs-host-runting syndrome in newborn hybrid recipients.

1. Optic glands transplanted from one Octopus vulgaris into another cause enlargement of the gonads and ducts of the recipient. 2. Enlargement occurs whether or not the gland was secreting when implanted and regardless of the sex of the donor or recipient. 3. Glands derived from Eledone moschata or Octopus macropus implanted into O. vulgaris are as effective as glands derived from O. vulgaris. 4. Implants derived from Sepia officinalis or Loligo vulgaris appear to be ineffective.

The innervation of the endocrine optic gland of Sepia, which controls sexual maturation, was studied by immunocytochemistry. Anti-FMRFamide (Phe-Met-Arg-Phe-NH2) serum revealed immunoreactive neurons in the olfactory and basal-dorsal lobe of the supra-esophageal brain mass. The axons of these neurons form a network from which fibers run to the optic gland. The fibers form many varicosities on the glandular cells, indicating synaptic innervation. Apparently, the two brain lobes containing the immunopositive cells function as a unit where visual and olfactory cues are integrated to regulate the endocrine activity of the optic gland.

Distances between neural, endocrinal and working cells in the gastric wall tissue do not exceed some hundreds nm, i. e. they are within limits of the physiological parameters for the effect of biologically active substances diffusely spreading along the interstitium. A structural scheme of the neurohormonal regulatory mechanism is suggested, basing on the author's data and those of the literature. Combination of producer-mediator-cells and target-cells united by the interstitial gap, along which biologically active substances are transported, serves as its base. Mast cells--mobile endocrinic glands--and neural terminals of various modality may serve as a source for changing the modulatory tonus in the given tissue area. The cells producing mediators (neural and endocrine) are, in their turn, target-cells for other biologically active substances getting into the interstitium. The whole structure can be compared with the synaptic system, where the membranes of the producer-mediator-cells serve as the presynaptic pole, while the membranes of the target-cells play the role of the postsynaptic pole. The interstitial gap performes the part of the synaptic gap. In this peculiar diffuse synapse, the membranes of neural and endocrine cells serve as pre- and postsynaptic membranes simultaneously.

Already at the beginning of this century a dualism of neural and endocrine regulation of the gastrointestinal tract was apparent. This dualism first characterized by I. P. Pavlov on the one side and W. M. Bayliss and E. H. Starling on the other has persisted in the present days. It is only recently that we begin to realize that neural and endocrine regulations represent no antipodes but a continuum. Neural, endocrine and paracrine transmission of chemical messengers form an integrated signal. This view is supperted by many peptides present both in nerves and endocrine cells and by neural regulation of endocrine hormone release. These interelationships are illustrated by experiments concerning the enkephalins, neurotensin and CCK. Concurrent with the evolution from bacteria to mammals the chemical messengers in the higher animals act in a complex organisation including neural, endocrine and paracrine mechanisms.