Biomedical Research 4 (3) 239-256, 1983

MESSENGER SUBSTANCES OF NEURONS AND PARA- NEURONS: THEIR CHEMICAL NATURE AND THE ROUTES AND RANGES OF THEIR TRANSPORT TO TARGETS

TSUNEO FUJITA Department of Anatomy, Niigata University School of Medicine, Asahimachi, Niigata 951, Japan

REVIEW

Neurons and paraneurons (/amine producing endocrine and sensory cells) share cell-biological features and chemistry of secretions. The bioactive substances or chemieal messengers secreted by neurons and paraneurons (, amines, acetylcholine, ATP, etc.) are conveyed to their targets which may be opposed only several nanometers apart or may be located at more or less remote sites in the body. The modes and ranges of the transport of different messengers from different neurons and paraneurons are reviewed. In order to visualize the gradational ranges of messenger transport, the following terms were defined: synaptocrinia, paracrinia, microhemocrinia (pericrinia), mesohemocrinia (meso- crinia) and macrohemocrinia (telecrinia). Transmitters and are thus continuous to each other both in their chemical nature and in the routes and ranges of their transport to the targets. This review further analyses the implications of the concept of internal secretion (endocrinia). The classical concept of endocrinia seems unable to account for the endocrine-exocrine partition of secretions (‘leakage’ of hormones into exocrine lumen and that of exocrine secretions into blood circulation) of which the mechanism remains to be elucidated in future studies.

HISTORICAL BACKGROUND contradiction, however, seems to have caused few substantial disputes on the nature of trans- Hormones and Transmirrers mitters and hormones, until numerous peptide- Until several years ago, it had been generally yet containing or ‘peptidergic’ neurons were recently vaguely understood that the chemical messengers discovered. The peptides contained in these produced and released (in a word, secreted) by neurons, , , vasoactive nerve cells or neurons are represented by trans- intestinal peptide (VIP), (CCK), mitters, and those secreted by endocrine cells are efc., obviously corresponded to hormones pro- hormones. Transmitters should traverse only duced by endocrine cells on one hand, and on the a very small distance (lO—100 nm) of an intercel- other, their ‘synaptic vesicles’ undistinguishably lular space to act upon a juxtaposed target cell resembled endocrine secretory granules. (15), whereas hormones are usually transferred Recent studies of gut hormones came to sug- by the circulatory system to remote targets (6). gest that they may be only partly transferred to An obvious contradiction to this categorization their remote targets by the circulation and mainly was the phenomenon that ‘neurohormones,’ such exert their actions upon vicinal targets in the as and , are produced by intestinal wall, including muscle cells, neurons ‘neurosecretory neurons’ and released into the and secretory cells. In the l970’s attention was circulation to be sent to remote targets (5). This gradually focused upon the role of gut hormones 240 T. FUJITA as locally acting messengers rather than as hor- elite cells which can and should be precisely dis- mones in the classical sense (36-38, 93). Actu- tinguished from other cells by their structure, ally it appeared that many of the peptidic and function, metabolism and origin. However, aminic hormones and their candidates found in each of these features of neurons was demon- the gut were so quickly inactivated after entering strated, in recent cell-biological studies, to be the circulation that they could exert very slight shared by many non-neuronal cells. Action effects on remote organs, if any at all (90). potential-like electric reaction was found to Diabetologists, on the other hand, came to con- occur in glucose-stimulated’ B cells of the pan- ceive the local or intra-insular actions of glucagon creas (14, 80) and several other endocrine cells and somatostatin on the secreting activ- (3, 9, 10, 113). The monoamine producing ities of B cells (28, 56, 91). ability was demonstrated by Pearse and associ- ates to be shared by many neurons and endocrine cells, which Pearse categorized as APUD series Feyrter’s Paracrinia (87-89). ‘Neurosecretory-like’ and/or ‘synaptic In 1953, Feyrter (24), a pathologist in Vienna vesicle-like’ granules correspond in structure to proposed the term, ‘Parakrinie’ (paracrinia) to the granules of peptide/amine-producing endo- indicate his hypothesis that ‘helle Zellen’ (clear crine cells and sensory cells. Based on this cells) which he found disseminated in the epithelia knowledge of the continuity of the endocrine of the digestive tract and airway (‘diffuse en- cells and sensory cells to the neurons, these non- dokrine epitheliale Organe’) (20-23), might send neuronal but neuron-like cells have been desig- their secretions to vicinally located targets. The nated as paraneurons (30, 31, 38). clear cells of Feyrter correspond to the endocrine The endocrine variation of neurons may be cells which at present are known to be the sources represented by classical neurosecretory neurons of a. large variety of peptidic and aminic mes- in the hypothalamo-hypophyseal system and sengers. Some recent researchers (36, 59, 90, other peptidergic neurons which are especially 93) noticed the usefulness of the Feyrter’s con- gathered densely in the but dis- cept of paracrinia in present-day disciplines, tributed widely in the central and peripheral especially in gastroenteric endocrinology. The nervous systems (101). Actually it has been term and concept of paracrinia have thus served criticized that the paraneuron family should in- the recognition of the short range transfer of clude the neurosecretory cells (47). We con- hormonal messengers. ceive that it is more reasonable and might cause Although the term paracrinia has become less confusion to scientists to leave the classical widely accepted, neither Feyrter nor recent advo- neurosecretory cells in the category of neurons, cators of his concept have defined the term pre- although they are located in cell-biological char- cisely. Apparently they have not been interested acters between neurons and paraneurons. As in determining the range and route of paracrine noted by B. Scharrer (100) already in 1969, the messengers. Feyrter himself seems to have used boundary between the ‘classical’ neurosecretory the term quite vaguely. On page 70 of his paper neurons and ‘ordinary’ neurons has become in- written in 1962, Feyrter (25) notes that paracrinia creasingly vague. A variety of ‘peptidergic’ is a ‘humorale Beeinflussung anliegender Zellen neurons (101) demonstrated in different parts of und Gewebe’ (humoral influence of closely op- the body and at different levels of evolution of posed cells and tissues) and includes, besides the animals accelerated to remove the boundary (72). transfer by diffusion, also that by such The cerebrospinal fluid-contacting neurons blood vessels as from the islet of Langerhans to seem to represent another category of cells locat- the exocrine pancreas and from the adrenal cor- ed at the boundary of neurons and paraneurons tex to medulla. and retaining primitive features of neurons (73, In a later section of this paper, we will define 119). As their homologues, pinealocytes in the the term, ‘paracrinia’ more precisely than pre- pineal body and visual cells in the retina (118, viously defined. Without such a definition, the 120) represent typical endocrine and sensory science of chemical messengers may encounter paraneurons, respectively. difficulty in advancing on a sound theoretical Olfactory cells have long been believed to be and experimental basis. typical neurons. As, however, evidence sup- ports their continuous renewal from the nasal epithelium (43), through an immature type of Neurons and Endocrine Ce//s Are Inseparoble basal-granulated cells (125), they are better cate- It has long been believed that neurons are special, gorized into the paraneuron (7, 38). NEURONS AND PARANEURONS 241

Numerous other instances can be counted neurons and paraneurons contain them, at least which indicate a non-neuronal nature of neurons in such a condensation as detectable by histo- or neuronal nature of endocrine or sensory cells. chemistry. There are different intermediate forms between More constant elements in the secretory neurons and paraneurons and no clear boundary granules of neurons and paraneurons are ATP can be drawn between them. This continuity in and other adenine nucleotides, large acidic car- cellular elements of the nervous and endocrine rier of glucoproteinic nature as well as systems obviously represents one of the pair of a high concentration of Ca“ (Table 2) (30, 32, wheels together with the continuity in chemistry 38). of messenger substances produced by both sys- Today’s knowledge on the chemical contents tems, which will now be dealt with. of neuronal and paraneuronal granules are based mainly on the advanced investigations of the SECRETIONS OF NEURONS AND chromaffin granules of the adrenal medulla. PARANEURONS These studies recently revealed that dopamine- ,3-hydroxylase (DBH), which is an important Secretions or Granule Contents of Neurons enzyme in chromaffin cells, is a kind of gluco- and Paraneurons proteins closely resembling, in molecular struc- Advances in chemical and immunohistochemical ture, the chromogranin A which has long been studies have made it clear that neurons in the known as an acidic carrier in the chro- central and peripheral nervous system share maffin granules (124). Chromaifin granules numerous bioactive peptides with the endocrine have been shown to contain also such strongly and sensory paraneurons, especially in the gut acidic mucopolysaccharides like haparan sulfide and pancreas (Table 1). The term, ‘brain-gut and chondroitin sulfate (77, 124). Highly nega- peptides’ has thus become useful. tively charged mucopolysaccharide resembling Morevoer, substances, other than peptides heparin has been demonstrated in cholinergic contained in the secretory granules (including the synaptic vesicles, representing the major con- synaptic vesicles) are believed to be common to stituent of vesiculin (108, 122). All these weakly neurons and paraneurons (30, 32, 38). The best and strongly acidic polysaccharides and gluco- known elements comprise bioactive monoamines proteins are believed to cause the metachromatic such as noradrenalin, adrenalin, dopamine, reactin of granules of neurons and paraneurons, serotonin (SHT) and occasionally histamine. after removal of the conjugated basic substances These amines may often serve as potent trans- by gentle hydrolysis of tissue sections with HCl mitters or hormones, although only a part of (107). These metachromatic substances have

Tablel Represem‘an've Bioactive Peptides in Neurons and Para- nenrons (‘Brain-Gut Peptides’) Based on the Know/edge Gathered in Human and Animals above Amp/n'br'a

Knownwonly Oxytocin, Vasopressin in NEURONS LHRH, GHRH, CRH Known to occur TRH both in NEURONS and PARANEU- ACTH, MSH, , RONS Somatostatin Substance P GIP (Gastric Inhibitory Peptide) VIP (Vasoactive Intestinal Peptide), PHI Glucagon/Glicentin, Insulin CCK (Cholecystokinin)/ GRP (Gastrin Releasing Peptide)/ PP (Pancreatic Peptide), NPY, PYY

Known only in Secretion PARANEURONS PTH (Parathormone) 242 T. FUJITA

Table 2 Secrerions (Granule Contents) of Neurons and Paraneurons Adrenal chromaffin Other endocrine and Small synaptic granules ‘peptidergic’ granules vesicles Polypeptides-peptides —l— ; e.g., pro-opioid- +; e.g., proinsulin- —? enkephafins insulin Somatostatin 28-14 Monoamines or + + (may be absent) + acetylcholine ATP and other nucleotides + + + . + ; chromogranins, Glucoprotems and DBH CO O1 + ; e.g., , + . mu p y- muco ol saccharides ’ - acidic glucoproteins p y saccharides Lipids + + ? Ca2+ + + + been demonstrated in a variety of neurons and Da/e’s Law Mus! Be Revised paraneurons, as far as they store a certain amount of secretory granules (34, 40, 63), Under the Dale’s law, it has long been believed whereas they are not recognized in other granule that one neuron produces and releases one containing cells like those of exocrine glands. transmitter. The theory in endocrinology cor- They must be important granule components of responding to the law of Dale reads that one neurons and paraneurons combining with basic cell secretes one hormone (one cell-one hormone substances including amines and peptides. theory). According to the recent knowledge The granules of neurons and paraneurons are introduced above, it is now apparent that these believed to contain also trypsin-like enzymes theories must be largely revised. involved in the processing of polypeptidic pre- The first reason for this revision is that it is hormones to final fragments. not a transmitter or hormone which corresponds The neuronal and paraneuronal granules con- to a neuron or an endocrine cell, but it is a set tain considerable amounts of lipids but the chem- of substances including a transmitter or hormone. ical and cytochemical studies are not advanced As detailed above, this set consists of peptides, (124). It seems possible that lipids are incor- amines or acetylcholine, ATP, glucoproteins and porated in glucoproteins to form glucolipopro- mucopolysaccharides, Ca“, etc. (30-32, 124). teins. The somewhat osmiophilic nature of the According to the cells, the bioactive substance granules of neurons and paraneurons under the comprises a peptide, amine or acetylcholine. light and electron microscopes seems primarily However, this means that the main bioactive due to the contents of lipids in the granules. agent is it. Different components of the sub- Although the chemical components of secre- stance set may possess bioactivity simultane- tory granules in different neurons and paraneu- ously. rons have not been demonstrated as precisely as Recent immunohistochemical studies indicate in the chromafiin granules, more and more data that ‘adrenergic’ or ‘cholinergic’ neurons may are being accumulated which suggest that every simultaneously be peptidergic. Sornatostatin neuron and paraneuron might contain essen- (55) or opioid peptides (123) have been demon- tially the same combination of substances in strated to be contained in mammalian peripheral their granule contents (30, 33, 124) (Table 2). noradrenergic nerves, whereas VIP in intestinal A possible exception seems to be represented cholinergic nerves (76, 102). It must be newly by small synaptic vesicles in so-called cholinergic investigated as to whether, for instance, VIP and adrenergic types of neurons. Recent chem- contained in the nerve concerned may be pre- ical studies suggest that they contain adenin dominant or subsidiary to the simultaneously nucleotides but neither peptides nor glucopro- contained acetylcholin in function. It is also a eins (60) (Table 2). These vesicles, differing problem to be settled as to whether peptides are from the ‘large cored vesicles’ (endocrine-like stored in ‘large cored vesicles’ (endocrine-like granules) usually mingling within them, are prob- granules) in the nerves, separately from amines ably formed at the terminal site of neurons and and acetylcholine which are contained in small their contents consist of reabsorbed secretions of synaptic vesicles. the neuron (60, 61). The endocrine-like paraneurons in the bron- NEURONS AND PARANEURONS 243

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chial epithelium contain simultaneously sero- in gastric G cell (65, 69, 94) and glucagon and tonin and gastrin releasing peptide (GRP) (110). GIP (2, 106), cholecystokinin (45) and/or oc- The serotonin containing EC cells in the gut are endorphin (46) seems to represent the instances believed to contain a , which in this category of peptide coexistence. In has not yet been identified (62). neurons, on the other hand, coexistence of two Not only peptidic and aminic substances, but peptides, such as oxytocin and cholecystokinin also ATP and other adenin nucleotides may in rat and bovine hypothalamus (116), en- exert their activities upon certain targets. It is kephalins together with oxytocin and vasopressin not only the Burnstock’s ‘purinergic’ neuron (12) in rat neurohypophysis (78), somatostatin and that releases adenin nucleotides but every neuron avian pancreatic peptide (APP) in rat and human and paraneuron secretes them and therefore can cerebral cortex (121), cholecystokinin and sub- be said to be more or less purinergic (32). stance P in rat dorsed root ganglia (13) and Studies have not advanced concerning the pos- mesencephalic neurons (105) occurs. sible functions of glucoproteins released from At any rate, it seems reasonable to postulate neurons and paraneurons, except for some un- that the coexistence of the same and different confirmed data on the activities of neurophysins categories of substances in the granule contents (97, 99, 115). of neurons and paraneurons might be accounted The second reason for the revision of the Dale’s for by the purposefulness of the simultaneous law and the one cell-one hormone theory is that release of these substances from the same cell by we may have increasing instances of two or more the same stimulus. In other words, it is pre- peptide hormones occurring in one and the same sumed that the set substances released from the neuron or paraneuron. There are two cate- same neuron or paraneuron will exert their gories in this phenomenon. One is that the ap- actions synergetically in a. broad sense, although parently different peptides are really fragments only little concrete evidence for this postulation produced by the procession of a single large is available at present. precursor molecule. As a typical example, MSH, ACTH, fi-endorphin, etc. in the same Re/ease of Secretions pituitary endocrine cells are the fragments of a large ACTH-B- precursor (82). In Electron microscope studies as well as physio- the second category of peptide coexistence, we logical experiments mostly support the view that could, at least at present, obtain son1e evidence the contents of their secretory granules (including for a common precursor. Simultaneous occur- synaptic vesicles) are extruded, at least in physio- rence of somatostatin and calcitonin in the logical states, by the Q-shaped opening of the parafollicular cell (117), gastrin and granule membrane to the plasma membrane of 244 T. FUJITA

Table 3 Gradations in the Routes and Ranges of C/tenu'cal Adessengers

Route Order of range Messenger 1. Synaptocrinia Intercellular diffusion 10-100 nm Synaptic messenger 2. Paracrinia Intercellular diffusion /.tm Parahormone 3. Microhemocrinia Microcirculations ,um—mm Perihormone :Pericrinia 4. Mesohemocrinia Intervisceral portal vessel cm Mesohormone 5. Macrohemocrinia General circulation cm-m Telehormone =Telecrinia

the cell. This mechanism of granule release, Typically, synaptocrinia is seen in neurotrans- called exocytosis, means that the set of the secre- mitters released by neurons into synapses. The tory substances above mentioned are liberated synaptic cleft usually is only 10-30 nm wide, but at the same time, and probably in a fairly con- a basement membrane may be intercalated, wid- stant quantitative ratio, from their membrane ening the cleft to about 60 nm, as in the case of package to the extracellular space (30, 38, 61, neuromuscular junctions (15). 124). Sensory paraneurons, such as olfactory, gusta- When a neuron or paraneuron is adequately tory and bronchial neuroepithelial cells as well stimulated, the stimulus-secretion coupling of the as Merkel cells in the skin, give their messengers cell is triggered and the exocytotic granule release to the juxtaposed afferent nerves by synap- results. By this mechanism, the secretions of tocrinia. the cell can be released in quanta, t'.e., package Endocrine paraneurons may occasionally ex- after package, according to the intensity of the hibit morphologic features suggesting synap- stimulus (38, 61) (Fig. 1). tocrinia. Somatostatin producing D cells in the fundic region of gastric mucosa may extend a slender process to contact with a parietal cell, ROUTES AND RANGES OF leaving only a synapse-like slit. The tip of the MESSENGERS process usually is swollen and filled with soma- Discussions in the previous sections provide us tostatin-immunoreactive granules (66-68). This with the basis upon which we can treat the secre- feature of D cells has been correlated to the tions of neurons and endocrine cells in common. known inhibitory effect of somatostatin upon From this basis, we will now turn to the routes acid secretion of the parietal cells (66-68). It is and ranges of bioactive missiles released from worthwhile to notice, however, that this inter- neurons and paraneurons. pretation could not be free of contradiction, as Missiles with the shortest range are repre- the parietal cells touched by a D cell process are sented by neurotransmitters which travel only limited to only a few percent of the whole 7-40 nm through the synaptic cleft to reach their parietal cells. Even if one admits a possibility target. Intercontinental bullistic missiles are that D cells might. busily move their processes hormones conveyed by the general circulation to touch different. parietal cells, only a small part through the body reaching remote targets. of parietal cells may be under the synaptocrine Every gradation exists between these extremities. control of the D cells. It seems reasonable to A large variety of intermediate and medium assume that somatostatin released by D cells range missiles can be found in different parts of affects the parietal cells partly by synaptocrinia the body and in different animals. The mode of and rather mainly by paracrinia, diffusion of a the transport of neuronal and paraneuronal mes- longer range. The same seems to hold true in sengers will be classified below according to the case of somatostatin cells extending a pro- their routes and ranges (Table 3, Fig. 2). cess in contact with gastrin producing G cells in the rat pyloric antrum (1). Direct contact of Synaptocrt'n1'a elongated processes of somatostatin producing D cells to exocrine cells in avian proventriculus When a messenger substance released from a cell (57) has been demonstrated. Similar synapto- runs by diffusion through an intercellular slit to crine figures of EC and some other cells have the surface of a juxtaposed target cell, this mode been also recorded (67). of messenger transfer may be called syna_ptocrt'tu'a'. It is presumed that synaptocrine as well as NEURONS AND PARANEURONS 245

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Fig. 2 Gradation in the rages of messenger transport. Note that neurons and paraneurons are equal with regard to their rela- tion to the target cell (T) and blood capillary (B). paracrine control or modulation of neighbor cells in recent studies, but nobody seems to intend to may be exerted also by other paraneurons, espe- define the concept precisely. Vaguely, it seems cially at those sites where different types of to be understood as indicating transfer of a paraneurons are gathered to form an endocrine chemical messenger through intercellular spaces organ. Gap junctions may serve the synchron- to vicinal targets, but its routes and ranges differ ous excitation of adjacent cells (86) but have conspicuously among authors. What we call nothing to do with the intercellular communica- synaptocrinia, e.g., D cell’s secretion upon its tion by chemical messengers, as these must be associated target cell (ride supra), has been called transferred, not through the plasma membrane paracrinia by Larsson (67, 68). Transfer of islet channels, but through an intercellular space to hormones to the exocrine pancreas by micro- exert their actions upon the receptors on the circulation has also been included in paracrinia free surface of the target cell. Recent experi- by Feyrter (25). ment supports that extracellular but not intracel- In this paper, it is proposed to use the term lular application of peptide hormones activates paracrinia in a more restricted range: Paracrinia the target cell (92). is transfer of a. chemical messenger to a vicinal target by fntercellzdar dtfi‘itst'0n. In neurons a ‘synapse a distance’ has long been Paracrt'nt'a known, in which the target is located some 200 As noted above, the concept and term of para- or even 400 nm apart from the neuronal terminal. crinia originated by Feyrter has become popular Some smooth muscle cells, for instance, have 246 T. FUJITA

been claimed to receive synapses a distance (74). by microcirculation may possibly be found in This category of ‘synapse’ falls in the range of different endocrine glands, but studies on this paracrinia (Fig. 2). Different endocrine para- viewpoint are very few if any. The characteris- neurons are suspected to be under a paracrine tic position of parafollicular cells disseminated control or modulation of nerves. Gut endo- in the thyroid follicles, for instance, must be con- crine cells, especially G cells (71) and EC cells sidered with regard to the possible actions of (37), may be found to approach nerve terminals, parafollicular cell secretions (somatostatin, cal- leaving a 200-300 nm distance. As if to corre- citonin and monoamines) upon the follicular spond to this finding, vagal effects upon gastrin cells either by paracrinia or by microhemocrinia, releasing G cells (8, 44, 79) and upon serotonin or by both. releasing EC cells (114) have been documented. In the villi and crypts of the intestine, blood capillaries are extended unusually long along the epithelium in which endocrine cells are dis- Mict'0/tettt0ct'iitia or Pert'crt'nt'a persed. These capillaries may presumably be In this category of messenger transport, a chem- involved in the transportation of gut hormones to ical messenger enters blood capillaries and, after other parts of the villus or crypt to exert secre- being carried by them for a certain distance may tory, contractile and possibly also trophic effects emerge from them to affect extravascularly upon different elements of these structures. located targets (Fig. 3). Recent. studies suggest that the capillaries in the In pancreatic islets, the possibility has been walls of intestinal crypts, where the endocrine discussed‘ that glucagon from A cells and so- cells are most numerous, send their blood‘ up to matostatin from D cells might be transferred by the capillaries in the base of the villi (42, 83, 85). microcirculation to B cells whose insulin secre- An advanced type of microhemocrinia is the tion is stimulated by glucagon and suppressed by transport of a. messenger by small portal vessels. somatostatin. This view is supported by the The messenger enters blood capillaries which morphological findings that blood capillaries in form the first vascular bed, then is transferred islet in different animals are so designed that via small portal vessels, which usually are also blood flows from the A and D cell areas to the capillaries in histological structure, to a second B cell area (29, 39, 41). vascular bed located not so far but at a distinctly Similar instances of hormone transportation different site, either within the same organ or in

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Fig. 4 Microcirculation of the mammalian pancreas. Note the insuloacinar portal vessels (P) radiating from the islet of Langerhans (L) to the exocrine capillary bed. A: intralobular artery, V: vein

an adjacent organ (53, 85). The well known in- physical information of the flowing bile might stance of this category of microhemocrinia is the exert a kind of feedback control upon the hepatic hypophyseal portal system conveying hypothala- lobule (31). Substance P has been reported to mic neurohormones (releasing and release-inhib- be contained in endocrine cells in the bile iting hormones) to the adenohypophysis. ductules (50, 51) and this peptide is furthermore In the pancreas insuloacinar portal vessels known to increase the sinusoidal blood flow in (Fig. 4) convey hormones and neurosubstances the liver (18). issued into the capillaries in the islet to the Further possible small portal vessels transport- exocrine pancreas to control its secretory activ- ing messenger substances have been and are ities (29, 39,41, 52, 54, 84). Electron micro- being searched. Attention has been focused to scopic and immunohistochemical observations an antrofundic portal system which might con- in some mammals suggest. that VIP, acetyl- vey gastrin released in the pyloric antrum to the choline, noradrenalin and presumably also gastric body which contains the HCl secreting dopamine, besides islet cell hormones, are parietal cells, the targets of gastrin. This portal released into the portal vessels and the secreta- system has been postulated because it seems gogous actions of these neurosubstances have very unpurposeful for gastrin to be transported been analyzed (35, 39). by the general circulation back to the closely In the liver, another example of microhemo- located gastric body (48, 112). Although some crinia may be seen in the periductular portal experiments pursuing the radioactive tracer in- vessels which originate from the capillary plexus jected in the rat antrum supported the existence surrounding the hepatic ductules and pour into of the portal system (112), no morphological the lobular sinusoids (81, 85) and presumably studies convincingly demonstrating it are avail- convey hormones issued from the endocrine able. cells in the ductular epithelium. It is an attrac- An enteropancreatic portal system, which tive hypothesis that these hormones released could account for the enteropancreatic and from the cells in reponse to the chemical or enteroinsular axis (48), was shown not to exist 248 T. FUJITA

(98). cerebrospinal fluid taken from the cerebral Whichever fact or dream might it be, attempts ventricles (95, 100). Histological observations to hypothesise or discover a new microcircular are available on the bulbous endings containing route for transport of a given hormone to a peptidergic, adrenergic or cholinergic vesicles vicinal target seem worthwhile and promising. and protruding into the ventricular space (100). Beaded axons have been recognized running on the surface of the ependymal lining (103). More- Meso/tet1toct'ittict or Mesocrt'nt'a over, dendrites of liquor contacting neurons, Transportation of neuronal and paraneuronal which are numerous in the hypothalamus of messengers by a larger portal system may be lower vertebrates, apparently release their neuro- called mesohemocrinia, or simply mesocrinia, as substances into the third ventricle (ride tnfia) it has an intermediate range between the above (73, 126). described small portal systems and the general The messenger substances released into the circulation. In mammals the only representa- cerebrospinal fluid are believed to exert a variety tive of the vascular route of this range is the of their actions upon different systems in the hepatic portal vein. The gastro-enteropan- brain without being hindered by the blood‘-brain creatic (GEP) neuroendocrine secretions-- barrier. One can mimic these actions by a large variety of peptidic, aminic and other injecting a known peptide or amine into the categories of bioactive substances—are conveyed human and animal cerebral ventricle. by this vein to the liver. Here the hormones The term, ventriculocrinia is proposed in this exert known and unknown effects on hepato- article as referring to the release of any mes- cytes, ductular cells and possibly other elements senger substances into the cerebrospinal fluid. in the liver. The best known among them may The Latin word ‘ventriculus’ does not fit the be the glycogenolytic and glycogenetic actions by Greek ‘crinia’, but the same awkward terminol- insulin and glucagon, respectively, upon the ogy is generally admitted in the case of cerebral hepatocytes, as well as ’s secretagogous ventricle, like ‘ventriculography’. In his recent effect on the water and bicarbonate release from classification of messengers, Epple (16) calls mes- the bile ductules in the liver (17). The effect of senger substances released into the cerebrospinal substance P enhancing the sinusoidal blood flow fluid, ‘CSF hormones’. (vtde sup:'a) must also be taken into account. Lymph0crt'nt'a It is possible that some chem- Furthermore, recent studies indicate that some ical messengers may be transferred by lymphat- GEP hormones, especially insulin and glucagon, ics, although studies on this problem seem very have trophic effects upon the liver parechyme meager. The thyroid contains a well developed (11, 49, 109). lymphatics in its lobules, which are believed to serve, though to a small part, the transport of thyroid hormones (64, 104). In neuroendocrine Macrohemocr1'nta or Te/ecrtnia tissues, lymphatics seem less important in the This is the classically known endocrinia via transport of the messenger substances, because general circulation. Some messengers have the lymph capillaries are usually distributed long half lives and circulate many times through much farther from the mucosa] epithelium con- the body, whereas others are inactivated or taining the secretory elements than blood capil- absorbed so quickly that they hardly round the laries are. body once. Not only the classical neurohor- Lymphocrinia, at any rate, may be included mones vasopressin and oxytocin, but also some in telecrinia and macrohemocrinia, as the sub- new , especially VIP, have been stances which have entered lymphatics must be known to be released amply into the circulation recovered into the blood circulation in order to after the nerves containing them are stimulated reach their targets. (19). The possible actions of these neurosub- Notes on Terminology Literature indicates stances by micro-, meso- or macrohemocrinia that some of the term proposed in this article seem an important task of the future study. had already been suggested by previous authors. ‘Hamokrinie’ was used by Feyrter (25) which is, in contrast to Parakrinie, hormone transfer to Other Routes remote targets by blood stream. The term Vetttt't'ctdocrt'm'a Numerous kinds of neu- ‘telecrinia’ had been proposed by Leibson (72) in ronal peptides and amines have been found to be his classification of messengers and their ranges contained in considerable concentrations in the which corresponds in principle to that proposed NEURONS AND PARANEURONS 249

Table 4 Classification of the Modes of Secretion or ‘External Secretion I T ENDOCRINIA or Internal Secretion in broad sense 1. Synaptocrinia 2. Paracrinia 3. Microhemocrinia (Pericrinia) Endocrinia in 4. Mesohemocrinia (Mesocrinia) narrow (classical) 5. Macrohemocrinia (Telecrinia) $61186 6. Ventriculocrinia Lymphocrinia, etc.

in this paper. reasons are as follows: Leibson (72) suggests terms of ‘parahormones’ 1) Endocrinia in the second sense (macro- and ‘telehormones’ for hormones and neuro- hemocrinia as designated in this paper) cannot hormones conveyed by paracrinia and telecrinia, include paracrinia and synaptocrinia, the phe- respectively. These terms seem very useful and nomena which are continuous to and not dis- are adopted in this paper (Table 3). Epple uses criminable from macrohemocrinia. also these terms in his recent review (16). It is 2) In lower animals without a circulatory sys- worthy of note that Karlson (59) recently pro- tem, ‘humoral’ or ‘hormonal’ agents are trans- posed the term of paramone instead of para- ferred to their targets by paracrinia; if we use hormone. This term sounds not logical because the second definition of endocrinia, they must ‘mone’ has no sense, but this seems not an be said to have no endocrine system or activity. enough reason to refuse this term as we have Yet it has been recently demonstrated that those long accepted the term pheromone. Messengers agents are common or similar in molecular struc- transferred by microhemocrinia (microcircula- ture to typical hormones in higher animals in- tion) may be called perihormones and those cluding mammals. by mesohemocrinia (via an intervisceral portal In consideration of these contradictions, a vessel), mesohormones (Table 3). reasonable and clear classification of the phe- nomena of secretion seems to be sought in the ENDOCRINIA AND EXOCRINIA first definition of endocrinia. Endocrinia, then, can be simply opposed against ‘exocrinia’ and Concept of Endocrt'nt'a includes not only paracrinia. but also synapto- Confusion is prevailing concerning the definition crinia (Table 4). This newly proposed concept of internal secretion or endocrinia. The first of endocrinia seems important to smoothly co- view is that the ‘internal’ or ‘endo-’ should be ordinate the new knowledge of the continuity of simply contrasted against the ‘external’ or ‘exo-’. transmitters and hormones. However, the I—Iistorically, the direction of secretion was con- second classical definition of endocrinia may be sidered‘ at the level of the organ, as to whether worthwhile to be retained as ‘endocrinia in its the gland is provided with an excretory duct or narrow sense’. The new system of secretion is ducts, or is ‘ductless’. However, in the present- diagrammatically shown in Table 4. day doctrine, the problem should be discussed at the cellular level. Endocrinia must be under- stood as secretion not towards the apical or Exocrine and Endocrine Polarity of Cell luminal pole of the cell but towards the basal or In the new system of secretory phenomena the connective tissue side of the cell. cell polarity is of essential importance, as to The second view is that endocrinia should be whether the secretions are released to the external the secretion into the blood circulation. By this milieu (or its continuation or modification) or to route the secreted substances, hormones, should the internal milieu. This system, theoretically, be transferred to remote targets in the body. appears complete and undisputable. In reality, Although both views seem faithful interpreta- however, there is a problem which might con- tions of Claude Bernard’s idea of secretion in- flict with this system: the possibility has been terne, it is apparent that the second view has repeatedly suggested or, at least partly, even evi- more difliculties to coordinate the recent. en- denced that exocrine glands send a part of their docrinological findings and concepts. The main secretions into the circulation and endocrine tis- 250 T. FUJITA sues release a part of their secretions into the The above discussion makes the view likely lumen or external milieu. that, in both neurons and paraneurons, a phe- As widely known, small portions of amylase, nomenon to be called ‘exocrine-endocrine parti- trypsinogen and other enzymes secreted by the tion’ might possibly be taking place, and mor- exocrine pancreas enter the blood circulation. phological and physiological analysis of its Pancreatic hormones, i.e., insulin, glucagon and mechanism seems of keen importance in future somastatin have been reported to be included in investigation. the pancreatic juice (4, 70, 96). Gastrin is released into the gut lumen in more or less Receivedfor publication 2 Mttjt 1983 significant amounts (26, 58). Without morphological or physiological find- REFERENCES ings convincingly supporting the view, these 1. ALUMETs J., EKELUND M., EL MUNSHID H. A., phenomena have often been explained as ‘leak- HAKANSON R., LonéN I. and SUNDLER F. 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