Endocrinology Neuroendocrinology Neuropeptides: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980

Advances in Physiological Sciences, Volume 14: Endocrinology, Neuroendocrinology, Neuropeptides, Part II focuses on the research on neuropeptides, endocrinology, and neuroendocrinology. Composed of various contributions of able researchers, the first part of the book is divided into eight chapters. These chapters cover studies on the physiology, biochemistry, and localization of suspected hypothalamic releasing and inhibiting hormones. Researchers show how hormones react in different controlled environments. The second part of the selection deals with the use of in vitro systems in studying neuroendocrine regulation and steroid hormone action. This part is composed of four chapters wherein the extensive discussion of the processes involved is supported by experiments conducted on animals. The third part of the book covers the use of neurotransmitters in the control of anterior pituitary function. Composed of nine chapters, this part offers a thorough investigation of how neurotransmitters function in different controlled conditions. The fourth part of the selection, which is comprised of eight chapters, focuses on the function of neuropeptides as neurotransmitters. Studies are presented to elaborate the processes how neuropeptides can be converted to act as neurotransmitters. The last part, which covers nine chapters, deals exclusively with research on the effects of endogenous opioid peptides on the neuroendocrine system. The book is a great find for those interested in biochemistry.

• Language: English
• Publisher: Elsevier Science
• Release date: Oct 22, 2013
• ISBN: 9781483155982

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HYPOTHALAMIC NEUROHORMONAL MECHANISMS OF ADAPTATION

A.L. Polenov,     Sechenov Institute of Evolutionary Physiology and Biochemistry of the Academy of Sciences of the USSR, Leningrad, USSR

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This chapter discusses the role of neuro-endocrine hypothalamic elements in the adaptive reactions of the organism. It is well known that most important integrative and regulatory centers that control vegetative functions and reproduction are located in the hypothalamus. These centers are composed of two main elements of the nervous tissue: (1) conventional neurons and (2) neuro-secretory cells (NSC). The former are inter-neurons in a rather complicated chain of the neuro-endocrine reflex arc and the latter, that is, the NSC, function as effecter elements of this arc, exerting their influence by the neuro-hormonal way. One of the most important functions of the hypothalamic neurosecretory centers is to control adaptive and defensive reactions. Three morpho-functional systems govern this regulation: (1) the hypothalamo-anterohypophysial (HAHS), (2) the hypothalamo-metabypophysial (HMHS), and (3) the hypothalamo-posthypophysial. The HAHS consists of the Gomori-positive peptidergic and monoaminergic NSC, whose axons contact the portal capillaries in the median eminence. The HMHS is formed by the Gomori-positive peptidergic and monoaminergic NSC.

Our position with respect to the role of neuroendocrine hypothalamic elements in the adaptive reactions of the organism is discussed in the present paper. Our concept is based on our own findings as well as on data obtained by other investigators. It is well known that most important integrative and regulatory centers which control vegetative functions and reproduction are located in the hypothalamus. These centers are composed of two main elements of the nervous tissue:(i) conventional neurons and (ii) neurosecretory cells (NSC). The former are interneurons in a rather complicated chain of the neuroendocrine reflex arc, and the latter, i.e. the NSC, function as effector elements of this arc, exerting their influence by the neurohormonal way (see Scharrer and Scharrer, 1963; Gabe, 1966; Voitkevich, 1967; Polenov, 1968, 1978, 1979).

One of the most important functions of the hypothalamic neurosecretory centers is to control adaptive and defensive reactions. Three morpho-functional systems (Fig. 1) govern this regulation: (i)the hypothalamo-anterohypophysial (HAHS), (ii)the hypothalamo-metabypophysial (HMHS) and (iii) the hypothalamo-posthypophysial (HESS). The HAHS consists of the Gomori-positive peptidergic and monoaminergic NSC, whose axons contact the portal capillaries in the median eminence (ME). The HMHS is formed by the Gomori-positive peptidergic and monoaminergic NSC. The axons of these NSC terminate on the cells of the intermediate lobe of the hypophysis which are known to produce MSH and ACTH. The HPHS contains only the Gomori-positive peptidergic NSC. Their axons end on the capillaries of the general circulation in the posterior pituitary (PP).

Fig. 1 ;serotoninergicˆ.…;? hypothetical projections of monoaminergic fibers. Optic chiasm (1), N. supraopticus (2). suprachiasmatic additional group of NSC (3). anterocommissural additional group of NSC (4), N. paraventricularis (5), N. postopticus (6), N. arcuatus (7), N. periventricularis (8), N. ventromedialis (9), median eminence (10), portal capillaries (11). pars posterior (12), capillaries of general circulation (13) pars tuberalis (14), pars distalis (15), pars intermedia (16), N. raphe dorsalis (17). substantia nigra (18). pons, medulla oblongata (19), extrahypothalamic peptidergic pathways (20).

According to the concept of dual neurohormonal control (Polenov, 1978, 1979), the regulation of adaptive reactions is carried out "by interaction of peptide and monoamine neurohormones (NH). Peptide NH are produced by the Gomori-positive NSC of the supraoptic, post optic and paraventricular nuclei as well as by those in numerous additional groups of the NSC in Mammalia and in the homologous hypothalamic structure of Submammalia. These NSC produce, according to our terminology, viscerotropic NH (oxytocin and vasopressin In Mammalia) or their homologues (in Submammalia) and adenohypophysiotropic NH (corticoliberin, melanoliberin and melanostatin) (Naik, 1972; Calas, 1976; Vandesande et al.; 1977; Terlou et al. 1978; Krisch, 1979). It looks likely that the last three NH are active fragments of oxytocin or vasopressin (Celis et al., 1971; Blech, 1978). Corticoliberin is supposed to be produced by the NSC of the anterocommissural group of the NSC (Fig. 1). In adrenalectomized rats with deafferented mediobasal hypothalamus the NSC of this group accumulate considerable amount of Gomori-positive neurosecretory material (NSM) (Danilova, 1978). Monoamine NH (dopamine, noradrenalin and serotonin) are produced by the NSC of the arcuate, periventricular and ventromedial nuclei in Mammalia (Fig. 1) and by those of their homologues in Submammalia, In this case all the above substances act rather as NH than as neurotransmitters (see Konstantinova. 1978; Polenov et al., 1980). There are evidences that in the external ME some of the terminals of noradrenergic and serotoninergic fibres are of extrahypothalamic origin (Fig. 1) and their cell bodies are found within the mesencephalon and medulla oblongata (see Polenov et al., 1980).

Corticoliberin and/or vasopressin and possibly monoamines elaborated within the HAHS regulate the synthesis and secretion of ACTH via the portal circulation (Konstantinova and Danilova, 1975; Gross et al,. 1976; Drozdovich and Budavtsev, 1979). The HMHS regulates the synthesis and secretion of MSH and ACTH with the help of dopamine produced by the NSC of the arcuate nucleus and by the peptide NH (melanoliberin and melanostatin and/or vasopressin), both being discharged into the intercellular clefts of the intermediate lobe. Hence, NH discharged by the HAHS an a HMHS are involved in the adaptive reactions of the organism exerting regulatory actions upon target organs through adenohypophysial tropic hormones (ACTH and MSH, i.e. via the transadenohypophysial pathway (Fig. 2).

Fig. 2 General principle of dual neuroendocrine control of visceral organ functions and possible ways of neuroconductive regulation of functions of neurosecretory and chromaffin cells (neuroendocrine reflex arc). Peptidergic Gomori-positive NSC (1). peptidergic Gomori-negative NSC (2), monoaminergic NSC (3), median eminence with fiber terminals of Gomori-positive and Gomori-negative peptidergic and monoaminergic NSC (4), PP with terminals of peptidergic Gomori-positive fiber (5), terminals of peptidergic and adrenergic fibers in intermed. lobe (6) and in tuberal part (7), distal part (8), double arrow showing influence of peptide adenohypophysiotropic neurohormones and monoamines on anterior pituitary via portal bloodstream (9), optic chiasm(10), exteroceptor (retina) (11), afferent pathway from retina (12), interneuron of optic pathway in corpora quadrigemina (13), pathway from optic center to monoaminergic centers of brain stem (14), monoaminergic neurons of brain stem (15), adrenergic pathways to hypothalamic NSC of various types (16), monoaminergic pathways to interneurons of hypothalamus (17), neurons of medial hypothalamus (for example, dorsomedial nucleus (l8), neuron of anterior hypothalamus (for instance, suprachiasmatic nucleus)(19), pathways to various types of NSC and hypothalamic neurons from suprahypothalamic areas of brain (for instance from limbic system) (20), neurons of brain stem projecting to vegetative centers of spinal cord (21), vegetative preganglionic neuron of spinal cord (22), vegetative postganglionic neuron that innervates adrenal medulla (23), chromaffin cell (24), interoceptor (25), afferent neuron of spinal ganglion (26), interneuron of afferent pathway from spinal cord (27), pathway of viscerotropic neurohormones from PP via general circulation - paraadenohypophysial pathway of peptide neurohormones (black arrow) (28), influence of tropic hormones of anterior pituitary (light arrow) (29) on: thyroid gland (TSH)(30), adrenal cortex (ACTH; (31), Langerhans islets (STH) (32), ovary (FSH, LH, LTH) (33), entry of catecholamines of suprarenal gland into general circulation (stippled arrow) (34); main vessel of general circulation (35), influence of viscerotropic peptide and catecholamine neurohormones on visceral organs (double arrow) (36), blood vessel (37), kidney (for example, effect of ADH) (38), uterus (39), and different peripheral endocrine glands: solid lines indicate well known interneuronal pathways, cross hatched: hypothetical pathways, small arrows show direction of nerve impulse.

The question arises as to what the significance of the HIHS in adaptive and defensive reactions is. It is well known that both vasopressin and oxytocin and their homologues are released from the PP in large amounts into the general circulation in stress conditions. In addition to conventional effects such as retaining water and salt and pressor activity, these NH exert inhibitory effects on gastrointestinal secretion and motility and some metabolic processes as well. As a matter of fact we take all these activities as necessary in these situations (Bogach, 1974; Bently, 1976; George, 1977; Hems, 1977; Konstantinova and Natochin, 1979; Abelson, 1980). For this reason octopeptides of the HPHS should be regarded as adaptive NH together with catecholamines produced by chromaffin cells of the adrenal medulla and paraganglia (peripheral neuroendocrine system). It is well established that in stressful situations a large amount of noradrenalin and adrenalin enters the general circulation from the chromaffin adrenal cells. Thus, account must be taken of the fact that in stress peptide viscerotropic NH as well as catecholamine NH enter the general circulation synchronously and exert their combined influence upon the same tissues and target organs. Some authors have shown similar effects of noradrenalin and adrenalin (the latter more frequently) on one hand, and vasopressin and oxytocin on the other, upon the function of visceral organs (see Ginetsinsky, 1963; Bogach, 1974; Bently, 1976; Polenov, 1978, 1979). Bartelstone and Nasmyth (1965) reported vasopressin to potentiate a pressor effect of catecholamines upon the blood vessels in bleeding. These data suggest possible interaction between hypothalamic peptide NH and catecholamines of the chromaffin tissue on the cellular level of the visceral organs including peripheral endocrine glands (Fig. 2). Viscerotropic NH discharged from the HPHS exert their influence upon these organs via the so-called paraadenohypophysial pathway which is of special importance in stress situations (Polenov, 1968, 1978, 1979). Consequently, the functions of the visceral organs as well as those of the pars distalis and the pars intermedia are controlled both by peptide and monoamine neurohormones -dual control (Polenov, 1978, 1979).

The HPHS differentiates and begins to function prior to the HMHS, and particularly the HAHS (see Polenov and Belenky, 1973; Polenov, 1978, 1979). In this connection, it is reasonable to assume that the paraadenohypophysial way of influence of viscerotropic NH upon target organs, and peripheral endocrine glands in particular, is phylogenetically older than the transadenohypophysial way of influence, exerted by adenohypophysiotropic peptide NH. This assumption is supported by the evidence that the peripheral endocrine glands in vertebrates differentiate and begin to function at the earlier ontogenic stages than the adenohypophysis (Jost, 1966; Mitskevich, 1974; Levina, 1976; see Polenov, 1978, 1979). This phenomenon is especially prominent in lower vertebrates (Yakovleva, 1949; Barannikova, 1974), It is also a common knowledge (Scharrer and Scharrear, 1963) that In the course of evolution of almost each type of Protostomia and Deuterstomia, neuroendocrine elements and systems which regulate both visceral functions and reproduction appeared in more ancient groups (Fig, 3). Later, in phylogenetically younger groups, peripheral endocrine glands were formed, and at the last stage central endocrine glands were developed (y-organ in Crustacea, corpora allata in Insecta, subneural gland in Tunicata and adenohypophysis in Craniata).

Fig. 3 Evolution of neuroendocrine reflex and general principle of neuroendocrine regulation (modified diagram of E. and B. Scharrer, 1963). Receptor-secretory cell (1), receptor cell (2), NSC (3), neurohaemal organ (4), neurons of analyzing centers (5); solid dots: phylogenetically ancient direct pathways of neurohormonal influence on target organs (6), light circles: indirect pathways of neurohormonal influence via peripheral endocrine glands (7) and encircled small dots: indirect pathways of neurohormonal influence via central endocrine glands (8), light ovals: direct pathways of hormonal influence of central endocrine glands.

Under stressful conditions all immorally functioning defensive mechanisms of the organism are mobilized. The humoral regulation is phylogenetically very ancient. Moreover, we regard stress as a situation close to a pathological state. According to Orbeli’s conception (1959), it is in the pathological situation when phylogenetically more ancient mechanisms come forth. Hence it becomes clear why the paraadenohypophysial pathway (via the HPHS), phylogenetically older, goes into action under strong and relatively prolonged stress and under pathological conditions. Thus it might be supposed that in critical accidental situations the phylogenetically older mechanism functioning via the HPHS insures by its readiness the phylogenetically younger HAHS mechanism. Peptide viscerotropic NH in large quantities seem to render an inhibitory influence on the function of some organs and tissues in order to save defensive potentials of the organism and exclude the functions unnecessary in stress situations. Small amounts of the NH are supposed to have a stimulatory effect on some organs.

Data in favour of these assumptions are rather scarce, fragmentary and contradictory. However, some of the observations are noteworthy. So under stress conditions, e.g. in the case of dehydration, when a large quantity of NH is discharged from the PP, or after administration of exogeneous NH (presumably in mammals), inhibition of the thyroid activity (Polenov, 1968, 1975) and of lipolysis in adipose tissue (Itoh, 1968; Mirsky, 1968; George, 1977) is observed. In addition, as it has been already mentioned, administration of vasopressin and oxytocin produces gastrointestinal secretory and motor inhibition. A dose dependent effect of the NH has been shown in salmon fry (McKeown et al., 1976). When coho salmon fry, Oncorhynchus kisutch, are injected intraperitoneally (15 mU AVT per fish), a significant increase in plasma free fatty acid (FPA) level at 30 min post-inject ion is seen whereas a much higher dose (150 mU AVT per fish) has the opposite effect.

When studying stress mechanisms, much attention is usually given to the functions of the HAHS, i.e. the hypothalamus-ACTH cells-adrenal cortex axis. The interrelations between the two latter parts in the chain have been studied in detail. The role of the HMHS and the HPHS in stress reactions has received less attention so far. For about 20 years the HJHS in the overstrained organism was of special concern in our comparative and histophysiological studies. A complex of morphometric methods on light and electron microscopic levels was used. Stress conditions were induced due to various factors: (i) stimuli acting mainly via exteroceptors (light, temperature, sound, pain, emotions), (ii) stimuli acting via interoceptors (penetrating radiation, toxic substances, administration of exogenous hormones, immunization, hypoxia, etc.), (iii) combination of influences via both kinds of receptors. Each of these factors is known to disturb water-salt, hormonal or other kinds of homeostasis. Ecologo-histophysiological investigations on animals in their natural habitat have shown activation of the HPHS at certain stages of their life cycle. Our studies carried out on species from almost all classes of vertebrates, including man, at different stages of ontogeny, predominantly adult, gave us good reasons to draw some conclusions as the result of these works (Krasnovskaya, 1974; Polenov and Krasnovskaya, 1974).

Under extreme conditions in vertebrates belonging to any level of organization the reaction of the HPHS as well as the HAHS and the HMHS to stress depends upon intensity and duration of stimuli and upon the state of the hypothalamic NSC at the moment. The latter, in turn, depends upon the stage of the life cycle (stage of ontogeny, in particular), ecology and genotype (Zhchukin, 1973) of the animal. So, the active state of the HPHS becomes progressively more active due to the influence of a relatively strong stimulus. This may lead to exhaustion and death of the animal. The characteristics of the stimulus are of much importance also. The analysis of changes in the functional state, first of the HPHS. especially of its most reactive neurohemal part - the PP - and analysis of changes in the state of the organism, dependent on strength and duration of the stimulating agent allowed us to differentiate tentatively six main types of reactions in the HPHS (see Fig. 4) caused by:

Fig. 4 Diagram illustrating correlation between amount of NSM in the posterior pituitary (intensity of discharge of NH into general circulation) and strength and duration of stimulating factors. Ordinate – amount of NSM, abscissa – duration of stimulating factors; — control level of NSM; amount of NSM in stress; strength of stimulating factor is shown by thickness of arrows; * – death. Stages and phases of reaction: A –alarm, R – resistence, E – exhaustion, D –deep depression, a –primary response, b – secondary response, c – primary adaptation, d – stable adaptation.

1. Moderate and of short duration (minutes-hours, Fig. 4, 1 a) or weak but lasting stimulation (days-months. Fig.4, 1 b). It leads to a short or prolonged moderate activation of the HPHS, respectively. This is evidenced by moderate hypertrophy of the NSC, some decrease in the amount of the neurosecretory material (NSM) and moderate hyperemia in all parts of the HPHS. These morphological changes are indirect indication of a moderate discharge of NH contained in NSM into the general circulation. This state may be observed, for instance, in the laboratory animals being prepared for an experiment, and more frequently in the animals in their natural habitat in summer months due to the influence of some ecological factors, e.g. rise of environmental temperature (Altufyev, 1977). This state is also characteristic of fish during upstream migration to spawning grounds (Barannikova, 1975; Polenov, 1975), and of downstream migrating fry when they reach the sea (Lagunova, 1977), as well as of animals during long-term periods of their life cycle, such as reproduction, moult, oviposition and lactation (see Scharrer and Scharrer, 1963; Gabe, 1966; Voitkevich, 1967; Polenov, 1968, 1975; George, 1977). (Fig. 5a).

Fig.5 Amount of neurosecretory material (arbitrary units) in neurohypophysis of Acipenser ruthenus and Acipenser güldenstädti: A –different seasons (A. ruthenus) B – different stages of gonadal maturity in May and June (A. ruthenus), C – different stages of gonadal maturity in May–July in sea and river during upstream migration (IV sgm), soon (VI sgm) and six weeks (VI–II sgm) after spawning (A, güldenstädti). Number of fishes – inside columns.

2. Strong and of short duration (hours, Fig. 4, II a) or moderate and lasting stimulation (days, Fig. 4, II b). The reaction to this type of stimulus is considered to be a typical stress (Seley, 1960). Two stages, alarm and resistence, are distinctly observed. Changes in the HPHS are similar to those due to type 1 stimulation. However, they are more pronounced and a drastic decrease in the content of NSM is detected in the PP (release of a large amount of NH). The animals survive and a complete recovery of the HPHS occurs after the stimulus is removed. This state is observed in fish caught in the river and contained for a short time in hypertonic saline (Polenov, 1968, 1975; Barannikova, 1975), in laboratory rodents exposed to intensive pain, loud sound or cold (Polenov, 1968; Popovichenko, 1973; Krasnovskaya and Tavrovskaya, 1980), in some species at the time of short-term metamorphosis, during short reproductive period accompanied by a strong emotional reaction (fish, amphibia, rodents), during parturition etc. (Voitkevich, 1967; Polenov, 1968, 1975; Polenov et al., 1976, 1979; Yurisova and Polenov, 1979). Such periods in the animal life cycle are referred to as physiological stress (Polenov, 1975). (Figs. 5 b, c; 6).

Fig. 6 after exposure to t=4° C for 2 hr (percentage to control)

3. Moderately strong and chronic stimulation (days-months, Fig.4 II a, b). Most of the animals get adapted to this kind of stimulus. Quite distinguishable stages-alarm and resistence - are evident in the state of the organism , in the HIES in particular. At the stage of alarm there is loss of the body weight, which is regained at the stage of resistence when the normal state of the animals comes back. In some experiments (5% salt load to mice) the stage of alarm is immediately followed by a short-term stage of exhaustion which leads to the death of some animals.

According to the state of the HPHS two phases have been revealed both at the stage of alarm and resistence. The first phase of the alarm stage, primary response, is characterized by some decrease in the amount of NSM in the PP (a discharge of a small quantity of NH) and some inhibition in the synthesis of NSM in the perikaiya of the NSC. The second phase of the alarm stage, secondary response, is marked by an intensified progressive decrease in the content of NSM in the PP (release of a large quantity of NH), strong hypertrophy of the NSC, an increased amount of RNA (intensified synthesis of NH) and hyperemia of all regions of the HPHS. At the resistence stage the phase of primary adaptation (when adaptation sets in) and the phase of stable adaptation (Okhonskaya, 1972) are differentiated in the HPHS. During the first phase accumulation of NSM in the PP takes place and the amount of NSM reaches the level of the control or might exceed it. This occurs in the NSC and PP which are hypertrophied and hyperactive. NSM in the perikarya, axons and terminals is loosely arranged. In the phase of stable adaptation a gradual normalization of all the structures of the NSC is seen. In this period a slight undulation in the state of the HPHS is observed, i.e. phases of higher and lower activity seem to interchange, and the activity of the HPHS gradually extinguishes (Fig. 4, III b). However, the HPHS is in a state intensified to some extent. Changes of this kind are observed in the fresh-water sterlet, Acipenser ruthenus. kept in 15‰ sea water (Altufyev, 1977) and in mice subjected to a prolonged salt load (Polenov, 1968; Okhonskaya, 1972). (Figs. 7,8).

Fig. 7 Amount of neurosecretory material in posterior pituitary (PP) and height of thyroid epithelium (Th) in white mice subjected to 5% NaCl load (percentage to control)

Fig. 8 Quantity of cytoplasmic RNA (- - -) and nucleolar volume (—) of neurosecretory cells of N. supraopticus in white mice subjected to 5% NaCl load (percentage to contr.)

4. Chronic stimulation with gradually increasing intensity (months-years, Fig, 4, IV). Usually some injuring factors join the main stimulus in the later period and this leads to death. At the alarm stage moderate activation of all the elements of the HPHS and a discharge of a moderate amount of NH from the PP into the general circulation occur. Then the stage of resistence follows which later transforms into a prolonged stage of exhaustion. During the resistence stage some incomplete normalization of the activity of the HPHS takes place, but as the stage of exhaustion lasts, gradual decrease in the activity of the HPHS is observed. In the neurosecretory centers small NSC (low activity and exhaustion) and degenerating elements are found. The PP is almost devoid of NSM, and its transport from the hypothalamus is disturbed. In the PP blood capillaries are not distinct. It evidences indirectly that a minimum amount of NH is secreted into the general circulation. This state of the HPHS is characteristic of fish (guppy, Lebistes reticulatus) subjected to chronic intoxication (Matei, 1973), of rats under prolonged hypobaric hypoxia (Krasnovskaya, 1974), and of patients with hard chronic cardio-vascular disturbances and oncologic diseases (Grintsevich et al., 1969; Baranov, 1980). (Figs. 9, 10).

Fig. 9 –6 months

Fig. 10 Amount of neurosecretory material in rat posterior pituitary (PP) and height of thyroid epithelium (Th) under hypobaric hypoxia (percentage to