The interrelations of the lymphatic capillaries with the nerve structures in the wall of the small intestine]

The character of interrelations of nervous structures and the lymphatic capillary walls has been studied in cats. Under the light microscope twisted nervous fiber terminals of the intestinal neuron dendrites have been revealed around the lymphatic capillaries. Electron microscopical investigation has not revealed any specialized contacts of the nervous terminals and the lymphatic capillary walls. The receptors and terminals of axons do not situate nearer than 10 nm from the latter. According to the structure of synaptic vesicles among the axonal terminals next to the lymphatic capillary walls cholinergic, adrenergic and purinergic ones are described. The influence of the nervous system to the function of the small intestine lymphatic capillaries is mediated via the precapillary space. The neuromediators from the axonal terminals get into it owing to absence of neurolemmocytic membranes around them.     

The physiological role of peripheral serotoninergic neurones. A review

1. Serotoninergic neurones and neurones which takes up 5-hydroxytryptamine (5-HT) have been observed in sensory ganglia, but their physiological role remains unknown. 2. Serotoninergic neurones participating in the neural control of gut motility are present within the enteric intramural nervous system. 3. 5-HT applied to the serosa inhibits the peristaltic reflex in the small intestine. In contrast, peristalsis is stimulated by 5-HT applied to the serosa. 4. Intracellular microelectrode investigations indicate that some neurones of the enteric nervous system are depolarized, whereas others are hyperpolarized by 5-HT. In addition, 5-HT can also decrease the release of acetylcholine by acting on presynaptic receptors located on cholinergic nerve endings. The release of 5-HT from serotoninergic enteric neurones is very probably under the control of a noradrenergic mechanism. 5. Electromyographic studies on the rabbit colon indicate that a nerve-mediated descending inhibition is modified by drugs interacting with the synthesis of 5-HT or its reuptake.     

Mechanism of the serotonin effect on motility of the duodenum,ileum, and jejunum in awake rabbits

I. v. administration of serotonin to alert rabbits produced a phasic change of contractile activity of duodenum, ileum, and jejunum including excitatory and inhibitory components. It is shown that stimulation of the small bowel motility is caused by serotonin activation of non-cholinergic excitatory mechanism with participation of effector cholinergic neurones. The initial suppression of the motility is caused by participation of nonadrenergic noncholinergic inhibitory mechanism, and the secondary inhibition of contractile activity of a small bowel with serotonin has an adrenergic nature.     

Peptide YY induces nerve-mediated responses in the guinea pig intestine.

The actions of peptide YY (PYY) were studied in longitudinal organ-bath preparations of the guinea pig intestine. PYY induced concentration-dependent (10(-9)-5 x 10(-8) M) relaxations of tissue from the duodenum, jejunum, ileum, and colon. These responses were unaffected by adrenergic blockade and atropine treatment but could be prevented by tetrodotoxin. The pharmacology of PYY actions in segments of the small and large intestine indicated the involvement of intrinsic nonadrenergic, noncholinergic inhibitory neurones in the relaxation response to this peptide. All tissues could be made tachyphylactic to PYY without affecting their ability to respond to the direct acting muscle relaxants ATP or papaverine. Moreover, nicotinic ganglion stimulated relaxations and cholinergic nerve-mediated contractions were also unaffected. These results show applied PYY to have potent neurogenic actions in the guinea pig intestine with some similarities to PYY actions in the rat intestine.     

The motoricity cycle of the small intestine

The electrical spike activity of the small intestine at the gastroduodenal junction occurs as migrating myoelectric complexes (MMCs), initiated regularly at intervals of 90-100 min. in the adult sheep and of 20-30 min. in the neonate. This ultradian rhythm, generated by the enteric nervous system, may become identical in the adult and in the neonate, by the use of methysergide which interacts with 5-HT myenteric neurones. The results suggest a postnatal development of a serotoninergic inhibitory system, involved in the control of the basic rest-activity cycle of the small intestine.     

Calretinin immunoreactivity in cholinergic motor neurones,interneurones and vasomotor neurones in the guinea-pig small intestine

Summary Immunoreactivity for calretinin, a calcium-binding protein, was studied in neurones in the guinea-pig small intestine. 26±1% of myenteric neurones and 12±3% of submucous neurones were immunoreactive for calretinin. All calretinin-immunoreactive neurones were also immunoreactive for choline acetyltransferase and hence are likely to be cholinergic. In the myenteric plexus, two subtypes of Dogiel type-I calretinin-immunoreactive neurones could be distinguished from their projections and neurochemical coding. Some calretinin-immunoreactive myenteric neurones had short projections to the tertiary plexus, and hence are likely to be cholinergic motor neurones to the longitudinal muscle. Some of these cells were also immunoreactive for substance P. The remaining myenteric neurones, immunoreactive for calretinin, enkephalin, neurofilament protein triplet and substance P, are likely to be orad-projecting, cholinergic interneurones. Calretinin immunoreactivity was also found in cholinergic neurones in the submucosa, which project to the submucosal vasculature and mucosal glands, and which are likely to mediate vasodilation. Thus, calretinin immunoreactivity in the guinea-pig small intestine is confined to three functional classes of cholinergic neurones. It is possible, for the first time, to distinguish these classes of cells from other enteric neurones.     

Neuropharmacologic regulation of the carcinogenic action of 1,2-dimethylhydrazine

Chronic experiments were made on 100 male rats to examine the modifying effects of adrenergic and cholinergic agents that regulate homeostasis on 1,2-dimethylhydrazine-induced intestinal carcinogenesis. The sympatholytic guanethidine (5 mg/kg) and the alfa-adrenoblocker butyroxan (2.5 mg/kg) did not influence the carcinogenesis in the intestine. The noradrenaline- and atropine-induced (1 mg/kg and 10 mg/kg) increase in the adrenergic component of the vegetative nervous system led to the decrease in the number (by 2-3 times) and size of the tumor nodes in the intestine. The drugs did not affect the morphology of neoplasms. The results are discussed in terms of essential importance of the vegetative nervous system in the mechanism of chemical carcinogenesis.     

Synaptic processes in smooth muscles

Synaptic potentials of smooth muscles of the gastrointestinal tract arising in response to intramural stimulation were studied by intracellular recording of potentials and the sucrose gap method. The results showed that muscarinic cholinergic neuromuscular transmission in smooth-muscle cells of the gastrointestinal tract is purely excitatory. This transmission is most marked in the fundal part of the stomach. Adrenergic control of motor activity is manifested as excitation and inhibition of smooth muscles. Relations between these phenomena differ in different parts of the gastrointestinal tract. Depression of inhibitory adrenergic effects by apamin discloses excitation of smooth muscles which is not found under ordinary conditions. Like its inhibitory action, the excitatory action of noradrenalin is exerted as a result of activation of -adrenoreceptors. Nonadrenergic synaptic inhibition, which is more effective than adrenergic, is found in smooth-muscle cells of the circular layer of all parts of the gastrointestinal tract studied. Inhibitory postsynaptic potentials consists of two components: a first fast, and a second slow. Apamin blocks mainly the first phase of the synaptic response. During inhibition of nonadrenergic inhibitory postsynaptic potentials by apamin, noncholinergic synaptic excitation resistant to the action of blockers of cholinergic, adrenergic, and serotoninergic transmission is found in smooth muscles of the cecum. It is complex in character in this part of the intestine: an initial excitatory postsynaptic potential and a slow late depolarization wave. In smooth-muscle cells of other parts noncholinergic excitation is manifested only as a slow depolarization wave. The following types of synaptic influences of the autonomic nervous system on smooth-muscle cells of the gastrointestinal tract are therefore postulated: nonadrenergic excitatory, both cholinergic and noncholinergic; nonadrenergic inhibitory, adrenergic excitatory and adrenergic inhibitory, and also presynaptic modulation of neuromuscular transmission.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 16, No. 3, pp. 307–319, May–June, 1984.     

Effect of intravascular laser irradiation of blood on the status of the adrenergic and cholinergic structures of the small intestine in experimental peritonitis

In the experiment performed on 60 mongrel dogs the effect of intravascular laser radiation of blood (ILRB) to adrenergic and cholinergic fibers of the small intestine has been studied at treatment of experimental generalized suppurative peritonitis. At treatment of the experimental peritonitis by means of traditional method only one month after its termination a positive reaction to acetylcholinesterase (AChE) is noted, structural organization of cholinergic fibers corresponds to the norm, and density of their plexuses increases. Application of ILRB at treatment of the experimental peritonitis facilitates to increasing density of the cholinergic fibers already on the 21st day after termination of the treatment; their AChE increases essentially, their structural organization corresponds to the norm. In cytoplasm of neurons of the muscular-intestinal plexus a positive reaction to AChE is revealed; this demonstrates their increased functional activity. The small intestine adrenergic apparatus at peritonitis undergoes less manifested structural-chemical alterations. After termination of treatment by means of traditional methods it corresponds to the norm on the 7th day, and after ILBR treatment----on the 3d day. Thus, application of ILBR in treatment of the experimental peritonitis enhances the development of regenerative processes in adrenal and cholinergic structures of the small intestine, facilitates a more manifested demonstration of compensatory-reparative possibilities of the organism.     

Decentralisation of neurones in the pelvic ganglion of the guinea-pig: Reinnervation by adrenergic nerves

An electron-microscopic study has been made of adrenergic and cholinergic nerve fibres and synapses in the pelvic ganglion of the guinea-pig at intervals of up to 60 days following section of the hypogastric and pelvic nerves. Transection of the hypogastric nerves led to degeneration of 80-90% of the cholinergic nerve profiles and synapses in the ganglion. The small number of adrenergic nerves and synapses did not change, but 30-60 days after section, this number increased 8-10 times. Transection of the pelvic nerves led to degeneration of about 15% of the cholinergic nerve terminals, but no change in adrenergic terminals. After transection of both hypogastric and pelvic nerves, only about 1% of cholinergic nerves survived, but after 30-60 days, the number of adrenergic nerves increased 8-10 times. It is concluded that following cholinergic nerve degeneration in the ganglion, adrenergic nerves, probably originating as collateral sprouts from postganglionic neurones and granule-containing cells, can replace them to some extent.     

The effects of ethylenediamine in the rat small intestine: a powerful relaxant of the muscularis.

The pharmacology of ethylenediamine (EDA) actions in the rat small intestine was examined using isolated gut-bath preparations of proximal segments of the duodenum, jejunum, and ileum. EDA evoked concentration-dependent tetrodotoxin-insensitive relaxations of the intestine, evidently by direct action on the muscularis. Such actions were simultaneous on the longitudinal and circular muscle layers. Investigation of EDA actions on the circular muscle showed that EDA actions were unrelated to any intrinsic GABAergic mechanisms. Moreover, EDA interacted with muscle sites distinct from ATP, histamine, bradykinin, muscarinic, and adrenergic receptors. The ability of EDA to relax the intestinal musculature was generally greater than the smooth muscle relaxant papaverine and substantially better than nicotinic stimulation of the intrinsic inhibitory neurones. It would appear that EDA may be useful as a direct acting smooth muscle relaxant for the study of the physiology-pharmacology of the rodent small intestine.     

Adrenergic and cholinergic innervation of the prostate in laboratory animals

The prostate innervation has been studied in 50 white rats, 12 rabbits, 12 guinea pigs, 6 cats and 6 dogs. Together with the impregnation techniques, Karnovsky-Roots method has been applied, for revealing cholinergic components, and the incubation method in 2% solution of glyoxylic acid, for revealing adrenergic nervous structures. Density of adrenergic and cholinergic nervous plexuses has been estimated by means of the planimetric point method. The prostate of the laboratory animals possesses well manifested adrenergic and cholinergic nervous plexuses. The organ's alveolus and ducts are covered with adrenergic and cholinergic fibers, however, the relative density of the cholinergic plexuses is less than that of the adrenergic ones. The guinea pig prostate is the most richly supplied with the adrenergic nervous plexuses, and the rabbit prostate--with the cholinergic nervous plexuses.     

Nerves containing substance P,vasoactive intestinal polypeptide,enkephalin or somatostatin in the guinea-pig taenia coli

Summary The guinea-pig taenia coli is rich in peptide-containing nerves. Nerve fibres containing substance P (SP), vasoactive intestinal peptide (VIP), or enkephalin, were numerous in the smooth muscle while somatostatin fibres were very few. Nerve fibres displaying SP or VIP immunoreactivity were numerous in the myenteric plexus. Enkephalin nerve fibres were fairly numerous in the plexus while somatostatin nerve fibres were sparse. Nerve cell bodies containing immunoreactive SP or VIP were regularly seen in the plexus. Delicate varicose elements of the different types of nerve fibres were found to ramify around nerve cell bodies in a manner suggestive of innervation.In the electron microscope the various peptide-storing nerve fibres (i.e., elements containing SP, VIP or enkephalin) were found to contain a varying number of fairly large, electron-opaque vesicles in the varicose swellings. These vesicles represent the storage site of the neuropeptides.The isolated taenia coli responded to electrical nerve stimulation with a contraction. After cholinergic and adrenergic blockade the contractile response was replaced by a relaxation followed by a contraction upon cessation of stimulation. SP contracted the taenia while VIP caused a relaxation. The enkephalins raised the resting tension slightly while somatostatin had no effect. These observations are compatible with a role for SP as an excitatory neurotransmitter and for VIP as an inhibitory one, and with the view that both SP neurones and VIP neurones act as motor neurones. In preparations contracted by SP the electrically induced contractions were reduced in amplitude while the electrically induced relaxations seen after adrenergic and cholinergic blockade were enhanced in amplitude. In preparations relaxed by VIP there was an increased contractile response to electrical stimulation, while in the atropine + guanethidine-treated preparation the electrically induce relaxations were reduced in amplitude. The enkephalins reduced the contractile response to electrical stimulation, while somatostatin induced a very small reduction in the amplitude of such responses. These observations suggest that SP neurones and VIP neurones may play additional roles as interneurones. Somatostatin neurones probably act as interneurones. Enkephalin-containing fibres may serve to modify the release of transmitter from other nerves in the smooth muscle, perhaps through axo-axonal arrangements. Alternatively, the enkephalin nerve fibres in the smooth muscle are afferent elements involved in mediating sensory impulses to the myenteric plexus.     

The enteric nervous system: region and target specific projections and neurochemical codes.

The goal of this report is to summarise the current knowledge on the projection pathways of enteric neurones innervating the muscle and mucosa in different regions of the gut. Combination of neuronal tracing, immunohistochemical and electrophysiological methods has allowed researchers to gain insight into the enteric hardwiring of specific target tissue in the gut. A polarised innervation pattern of the circular muscle was demonstrated for the stomach fundus/corpus and the ileum with descending pathways being primarily nitrergic while ascending pathways were primarily cholinergic. This characteristic hardwiring is thought to set in part the functional basis for peristalsis. A similar polarised innervation pathway was found for the enteric innervation of the mucosa in the stomach and large intestine but not in the small intestine. In both the stomach (myenteric neurones) and in the proximal and distal colon (submucosal neurones), ascending pathways to the mucosa are primarily cholinergic while descending pathways are primarily non-cholinergic. In the colon, results suggest that activation of both pathways induces a cross potentiation of cholinergic and vasoactive intestinal polypeptidergic mediated secretion. Furthermore, a large population of myenteric neurone s projecting to the mucosa in the small and large intestine are probably intrinsic primary afferent neurones sensitive to mechanical as well as chemical stimuli.     

Inhibition and facilitation in parasympathetic ganglia of the urinary bladder

Neurons in vesical parasympathetic ganglia receive excitatory and inhibitory inputs from both divisions of the autonomic nervous system. Sacral parasympathetic pathways (cholinergic) provide the major excitatory input to these ganglia via activation of nicotinic receptors. Parasympathetic pathways also activate muscarinic inhibitory and excitatory receptors, which may exert a modulatory influence on transmission. Cholinergic transmission is relatively inefficient when preganglionic nerves are stimulated at low frequencies (< 1 Hz). However, excitatory postsynaptic potentials (EPSPs) and postganglionic firing markedly increase during repetitive stimulation at frequencies of 1-10 Hz. It is concluded that enhanced transmitter release accounts for the temporal facilitation and that vesical ganglia function as "high pass filters" that amplify the parasympathetic excitatory input to the detrusor muscle during micturition. Transmission in vesical ganglia is also sensitive to adrenergic inhibitory and facilitatory synaptic mechanisms elicited by efferent pathways in the hypogastric nerves. The effects of exogenous norepinephrine indicate that adrenergic inhibition is mediated by alpha receptors and reflects primarily a presynaptic depression of transmitter release although postsynaptic adrenergic hyperpolarizing and depolarizing effects have also been noted. Adrenergic facilitation is mediated by beta receptors as well as unidentified receptors. Norepinephrine also can inhibit or excite spontaneously active neurons in vesical ganglia. The existence of inhibitory and facilitatory synaptic mechanisms in vesical ganglia provides the basis for a complex ganglionic modulation of the central autonomic outflow to the bladder.     

Calcitonin gene-related peptide (CGRP) modulates cholinergic neurotransmission in the small intestine of man, pig and guinea-pig via presynaptic CGRP receptors.

The effect of calcitonin gene-related peptide (CGRP) on the cholinergically mediated twitch contraction in longitudinal muscle strips of the small intestine (duodenum, jejunum, ileum) of guinea-pig, pig and man was investigated. Independently of the anatomical region, CGRP inhibited the twitch response in the different specimens of all three species by about 40% with similar IC50 values (1.5-2.4 nmol/l). Only in the guinea-pig small intestine CGRP induced a contraction of the smooth muscle which was sensitive to scopolamine and tetrodotoxin. The electrically evoked [3H]acetylcholine release from jejunal longitudinal muscle strips with myenteric plexus attached of the guinea-pig, which were incubated with [3H]choline, was concentration-dependently inhibited by CGRP. A direct relaxant effect of CGRP on smooth muscle tone of carbachol precontracted preparations was only observed in specimens of the guinea-pig. In conclusion, presynaptic inhibitory CGRP receptors on cholinergic neurones modulate the release of acetylcholine in different parts of the small intestine.     

Excitatory beta-adrenoreceptors on enteral cholinergic interneurons of the large intestine and ileocecal sphincter]

Acute experiments were performed on the isolated intestinal loop, vascularly perfused with arterial blood by means of the constant flow perfusion pump. Contractile activity of the ileocecal sphincter and proximal parts of the large intestine was estimated by the maximal isometric tension and total (integrated) contractile activity. Isoprenaline (1-2 mg) induced contractile responses of the colonic segment and ileocecal sphincter. These responses were abolished or dramatically diminished by the blockade of beta-adrenoceptors, muscarinic, and nicotinic cholinergic receptors. Data obtained support the idea, that the large intestine and ileocecal sphincter have excitatory beta-adrenoceptors localized on cholinergic interneurones of the enteric nervous system.     

A Histochemical Study of the Gas Gland Innervation in the Atlantic God,Gadus morhua

A histochemical study was made of the distribution of catecholamines and cholinesterases in two autonomic ganglia closely associated with the swimbladder of the Atlantic cod, Gadus morhua. The “swimbladder nerve ganglion” comprised large (40 μm) neurones, the majority of which are positive for both catecholamines and acetylcholinesterase. It is argued that these neurones are mainly adrenergic postganglionic elements of sympathetic pathways which pass through the vago-sympathetic trunk. The “gas gland ganglion” comprised small (20 μm) neurones, positive for acetylcholinesterase but showing no catecholamine reaction. It is argued that these neurones are cholinergic postganglionic elements of the parasympathetic vagal innervation of gas gland cells.     

An electrophysiological study of olfactory interneurones in the brain of the honey-bee

Discharges of the olfactory units in the brain of the honey-bee were recorded extracellularly. Discharges were excitatory and inhibitory and showed on and on-off responses. In the on responses, phasic, phasic-tonic, and tonic patterns were found. No relation between discharge pattern and the region in the brain was found. The dominant pattern was phasic-tonic in the excitatory and tonic in the inhibitory units. Rebound or long-lasting phenomena seemed to be one of the characteristics of the neurones in the central nervous system.The latency of the response showed that olfactory information entering the deutocerebrum from the antenna was carried to the calyx of the ipsilateral brain via the antenno-cerebral tracts reported by Kenyon (1896), and then to the protocerebral lobe through the stalk of the mushroom body. The information was also carried to the contralateral brain after passing through the calyx of the ipsilateral brain or the central commissure.     

Increased Activity of Choline Acetyl-transferase in Sympathetic Ganglia after Prolonged Administration of Nerve Growth Factor

A prolonged increase in the activity of preganglionic sympathetic nerves produces characteristic changes in the enzyme pattern of the postganglionic adrenergic neurones in adult rats^1–4. In newborn mice the normal development of adrenergic neurones depends materially on the intactness of the preganglionic cholinergic nerves⁵. These two findings contribute to the definition of the so far vague term “trophic response to neuronal activity” and the question arises whether these trophic actions are unidirectional only, or whether there is also a retrograde effect, that is, a dependence of the preganglionic cholinergic nerves on the function of the postjunctional adrenergic neurones. Transection experiments in the brain have shown that after lesioning of particular areas, for example, optic nerve tract, cingulate or visual cortex, there occurs not only orthograde but also retrograde trans-synaptic degeneration⁶. It seemed of interest to study this possible retrograde trophic effect in a less complex system and to investigate whether there are not only negative (degeneration) but also positive effects. The administration of nerve growth factor (NGF) to newborn rats produces a marked growth and enhanced differentiation of the adrenergic neurones⁷. The biochemical correlate to these morphological changes is a selective induction of tyrosine hydroxylase and dopamine β-hydroxylase⁸. We have investigated whether these effects are also reflected by changes in the preganglionic nerves.