Tachykinins and their functions in the gastrointestinal tract

In the gastrointestinal tract, tachykinins are peptide neurotransmitters in nerve circuits that regulate intestinal motility, secretion, and vascular functions. Tachykinins also contribute to transmission from spinal afferents that innervate the gastrointestinal tract and have roles in the responses of the intestine to inflammation. Tachykinins coexist with acetylcholine, the primary transmitter of excitatory neurons innervating the muscle, and act as a co-neurotransmitter of excitatory neurons. Excitatory transmission is mediated through NK1 receptors (primarily on interstitial cells of Cajal) and NK2 receptors on the muscle. Tachykinins participate in slow excitatory transmission at neuro-neuronal synapses, through NK1 and NK3 receptors, in both ascending and descending pathways affecting motility. Activation of receptors (NK1 and NK2) on the epithelium causes fluid secretion. Tachykinin receptors on immune cells are activated during inflammation of the gut. Finally, tachykinins are released from the central terminals of gastrointestinal afferent neurons in the spinal cord, particularly in nociceptive pathways. Received 24 March 2007; received after revision 30 August 2007; accepted 14 September 2007     

Reflex motility of the stomach evoked by electrical stimulation of the hepatic vagus nerve

Summary Electrical stimulation of the cranial end of the cut hepatic branch of the vagus nerve produced an increase in the motility of the empty stomach in the rat, whereas systemic injection of insulin produced a gradual increase in the motility.Acknowledgment. The authors are indebted to Dr K. Yamaguchi and Prof. A. Niijima for their encouragement of the project.     

Ventral neural tube cells differentiate into hepatocytes in the chick embryo

A population of ventral neural tube cells has recently been shown to migrate out of the hind brain neural tube via the vagus nerve and contribute to the developing gastrointestinal tract. Since liver is also innervated by the vagus nerve, we sought to determine if these cells also migrate into the liver. Ventral neural tube cells in the caudal hindbrain of chick embryos were tagged with a replication-deficient retroviral vector containing the LacZ gene on embryonic day 2. Embryos were processed for detection of labeled cells on embryonic day 5 and 11. Labeled cells were seen in the liver on both days and identified as hepatocytes. Previously, it was believed that all hepatocytes develop from the gut endoderm. Results of the present study show an additional source for the formation of liver cells. Received 25 August 1998; received after revision 5 November 1998; accepted 5 November 1998     

Roles of innervation in developing and regenerating orofacial tissues

The head is innervated by 12 cranial nerves (I–XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.     

The intrapulmonary neuroepithelial bodies after vagotomy: demonstration of their sensory neuroreceptor-like innervation

Summary In the neonatal rabbit, infranodosal vagotomy destroys most of the intracorpuscular nerve endings of the pulmonary neuroepithelial bodies (NEB), while supranodosal vagotomy leaves these nerve endings intact. We conclude that NEB are mainly innervated by sensory neurons whose cell bodies lie in the nodose ganglion of the vagus nerve. These findings support the hypothesis that although secretory in nature, NEB are neuroreceptor structures.This study was supported by the Nationaal Fonds voor Wetenschappelijk Onderzoek. Fonds voor Geneeskundig Wetenschappelijk Onderzoek, Belgium. The authors thank R. Renwart and K. Armee for technical, G. Pison for photographical assistance.     

Peptides in the mammalian cardiovascular system

Summary Ample immunocytochemical evidence is now available demonstrating that several peptides are present in the mammalian cardiovascular system where they are localised to nerve fibres and myocardial cells. The neuropeptides (neuropeptide Y, calcitonin gene-related peptide, tachykinins and vasoctive intestinal polypeptide) are localised to large secretory vesicles in subpopulations of afferent or efferent nerves supplying the heart and vasculature of several mammals, including man. Although they often exert potent pharmacological effects on the tissues in which they occur their physiological significance has still to be established. They may act directly via specific receptors and/or indirectly by influencing the release and action of other cardiovascular transmitters. In marked contrast, atrial natriuretic peptide is produced by cardiac myocytes and considered to act as a circulating hormone.     

Peptides in the mammalian cardiovascular system

Ample immunocytochemical evidence is now available demonstrating that several peptides are present in the mammalian cardiovascular system where they are localised to nerve fibres and myocardial cells. The neuropeptides (neuropeptide Y, calcitonin gene-related peptide, tachykinins and vasoactive intestinal polypeptide) are localised to large secretory vesicles in subpopulations of afferent or efferent nerves supplying the heart and vasculature of several mammals, including man. Although they often exert potent pharmacological effects on the tissues in which they occur their physiological significance has still to be established. They may act directly via specific receptors and/or indirectly by influencing the release and action of other cardiovascular transmitters. In marked contrast, atrial natriuretic peptide is produced by cardiac myocytes and considered to act as a circulating hormone.     

Acetylcholine synthesis and its dependence on nervous activity

Summary The findings discussed in this paper mainly derived from studies on salivary glands, serving as model organs, indicate that the capacity to form the neurotransmitter acetylcholine, as judged by the activity of choline acetyltransferase, is influenced by the traffic of nerve impulses, as a long term effect. In the glands, choline acetyltransferase seems to be exclusively localized to the cholinergic nerves. In the postganglionic parasympathetic nerves of the glands, the activity of choline acetyltransferase decreases when the flow of secretory impulses in these nerves is abolished or reduced either by isolating the nerves from the central nervous system, surgically or pharmacologically, or by diminishing the reflex activation of the glands from the mouth. The opposite occurs when the reflex activation of the salivary glands is enhanced, i.e. the activity of choline acetyltransferase increases. Observations on various other organs are quoted in support of the view that the traffic of nerve impulses is of importance for the activity of the enzyme. An increase, in choline acetyltransferase activity also occurs in some salivary glands after sympathetic denervation. This puzzling observation is discussed in relation to impulse traffic. Increased nerve impulse traffic and collateral sprouting seem to be responsible for the rapid restitution of choline acetyltransferase activity from a low level in an organ partially deprived of its cholinergic nerve supply.     

Acetylcholine synthesis and its dependence on nervous activity.

The findings discussed in this paper mainly derived from studies on salivary glands, serving as model organs, indicate that the capacity to form the neurotransmitter acetylcholine, as judged by the activity of choline acetyltransferase, is influenced by the traffic of nerve impulses, as a long term effect. In the glands, choline acetyltransferase seems to be exclusively localized to the cholinergic nerves. In the postganglionic parasympathetic nerves of the glands, the activity of choline acetyltransferase decreases when the flow of secretory impulses in these nerves is abolished or reduced either by isolating the nerves from the central nervous system, surgically or pharmacologically, or by diminishing the reflex activation of the glands from the mouth. The opposite occurs when the reflex activation of the salivary glands is enhanced, i.e. the activity of choline acetyltransferase increases. Observations on various other organs are quoted in support of the view that the traffic of nerve impulses is of importance for the activity of the enzyme. An increase in choline acetyltransferase activity also occurs in some salivary glands after sympathetic denervation. This puzzling observation is discussed in relation to impulse traffic. Increased nerve impulse traffic and collateral sprouting seem to be responsible for the rapid restitution of choline acetyltransferase activity from a low level in an organ partially deprived of its cholinergic nerve supply.     

Ricerche fisiologiche sulla distribuzione periferica del nervo depressore aortico destro nel cane

Summary The periferal distribution of the right aortic nerve has been studied in physiological experiments on the dog. It has been found that after section of both Hering's nerves and left vago-depressor trunk and after denervation of the baroceptor area ofMuratori-Nonidez lying at the root of the right subclavian artery, the electrical stimulation of one splancnic nerve or the intravenous injection of adrenaline still produces a reflex bradycardia; moreover the cooling of the vagus nerve still results in a rise of the blood pressure. It is inferred that a group of baroceptor fibres of the right aortic nerve originate from areas situated in the aortic region.     

Hemokinins and endokinins

The mammalian tachykinins are a family of peptides that, until recently, has included substance P (SP), neurokinin A and neurokinin B. Since, the discovery of a third preprotachykinin gene (TAC4), the number of tachykinins has more than doubled to reveal several species-divergent peptides. This group includes hemokinin-1 (HK-1) in mouse and rat, endokinin-1 (EK-1) in rabbit, and EKA, EKB, human HK-1 (hHK-1) and hHK(4–11) in humans. Each exhibits a remarkable selectivity and potency for the tachykinin NK₁ receptor similar to SP. Their peripheral expression has led to the proposal that they are the endogenous peripheral SP-like endocrine/paracrine agonists where SP is not expressed. Moreover, their strong cross-reactivity with a specific SP antibody leads us to question many of the proposed locations and roles of SP in the periphery. Additionally, three orphan tachykinin gene-related peptides are identified on TAC4, in rabbit, EK-2 and in humans, EKC and EKD.Received 25 January 2004; received after revision 18 February 2004; accepted 27 February 2004     

The right neuron at the wrong place: biology of heterotopic neurons in cortical neuronal migration disorders, with special reference to associated pathologies

During the development of the neocortex, neurogenesis and neuronal differentiation occur in two separate locations. Thus neurons have to migrate through the future white matter. Arrested or excessive migration leads neurons to differentiate in a heterotopic position. Such neuronal migration disorders (NMDs) occur sporadically in normal development but are markedly increased as a consequence of genetic defects or after exposure to toxic drugs during the period of migration. Anatomofunctional studies in rodents with NMDs have revealed that heterotopic neurons form essentially normal afferent and efferentconnections, which has been interpreted as evidence that the connectionpattern of cortical neurons is specified prior to migration. In addition, recent data show that heterotopic neurons can be contacted by environmental, that is local, fibres that normally never innervate the neocortex. This dual connectivity leads heterotopias to form bridges between their environmental and original network. Such an abnormal pattern of connectivity could contribute to the pathophysiology of disorders associated with NMDs such as epilepsy. Received 16 December 1998; received after revision 5 February 1999; accepted 9 February 1999     

Dysfunctional insulin secretion in type 2 diabetes: role of metabolic abnormalities

Insulin secretion is finely tuned to the requirements of tissues by tight coupling to prevailing blood glucose levels. The normal regulation of insulin secretion is coupled to glucose metabolism in the pancreatic B cell, a major but not exclusive signal for secretion being closure of K⁺ATP (adenosine triphosphate)-dependent channels in the cell membrane through an increase in cytosolic ATP/adenosine diphosphate. Insulin secretion in type 2 diabetes is abnormal in several respects due to genetic causes but also due to the metabolic environment of the pancreatic B cells. This environment may be particularly important for the deterioration of insulin secretion which occurs with increasing duration of diabetes. Factors in the environment with potential importance include overstimulation, a negative effect of hyperglycemia per se (‘glucotoxicity’) as well as adverse effects of elevated fatty acids (‘lipotoxicity’). Elucidating the mechanisms behind these factors as well as their clinical importance will pave the way for treatment which could preserve B-cell function in type 2 diabetic patients. Received 4 October 1999; received after revision 1 November 1999; accepted 3 December 1999     

Identification of the bioactive peptide PEC-60 in brain

PEC-60 is a 60-residue peptide originally isolated from pig intestine. It inhibits glucose-induced insulin secretion from perfused pancreas in a hormonal manner and also has biological activity in the immune system. PEC-60-like immunoreactive material has been reported in catecholamine neurons of the central and peripheral nervous systems, but the peptide has not been identified from that material. We have now isolated PEC-60 from pig and rat brains with a method that combines column purification procedures with the specificity of a radioimmunoassay and the sensitivity of mass spectrometry to directly identify the peptide. The results show that PEC-60, like many other peptides, is expressed in the gastrointestinal tract and the central nervous system. The specific regional brain distribution and interaction with classical neurotransmitters raise the possibility that PEC-60may play a role in the central nervous system disorders involving dopamine dysregulation. Received 6 December 2002; received after revision 10 December 2002; accepted 11 December 2002 RID="*" ID="*"Corresponding author.     

A comparative study of the innervation of the choroid plexus in amphibia

The aminergic and cholinergic innervation of choroid plexuses in three species of amphibia was investigated. Plexuses of the Japanese toad and the bullfrog had poor innervation by adrenergic nerves of sympathetic origin, but in the clawed toad, these plexuses were heavily innervated by adrenergic axons from ganglion cells located in the plexus stroma. Nerve fibers positive for acetylcholinesterase were not found in the plexuses, except for a few fibers with very weak enzyme activity in the clawed toad.     

Neuromuscular synaptogenesis: clustering of acetylcholine receptors revisited

Clustering of neurotransmitter receptors in the postsynaptic membrane is critical for efficient synaptic transmission. During neuromuscular synaptogenesis, clustering of acetylcholine receptors (AChRs) is an early sign of postsynaptic differentiation. Recent studies have revealed that the earliest AChR clusters can form in the muscle independent of motorneurons. Neurally released agrin, acting through the muscle-specific kinase MuSK and rapsyn, then causes further clustering and localization of clusters underneath the nerve terminal. AChRs themselves are required for agrin-induced clustering of several postsynaptic proteins, most notably rapsyn. Once formed, AChR clusters are stabilized by several tyrosine kinases and by components of the dystrophin/utrophin glycoprotein complex, some of which also direct postnatal synaptic maturation such as formation of postjunctional folds. This review summarizes these recent results about AChR clustering, which indicate that early clustering can occur in the absence of nerves, that AChRs play an active role in the clustering process and that partly different mechanisms direct formation versus stabilization of AChR clusters. Received 10 April 2002; received after revision 4 June 2002; accepted 10 June 2002     

Interaction of vasoactive intestinal peptide (VIP) with cholinergic stimulation of glucagon secretion

Summary VIP-containing nerve fibers as well as cholinergic nerve fibers have a ubiquitous distribution in the body and both types of nerves have been demonstrated to innervate the pancreatic islets. The present study shows, in the intact, conscious mouse, that VIP and the cholinergic agonist carbachol stimulate glucagon secretion in a dose-dependent manner. Furthermore VIP and carbachol were found to exert potentiating interactions on glucagon secretion. These results suggest the existence of an interactive neural regulation of glucagon secretion, exerted by acetylcholine and VIP.We thank Professor V. Mutt, Karolinska Institutet, Stockholm, for giving us VIP. The skilful technical assistance of Lena K vist and Peter Okmark is gratefully acknowledged. This study was supported by grants from the Swedish Medical Research Council (14P-4289, 14X-4286) and the Medical Faculty, University of Lund, Sweden.     

Studies on peripheral neurons and neurohaemal tissue in the thorax of the stick insect (Carausius morosus)

Summary The distribution of peripheral neurosecretory and non-neurosecretory neurons, and transverse nerve neurohaemal swellings, is described in the thorax ofCarausius morosus. The electrical activity of the isolated transverse nerves has been recorded.We are grateful to the Science Research Concil for financial support, and to Dr Sue Fifield and Steven Irving for methylene blue and electron microscope preparations.     

Benzodiazepine receptors resolved

Summary To date, attempts to map the distribution and density of benzodiazepine receptors in the CNS have been dominated by radiohistochemical techniques with conventional receptor binding. Their limited resolution, however, prompted us to try an immunohistochemical approach. Purified GABA/benzodiazepine receptors, prepared from bovine cerebral cortex, have been used to raise monoclonal antibodies for this purpose. Immunoreactive sites in rat brain, spinal cord and retina as well as in bovine and post-mortem human brain were found to be concentrated on neuronal cell bodies and processes in those regions known to be innervated by GABAergic neurons. Electron microscopic analysis revealed a selective staining of axosomatic and axodendritic pre- and postsynaptic contacts.