Dorsal vagal preganglionic neurons: Differential responses to CCK1 and 5-HT3 receptor stimulation (original) (raw)
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The dorsal motor nucleus of the vagus and regulation of pancreatic secretory function
Experimental Physiology, 2013
New Findings r What is the Topic of this review? This review describes new evidence for the control of pancreatic exocrine and endocrine secretion by the dorsal motor nucleus of the vagus. It describes the effects of several gastrointestinal peptides on pancreatic secretion and considers their sites of action in the vago-vagal reflex pathway. r What advances does it highlight? This review draws together recent electrophysiological, anatomical and pharmacological studies to provide a state-of-art view of the parasympathetic control of the exocrine and endocrine pancreas. Recent investigation of the factors and pathways that are involved in regulation of pancreatic secretory function (PSF) has led to development of a pancreatic vagovagal reflex model. This model consists of three elements, including pancreatic vagal afferents, the dorsal motor nucleus of the vagus (DMV) and pancreatic vagal efferents. The DMV has been recognized as a major component of this model and so this review focuses on the role of this nucleus in regulation of PSF. Classically, the control of the PSF has been viewed as being dependent on gastrointestinal hormones and vagovagal reflex pathways. However, recent studies have suggested that these two mechanisms act synergistically to mediate pancreatic secretion. The DMV is the major source of vagal motor output to the pancreas, and this output is modulated by various neurotransmitters and synaptic inputs from other central autonomic regulatory circuits, including the nucleus of the solitary tract. Endogenously occurring excitatory (glutamate) and inhibitory amino acids (GABA) have a marked influence on DMV vagal output to the pancreas. In addition, a variety of neurotransmitters and receptors for gastrointestinal peptides and hormones have been localized in the DMV, emphasizing the direct and indirect involvement of this nucleus in control of PSF.
European Journal of Pharmacology, 2008
Cholecystokinin and serotonin are released from the gastrointestinal tract in response to the products of digestion and play critical roles in mediating pancreatic secretion via vago-vagal reflex pathways. This study was designed to investigate the effects of activation of cholecystokinin CCK 1 and serotonin (5-hydroxytryptamine, 5-HT) 5-HT 3 receptors on pancreatic vagal afferent discharge and to determine whether there is an interaction between these receptors. Male Sprague Dawley rats anaesthetised with isoflurane (1.5%/100% O 2) were used in all experiments. The effects of systemic administration of cholecystokinin and the serotonin 5-HT 3 receptor agonist phenylbiguanide on pancreatic vagal afferent discharge were recorded before and after administration of cholecystokinin CCK 1 and serotonin 5-HT 3 receptor antagonists. Cholecystokinin (0.1-10 µg/kg, i.v.) and phenylbiguanide (1 and 10 µg/kg, i.v.) increased pancreatic vagal afferent discharge dose-dependently. Cholecystokinin CCK 1 receptor antagonists, lorglumide (10 mg/kg, i.v.) and devazepide (0.5 mg/kg, i.v.), reduced cholecystokinin-and phenylbiguanide-induced increases in pancreatic vagal afferent discharge significantly (n =5, P b 0.05). On the other hand, serotonin 5-HT 3 receptor blockade with granisetron (1 mg/kg, i.v.) or MDL72222 ([(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 3,5-dichlorobenzoate; 0.1 mg/kg, i.v.) inhibited the pancreatic vagal afferent discharge responses to phenylbiguanide but not those to cholecystokinin. This study has confirmed that cholecystokinin and phenylbiguanide activate pancreatic vagal afferent discharge via activation of cholecystokinin CCK 1 and serotonin 5-HT 3 receptors, respectively. In addition, it has demonstrated that (i) the serotonin 5-HT 3 agonist phenylbiguanide acts partly via an interaction with cholecystokinin CCK 1 receptors, and (ii) the actions of cholecystokinin are not dependent on serotonin 5-HT 3 receptor activation.
Distribution and neurochemical identification of pancreatic afferents in the mouse
The Journal of Comparative Neurology, 2008
Dysfunction of primary afferents innervating the pancreas has been shown to contribute to the development of painful symptoms during acute and chronic pancreatitis. To investigate the distribution and neurochemical phenotype of pancreatic afferents, Alexa Fluor-conjugated cholera toxin B (CTB) was injected into the pancreatic head (CTB-488) and tail (CTB-555) of adult male mice to label neurons retrogradely in both the dorsal root ganglia (DRG) and nodose ganglia (NG). The NG and DRG (T5-T13) were processed for fluorescent immunohistochemistry and visualized by using confocal microscopy. Spinal pancreatic afferents were observed from T5 to T13, with the greatest contribution coming from T9-T12. The pancreatic afferents were equally distributed between right and left spinal ganglia; however, the innervation from the left NG was significantly greater than from the right. For both spinal and vagal afferents there was significantly greater innervation of the pancreatic head relative to the tail. The total number of retrogradely labeled afferents in the nodose was very similar to the total number of DRG afferents. The neurochemical phenotype of DRG neurons was dominated by transient receptor potential vanilloid 1 (TRPV1)positive neurons (75%), GDNF family receptor alpha-3 (GFRα3)-positive neurons (67%), and calcitonin gene-related peptide (CGRP)-positive neurons(65%) neurons. In the NG, TRPV1-, GFRα3-, and CGRP-positive neurons constituted only 35%, 1%, and 15% of labeled afferents, respectively. The disparity in peptide and receptor expression between pancreatic afferents in the NG and DRG suggests that even though they contribute a similar number of primary afferents to the pancreas, these two populations may differ in regard to their nociceptive properties and growth factor dependency.
Activation of the dorsal vagal nucleus increases pancreatic exocrine secretion in the rat
Neuroscience Letters, 2008
Pancreatic secretion is regulated by the dorsal vagal nucleus (DVN) which is modulated by several neurotransmitters and diverse synaptic inputs. The inhibitory neurotransmitter GABA is a major modulator of the vagal output to the gastrointestinal tract. The present study investigated the effects of GABA A receptor blockade in the DVN, using bicuculline methiodide (BIM, GABA A receptor antagonist, 100 pmol/25 nl), on pancreatic exocrine secretion (PES). Male Sprague-Dawley rats anaesthetised with isoflurane were used in all experiments. PES was collected from the common bilepancreatic duct and was used to determine the pancreatic protein output (PPO). PES and PPO were measured prior to, and after, microinjection of BIM into the DVN. Bilateral microinjection of BIM into the DVN significantly increased PES and PPO from 23.4 ± 3.2 l/h to 66.1 ± 17.5 l/h and 19.3 ± 1.7 g/h to 35.7 ± 3.0 g/h (P < 0.05), respectively. Atropine methonitrate (100 g/(kg min), i.v.) blocked the excitatory effect of BIM microinjection on PES and PPO. These results suggest that activation of DVN neurons stimulates pancreatic secretion via a cholinergic muscarinic mechanism.
Preganglionic innervation of the pancreas islet cells in the rat
Journal of the Autonomic Nervous System, 1984
The position and number of preganglionic somata innervating the insulin-secreting beta-cells of the endocrine pancreas were investigated in Wistar rats. This question was approached by comparing the innervation of the pancreas of normal rats with the innervation of the pancreas in alloxan-induced diabetic animals. The presumption was made that alloxan treatment destroys the beta-cells of the islet of Langerhans and results in a selective degeneration of the beta-cells innervation. Cell bodies of preganglionic fibers innervating the pancreas were identified by retrograde transport of horseradish peroxidase following pancreas injections. It was found that 25% of the cells innervating the pancreas in the left dorsal vagal motor nucleus, 50% of the cells in the ambiguous nucleus and 50% of the cells innervating the pancreas, that originate in segments C3-C4 of the spinal cord, fail to become labeled after alloxan treatment. The position and distribution of these cell groups are described in detail and are assumed to be involved in preganglionic beta-cell innervation. A second cell population in the ventral horn and intermediolateral column of the segments T3-L2 of the cord also was labeled in normal rats and was not affected by the alloxan treatment. These thoracic cell groups are thus considered as sympathetic preganglionic somata that maintain direct connections to the pancreas. Additional preliminary information is presented dealing with the general aspects of sympathetic and parasympathetic organization of the pancreas innervation.
Innervation of the pancreas by neurons in the gut. J Neurosci
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Experiments were done in order to test the hypothesis that neurons in the bowel send axonal projections to the pancreas and can modify pancreatic activity. Pancreatic injections of the retrograde tracer, Fluoro-Gold, labeled neurons in the myenteric plexus of the antrum of the stomach and in the first 6 cm of the duodenum. This labeling was not due to the diffusion of Fluoro-Gold from the pancreas, because the injections did not label longitudinal muscle cells overlying labeled ganglia in the bowel or neurons in the phrenic nerve nucleus or nucleus ambiguous; nor were enteric neurons labeled if insufficient time was allotted for retrograde transport. More Fluoro-Gold labeled neurons were found in the stomach (9.2 f O.g/ganglion) than in the duodenum (3.6 f 0.3/ganglion; p < 0.001). Neurons were found in myenteric ganglia of both duodenum and stomach that were doubly labeled by retrograde transport of Fluoro-Gold and anti-serotonin (5HT) sera. In addition, thick bundles of 5-HT immunoreactive nerve trunks were found to run between the duodenum and the pancreas. Most 5-HT immunoreactive axons in the pancreas terminated in ganglia, although some fibers were also observed near acini, ducts, vessels, and islet cells. The B subunit of cholera toxin (B-CT) was microinjected into single myenteric ganglia in order to determine if axon terminals in the pancreas would become labeled by anterograde transport in the pancreas. B-CT labeled bundles of axons in the pancreatic stroma. Branches of these bundles entered the pancreatic parenchyma and varicose B-CT labeled terminal axons were found in pancreatic ganglia and in proximity to acinar and insulin immunoreactive cells. The intercalating fluorochrome 1, 1 ', dioctadecyl-3,3,3',3'-tetramethylcarbocyanine perchlorate (Dil), which moves by lateral diffusion to outline entire cells, was introduced by microinjection into individual myenteric ganglia of fixed preparations. Fluorescence was seen in sequential observations to move away from the injected ganglion along connectives of the myenteric plexus. After about a month, neurons in ganglia at some distance from the injection site displayed Dil fluorescence as did nerve bundles that exited from the myenteric plexus and pierced the longitudinal muscle in the direction of the pancreas. Varicose Dil fluorescent terminal varicosities were also observed in the pancreas. These observations indicate that there is an extensive en
The Journal of Physiology, 2012
• The pancreas consists of two functional parts, exocrine, which releases digestive enzymes, and endocrine, which releases hormones, such as insulin. • Both parts are under neural regulatory control by the vagus nerve. Vago-vagal neurocircuits integrate the sensory information, chemical or mechanical, from the gastrointestinal tract with the motor output back to the gastrointestinal system, including the pancreas. • Both excitatory and inhibitory vago-vagal neural circuits are regulated by many neurotransmitters, including glutamate acting on different types of metabotropic glutamate receptors. • In this study, we show that different subtypes of metabotropic glutamate receptors regulate differentially exocrine and endocrine pancreatic functions by affecting different neurocircuits. • The present study provides the physiological basis to develop pharmacological strategies aimed to provide a better understanding of pathophysiological conditions, such as pancreatitis or diabetes, that affect selectively the exocrine or endocrine pancreas.
Noradrenergic innervation of rabbit pancreatic ganglia
Autonomic Neuroscience, 2005
Sympathetic nerve stimulation indirectly regulates pancreatic endocrine and exocrine secretion, in part, through actions on the cholinergic parasympathetic innervation of the secretory tissues. Earlier work identified noradrenergic nerves in pancreatic ganglia and demonstrated the effects of exogenous norepinephrine (NE) on synaptic transmission but no quantitative studies of ganglionic NE content and release exist. Therefore, the distribution and density of catecholamine (CA)-containing nerves in rabbit pancreatic ganglia were studied using paraformaldehyde/glutaraldehyde (FAGLU) staining and HPLC analysis of CA concentrations. Neural release of [ 3 H]NE was measured in ganglia isolated from the head/neck or body regions of the pancreas. CA-containing nerves densely innervated most ganglia (86%) from both regions, while neural and non-neural CA-containing cell bodies were rarely found. Ganglia from the head/neck region contained significantly higher concentrations of NE. Both 40 mM K + and veratridine evoked Ca 2+ -dependent [ 3 H]NE release and tetrodotoxin inhibited 80% of veratridine-stimulated release. N-Conotoxin GVIA alone antagonized veratridine-stimulated release by 40% but the addition of nifedipine or N-agatoxin IVA caused no further inhibition. There were no apparent regional differences in the Ca 2+ -dependence or toxin-sensitivity of NE release. In conclusion, ganglia throughout the rabbit pancreas receive a dense, functional noradrenergic innervation and NE release is dependent upon N-but not P/Q-or L-type voltage-dependent Ca 2+ channels. These noradrenergic nerves may indirectly regulate pancreatic secretion through actions on ganglionic transmission. D
Innervation of the pancreas by neurons in the gut
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1990
Experiments were done in order to test the hypothesis that neurons in the bowel send axonal projections to the pancreas and can modify pancreatic activity. pancreatic injections of the retrograde tracer, Fluoro-Gold, labeled neurons in the myenteric plexus of the antrum of the stomach and in the first 6 cm of the duodenum. this labeling was not due to the diffusion of Fluoro-Gold from the pancreas, because the injections did not label longitudinal muscle cells overlying labeled ganglia in the bowel or neurons in the phrenic nerve nucleus or nucleus ambiguous; nor were enteric neurons labeled if insufficient time was allotted for retrograde transport. More Fluoro-Gold labeled neurons were found in the stomach (9.2 +/- 0.9/ganglion) than in the duodenum (3.8 +/- 0.3/ganglion; p less than 0.001). Neurons were found in myenteric ganglia of both duodenum and stomach that were doubly labeled by retrograde transport of Fluoro-Gold and anti-serotonin (5-HT) sera. In addition, thick bundles ...