Roles of central glutamate, acetylcholine and CGRP receptors in gastrointestinal afferent inputs to vagal preganglionic neurones
Introduction
The peripheral endings of vagal and spinal gastrointestinal primary afferents are found in all three (mucosal, muscular and serosal) layers of the gut wall, from the oesophagus to the colon (Clerc and Mei, 1983, Grundy and Scratcherd, 1989, Blackshaw and Grundy, 1990, Blackshaw and Grundy, 1991, Sengupta et al., 1992, Page and Blackshaw, 1998, Lynn and Blackshaw, 1999). Vagal and spinal afferents may have direct or indirect central connections with vagal preganglionic neurones found throughout the dorsal motor vagal nucleus (DMVN) (Blackshaw and Grundy, 1988, Rinaman et al., 1989), to form a reflex loop which projects to the abdominal and thoracic viscera. Although few studies have concentrated on the neurotransmitter content of gastrointestinal afferents, it is known that spinal and vagal primary afferents in general contain a large number of neuroactive substances (Dietrich et al., 1982, Kalia et al., 1984, Gibbins et al., 1985, Green and Dockray, 1988, Falempin et al., 1989, Sykes et al., 1994). These include glutamate, acetylcholine, calcitonin gene-related peptide (CGRP), adrenaline, noradrenaline, 5-hydroxytryptamine, γ-amino-butyric acid (GABA), substance P, and cholecystokinin.
It is known in cardiovascular and respiratory afferents that transmitter content provides functional specificity (Wilson et al., 1996, Paton, 1998). For example, the neurokinin-1 (NK-1) receptor is selectively involved in mediating vagal inputs from cardiac fibres to neurones in the nucleus tractus solitarius (NTS) — the main site of vagal afferent termination in the brainstem, but not those inputs from peripheral chemoreceptors or pulmonary C-fibres (Paton, 1998). On the other hand, non-NMDA (N-methyl-d-aspartate) receptors in the NTS are important in the transmission of information from pulmonary C-fibres (Wilson et al., 1996). From the gastrointestinal tract, so far we have only determined that NK-1 receptors are unlikely to be involved in transfer of sensory information (Partosoedarso and Blackshaw, 1997). Therefore it is not known which transmitters are released by mucosal and muscular afferents from different regions of the gut, and if each type releases different transmitters. This may be clinically relevant in the treatment of functional disorders such as irritable bowel syndrome and functional dyspepsia. We used an established in vivo electrophysiological technique where inputs from different afferent populations to vagal preganglionic neurones could be selectively activated (Iggo and Leek, 1967, Partosoedarso and Blackshaw, 1997), and combined this with pharmacological blockade of central neurotransmitter receptors. We focused on the role of the putative transmitters glutamate (via non-NMDA receptors), acetylcholine (via M1 muscarinic receptors), and CGRP (via CGRP1 receptors).
Section snippets
General
Experiments were performed on 21 male and female ferrets (Mustela putorius furo L.) weighing 0.5–1.4 kg, each initially anaesthetized with 1.25 g/kg urethane intraperitoneally. They were fed a standard carnivore diet with free access to water but were deprived of food for ∼18 h before experimentation. Studies were conducted in accordance with guidelines of the Animal Ethics Committee of the Royal Adelaide Hospital and Institute of Medical and Veterinary Sciences. Experiments were terminated by
Resting neuronal activity
In the absence of any intentional stimulus, vagal efferent neurones were either silent or possessed a low level of discharge (2.6±0.7 Hz, n=21). This basal discharge was irregular and not correlated with the cardiovascular, respiratory or gastrointestinal motility rhythms of the animal and remained steady prior to the administration of drug antagonists when not associated with a particular stimulus.
Efferent responses to peripheral stimuli
Responses to oesophageal balloon distension (1–2 ml air for 30 s) were evoked in 15/21 neurones.
Discussion
This study provides evidence for the involvement of at least three major transmitter mechanisms in central pathways from gastrointestinal afferents to vagal preganglionic neurones. These are acetylcholine acting via M1 muscarinic receptors, glutamate acting via non-NMDA receptors and CGRP acting via CGRP1 receptors. M1 muscarinic receptors were specifically involved in gastric mechanoreceptor inputs. Non-NMDA and CGRP1 receptors were not involved in mediating any particular type of afferent
Conclusions
There are at least three excitatory central neurotransmitter mechanisms involved in mediating afferent inputs to vagal preganglionic neurones. We found that non-NMDA and CGRP1 receptors together mediate inputs from the majority of oesophageal and gastric mechanoreceptors, gastrointestinal mucosal afferents and bradykinin-sensitive afferents. M1 muscarinic receptors are selectively involved in the transmission of inputs from gastric mechanoreceptors. Identification of selectivity in mechanisms
References (34)
- et al.
The distribution of glutamate, GABA, and aspartate in the nucleus tractus solitarius of the cat
Brain Res.
(1982) - et al.
Presence of cholinergic neurones in the vagal afferent system: involvement in a heterogenous reinnervation
J. Auton. Nerv. Syst.
(1989) - et al.
Colocalization of calcitonin gene-related peptide-like immunoreactivity with substance P in cutaneous, vascular, and visceral sensory neurons of guinea pigs
Neurosci. Lett.
(1985) - et al.
Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains
Brain Res.
(1986) - et al.
The role of neurokinin and N-methyl-d-aspartate receptors in synaptic transmission from capsaicin-sensitive primary afferents in the rat spinal cord in vitro
Neuroscience
(1993) - et al.
Vagal efferent fibre responses to gastric and oesophageal mechanical and chemical stimuli in the ferret
J. Auton. Nerv. Syst.
(1997) - et al.
Evidence for cholinergic vagal afferents and vagal presynaptic M1 receptors in the ferret
Neurochem. Int.
(1994) - et al.
Central distribution of substance P, calcitonin gene-related peptide and 5-hydroxytryptamine in vagal sensory afferents in the rat dorsal medulla
Neuroscience
(1994) - et al.
Central oxotremorine antagonist properties of pirenzepine
Life Sci.
(1988) - et al.
Effects of pirenzepine and atropine on basal lower esophageal pressure and gastric acid secretion in man: a placebo-controlled randomized study
Dig. Dis. Sci.
(1991)
Non-NMDA receptors mediate sensory afferent synaptic transmission in medial nucleus tractus solitarius
Am. J. Physiol.
Non-NMDA and NMDA receptors in the synaptic pathway between area postrema and nucleus tractus solitarius
Am. J. Physiol.
Reflex responses of vagal efferent fibres influenced by gastrointestinal mechanoreceptors to electrical afferent stimulation in the anaesthetized ferret
Q. J. Exp. Physiol.
Effects of cholecystokinin (CCK-8) on two classes of gastroduodenal vagal afferent fibre
J. Auton. Nerv. Syst.
Bradykinin effects on motility and vagal afferent discharge in the ferret stomach and duodenum
J. Gastrointest. Motil.
Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats
J. Physiol. (Lond.)
The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro
J. Physiol. (Lond.)
Cited by (25)
Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases
2018, Neurochemistry InternationalCitation Excerpt :This notion is supported by other findings, such as the discovery that Lactobacillus spp. and Bacillus spp. have the ability to produce acetylcholine, a neurotransmitter reduced in the brains of AD patients (Kawashima et al., 2007; Wall et al., 2014). It can be hypothesized that healthy gut microbiota aid in cholinergic signaling by way of the vagus nerve (Partosoedarso and Blackshaw, 2000). Investigations utilizing GF mice, as well as mice treated with probiotics or antibiotics, indicate that, in addition to impacting the molecular hallmarks of AD, bacteria have an important role in regulating learning, memory, and cognition (Hu et al., 2016).
Role of glutamatergic neurotransmission in the enteric nervous system and brain-gut axis in health and disease
2016, NeuropharmacologyCitation Excerpt :In functional studies carried out in the dog and rat, NMDA and AMPA/kainate receptor antagonists were able to attenuate the mechano-transduction properties of vagal sensory afferents after antrum distension (Furukawa et al., 2001; Sengupta et al., 2004). Electrophysiological measurement of the ferret vagal preganglionic neurons projecting to the periphery, showed that AMPA/kainate, more than NMDA, receptors are required for synaptic neurotransmission of mechano- and chemosensitive vagal inputs from the esophagus and stomach onto vagal efferents (Partosoedarso and Blackshaw, 2000). A small proportion of rat DMV neurons may, however, be excited by gastrointestinal distension, possibly as a consequence of a direct effect of glutamate released from vagal afferents departing from the NVG and directly contacting DMV neurons (Zhang and Fogel, 2003).
Regulation of the brain-gut axis by group III metabotropic glutamate receptors
2013, European Journal of PharmacologyCitation Excerpt :These enteric neurons express glutamate transporters and receptors just like the ones present in the CNS (Liu et al., 1997). Additionally, glutamate is an important activator of vagal pathways, mediating a range of upper gastrointestinal mechano and chemosensitive afferent inputs onto vagal efferents (Partosoedarso and Blackshaw, 2000; Uneyama et al., 2006). Both ionotropic and metabotropic glutamate receptors modulate glutamate transmission relevant to gastrointestinal reflexes such as swallowing, gastric accommodation and emesis (Hornby, 2001) and therefore are attractive candidates for development of pharmacological treatments.
Metabotropic glutamate receptors: From the workbench to the bedside
2011, NeuropharmacologyCitation Excerpt :These drugs, however, inhibit acid secretion without affecting LES tone. Interestingly, glutamate is a potent activator of the vagal pathway mediating LES relaxation (Partosoedarso and Blackshaw, 2000), and mGlu receptors, including mGlu5, are expressed by gastric vagal afferents (Page et al., 2005). Preclinical studies have shown that mGlu5-receptor NAMs such as MPEP and MTEP increase basal LES pressure and inhibit LES relaxation (Frisby et al., 2005; Jensen et al., 2005).
Intracellular acidification is associated with changes in free cytosolic calcium and inhibition of action potentials in rat trigeminal ganglion
2011, Journal of Biological ChemistryCitation Excerpt :We found that TRPV1, the receptor activated by capsaicin, was expressed only in small and intermediate sized TG neurons that are thought to be nociceptive (28). Glutamate has been shown to sensitize mechanosensitive afferents (29), and capsaicin has been shown to activate and sensitize trigeminal afferents; TRPV1 may also mediate Ca2+-dependent intracellular acidification in dorsal root ganglion neurons (7). Thus, both glutamate and capsaicin may possibly modulate the processing of nociceptive input in TG neurons from craniofacial tissues (30) via mechanisms involving [Ca2+]i elevation and pHi acidification.
Glutamate receptors within the nucleus of solitary tract contribute to pancreatic secretion stimulated by intraduodenal hypertonic saline
2005, Autonomic Neuroscience: Basic and Clinical