Identifying spinal sensory pathways activated by noxious esophageal acid (original) (raw)
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Brain Research, 2005
Little is known about transmitters that encode noxious gastric stimuli in the spinal cord. The release of glutamate, substance P, and CGRP from the spinal cord was therefore investigated in response to acid injury of the gastric mucosa. Dorsal halves of the caudal thoracic spinal cord (T7-T13) were removed 6 h after oral application of 0.5 M HCl or saline, transferred to a superfusion chamber, and the basal and capsaicin-stimulated (3.3 AM) transmitter release was determined. After acid injury, basal glutamate release increased 134% as compared to saline-treated animals. Capsaicin-stimulated release of CGRP and SP was 48% and 58% lower in acid-than in saline-treated animals, indicating that capsaicin-sensitive fibers in the dorsal spinal cord were already partially depleted by acid treatment. Capsaicin denervation reduced basal glutamate release by 33% after acid injury as compared to non-denervated acid-treated animals. Gastric origin and capsaicin sensitivity of glutamatergic, CGRP-and SP-containing primary afferents in thoracic dorsal root ganglia were then determined by retrograde tracing with True Blue and immunohistochemical labeling with the vanilloid receptor TRPV1. About 65% of True Blue-labeled cells were glutamatergic and more than 73% of this population expressed the TRPV1 receptor. Nearly all True Blue/CGRP (85%)-and True Blue/SPpositive cells (97%) coexpressed TRPV1. We conclude that noxious gastric stimulation with acid induces release of glutamate, SP, and CGRP from capsaicin-sensitive sensory afferents in the dorsal horn of the spinal cord where they may play an important role in gastric nociception and hyperalgesia. D 2005 Elsevier B.V. All rights reserved. Theme: Sensory system Topic: Somatic and visceral afferents
European Journal of Neuroscience, 2004
It is still unknown which receptors of peripheral sensory pathways encode and integrate an acid-induced nociceptive event in the gastric mucosa. The transient receptor potential vanilloid receptor 1 (TRPV1) and the acid-sensing ion channel 3 (ASIC3) are two nociceptionrelated receptors. Here we investigated (i) to what extent these receptors are distributed in stomach-innervating neurons of dorsal root and nodose ganglia, using immunohistochemistry and retrograde tracing, and (ii) whether their expression is altered in response to a noxious acid challenge of the stomach. We also explored the presence of TRPV1 in the gastric enteric nervous system because of its possible expression by intrinsic sensory neurons. Most stomach-innervating neurons in nodose ganglia were immunoreactive for TRPV1 (80%) and ASIC3 (75%), these results being similar in the dorsal root ganglia (71 and 82%). RT-PCR and Western blotting were performed up to 6 h after oral application of 0.5 M HCl to conscious rats. TRPV1 protein was increased in dorsal root but not in nodose ganglia whereas TRPV1 and ASIC3 mRNAs remained unchanged. TRPV1 mRNA was detected in longitudinal muscle±myenteric plexus preparations of control stomachs and was not altered by the acid challenge. Combined vagotomy and ganglionectomy abolished expression of TRPV1, indicating that it may derive from an extrinsic source. In summary, noxious acid challenge of the stomach increased TRPV1 protein in spinal but not vagal or intrinsic sensory afferents. The TRPV1 receptor may be a key molecule in the transduction of acid-induced nociception of the gastric mucosa and a mediator of visceral hypersensitivity.
Histochemistry and Cell Biology, 2013
The calcitonin gene-related peptide (CGRP)-receptor is a heterodimer of calcitonin receptorlike receptor (CLR) and receptor activity modifying protein 1 (RAMP1). Despite the importance of CGRP in regulating gastrointestinal functions, nothing is known about the distribution and function of CLR/RAMP1 in the esophagus, where up to 90% of spinal afferent neurons contain CGRP. We detected CLR/RAMP1 in the mouse esophagus using immunofluorescence and confocal laser scanning microscopy and examined their relationship with neuronal elements of the myenteric plexus. Immunoreactivity for CLR and RAMP1 colocalized with VGLUT2-positive IGLEs, which were contacted by CGRP-positive varicose axons presumably of spinal afferent origin, typically at sites of CRL/ RAMP1 immunoreactivity. This provides an anatomical basis for interaction between spinal afferent fibres and IGLEs. Immunoreactive CLR and RAMP1 also colocalized in myenteric neurons. Thus, CGRP-containing spinal afferents may interact with both vagal IGLEs and myenteric neurons in the mouse esophagus, possibly modulating motility reflexes and inflammatory hypersensitivity.
Attenuation of acid induced oesophagitis in VR-1 deficient mice
Gut, 2006
BACKGROUND AND AIMS: Activation of the vanilloid receptor subtype-1 (VR-1) results in release of pro-inflammatory peptides, which initiate an inflammatory cascade known as neurogenic inflammation. We investigated its role in an acute model of surgically-induced esophagitis. METHODS: Esophagitis was induced by pyloric ligation in wild-type, and VR-1 deficient mice. A subset of animals were administered the VR-1 antagonist capsazepine, famotidine, or omeprazole 1 hour before surgery. Five hours after surgery, myeloperoxidase activity (MPO), histologic damage scores, intragastric pH, and immunocytochemical analysis of substance P (SP) receptor endocytosis were determined. RESULTS: Esophagitis-induced knockout mice exhibited significantly lower levels of MPO activity, histologic damage scores, and SP receptor endocytosis than wild-type mice. Inflammatory parameters were significantly reduced by acid inhibition and capsazepine in wild-type mice. CONCLUSIONS: We conclude that acute acid-induced esophagitis is reduced in animals lacking VR-1. This suggests that acid-induced esophagitis may act through VR-1 and that inhibition of the receptor may reduce inflammation. Gastroesophageal reflux disease (GERD) is a common disorder affecting an estimated 5% to 7% of the global population, [1] and refers to the backflow of gastric or biliary contents into the esophagus resulting in inflammation and tissue damage of the esophagus. Continuous exposure to these compounds may result in pre-cancerous conditions such as Barrett's esophagus or invasive subsequent cancer. Although symptomatic relief is achieved in a number of patients who are treated with therapies aimed to correct the altered anatomic or physiologic conditions, none of these correct the underlying inflammation. Previous studies have investigated the mechanisms of neurogenic inflammation in the pancreas [2] and the intestine; [3] [4] [5] however, there has been little research focused on the association between the enteric nervous system and esophageal diseases. Neurogenic inflammation refers to the stimulation of primary sensory neurons, which in turn conveys nociceptive information to the spinal cord and exacerbates the inflammatory and immune responses in the peripheral tissues via an axon reflex.[6] [7] This neurogenic response is characterized by plasma extravasation, vasodilatation, neutrophil infiltration, and activation of immune cells.
The Journal of physiology, 2007
Emerging evidence indicates a nociceptive role of vagal afferents. A distinct oesophageal innervation in the rat, with muscular and mucosal afferents travelling predominantly in the recurrent (RLN) and superior laryngeal nerve (SLN), respectively, enabled characterization of mucosal afferents with nociceptive properties, using novel isolated oesophagus-nerve preparations. SLN and RLN single-fibre recordings identified 55 and 14 units, respectively, with none conducting faster than 8.7 m s(-1). Mucosal response characteristics in the SLN distinguished mechanosensors (n = 13), mechanosensors with heat sensitivity (18) from those with cold sensitivity (19) and a mechanoinsensitive group (5). The mechanosensitive fibres, all slowly adapting, showed a unimodal distribution of mechanical thresholds (1.4-128 mN, peak approximately 5.7 mN). No difference in response characteristics of C and Adelta fibres was encountered. Mucosal proton stimulation (pH 5.4 for 3 min), mimicking gastro-oesoph...
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2014
Acid-sensing ion channels (ASICs) have been implicated in esophageal acid sensing and mechanotransduction. However, insufficient knowledge of ASIC subunit expression profile in esophageal afferent nerves hampers the understanding of their role. This knowledge is essential because ASIC subunits form heteromultimeric channels with distinct functional properties. We hypothesized that the esophageal putative nociceptive C-fiber nerves (transient receptor potential vanilloid 1, TRPV1-positive) express multiple ASIC subunits and that the ASIC expression profile differs between the nodose TRPV1-positive subtype developmentally derived from placodes and the jugular TRPV1-positive subtype derived from neural crest. We performed single cell RT-PCR on the vagal afferent neurons retrogradely labeled from the esophagus. In the guinea pig, nearly all (90%–95%) nodose and jugular esophageal TRPV1-positive neurons expressed ASICs, most often in a combination (65–75%). ASIC1, ASIC2, and ASIC3 were e...
BMC neuroscience, 2005
Hydrochloric acid (HCl) is a potential threat to the integrity of the gastric mucosa and is known to contribute to upper abdominal pain. We have previously found that gastric mucosal challenge with excess HCl is signalled to the rat brainstem, but not spinal cord, as visualized by expression of c-fos messenger ribonucleic acid (mRNA), a surrogate marker of neuronal excitation. This study examined whether gastric mucosal exposure to capsaicin, a stimulant of nociceptive afferents that does not damage the gastric mucosa, is signalled to both brainstem and spinal cord and whether differences in the afferent signalling of gastric HCl and capsaicin challenge are related to different effects on gastric emptying. Rats were treated intragastrically with vehicle, HCl or capsaicin, activation of neurons in the brainstem and spinal cord was visualized by in situ hybridization autoradiography for c-fos mRNA, and gastric emptying deduced from the retention of intragastrically administered fluid....
Spinal afferent neurons projecting to the rat lung and pleura express acid sensitive channels
Respiratory research, 2006
The acid sensitive ion channels TRPV1 (transient receptor potential vanilloid receptor-1) and ASIC3 (acid sensing ion channel-3) respond to tissue acidification in the range that occurs during painful conditions such as inflammation and ischemia. Here, we investigated to which extent they are expressed by rat dorsal root ganglion neurons projecting to lung and pleura, respectively. The tracer DiI was either injected into the left lung or applied to the costal pleura. Retrogradely labelled dorsal root ganglion neurons were subjected to triple-labelling immunohistochemistry using antisera against TRPV1, ASIC3 and neurofilament 68 (marker for myelinated neurons), and their soma diameter was measured. Whereas 22% of pulmonary spinal afferents contained neither channel-immunoreactivity, at least one is expressed by 97% of pleural afferents. TRPV1+/ASIC3- neurons with probably slow conduction velocity (small soma, neurofilament 68-negative) were significantly more frequent among pleural (...
Cortical changes to experimental sensitization of the human esophagus
Neuroscience, 2006
Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation.