Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach

Sugiura, T.; Dang, K.; Lamb, Kenneth; Bielefeldt, Klaus; Gebhart, G. F.

doi:10.1523/jneurosci.2894-04.2005

Cited by 97 publications

(96 citation statements)

References 63 publications

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“…Colorectal afferent neurons containing CGRP␣ were significantly larger than the average size of all lumbosacral spinal afferents expressing CGRP␣ (804 Ϯ 286 vs. 464 Ϯ 231 m 2 , independent-samples t-test, P Ͻ 0.001, n ϭ 748 cells). This is consistent with observations in mouse (56) and rat (21,45,57) that visceral sensory somata with unmyelinated or thinly myelinated axons tend to be larger than nonvisceral sensory neurons within the same ganglia.…”

Section: Discussionsupporting

confidence: 92%

Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse

Hibberd

Kestell

Kyloh

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hibberd TJ, Kestell GR, Kyloh MA, Brookes SJ, Wattchow DA, Spencer NJ. Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRP␣ transgenic reporter mouse. Am J Physiol Gastrointest Liver Physiol 310: G561-G573, 2016. First published January 28, 2016 doi:10.1152/ajpgi.00462.2015.-Spinal afferent neurons detect noxious and physiological stimuli in visceral organs. Five functional classes of afferent terminals have been extensively characterized in the colorectum, primarily from axonal recordings. Little is known about the corresponding somata of these classes of afferents, including their morphology, neurochemistry, and electrophysiology. To address this, we made intracellular recordings from somata in L 6/S1 dorsal root ganglia and applied intraluminal colonic distensions. A transgenic calcitonin gene-related peptide-␣ (CGRP␣)-mCherry reporter mouse, which enabled rapid identification of soma neurochemistry and morphology following electrophysiological recordings, was developed. Three distinct classes of low-threshold distension-sensitive colorectal afferent neurons were characterized; an additional group was distension-insensitive. Two of three low-threshold classes expressed CGRP␣. One class expressing CGRP␣ discharged phasically, with inflections on the rising phase of their action potentials, at low frequencies, to both physiological (Ͻ30 mmHg) and noxious (Ͼ30 mmHg) distensions. The second class expressed CGRP␣ and discharged tonically, with smooth, briefer action potentials and significantly greater distension sensitivity than phasically firing neurons. A third class that lacked CGRP␣ generated the highest-frequency firing to distension and had smaller somata. Thus, CGRP␣ expression in colorectal afferents was associated with lower distension sensitivity and firing rates and larger somata, while colorectal afferents that generated the highest firing frequencies to distension had the smallest somata and lacked CGRP␣. These data fill significant gaps in our understanding of the different classes of colorectal afferent somata that give rise to distinct functional classes of colorectal afferents. In healthy mice, the majority of sensory neurons that respond to colorectal distension are low-threshold, wide-dynamic-range afferents, encoding both physiological and noxious ranges. colon; afferent; nociceptor; pain; sensory neuron IN MAMMALS, SPINAL AFFERENT neurons, with somata in dorsal root ganglia (DRG), encode noxious and physiological sensory stimuli in visceral organs. Most recordings from spinal afferents have been obtained via extracellular recording of nerve trunks containing a mix of different types of efferent and afferent nerve axons (12,27,33). In the large intestine of mice, extracellular recordings have been used to generate a classification scheme consisting of approximately five different functional types of colorectal afferents (5, 16). Numerous studies also report characteristics of colorectal-projecting spinal afferent som...

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Section: Discussionsupporting

confidence: 92%

Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse

Hibberd

Kestell

Kyloh

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This notion was confirmed by analyzing T-type current density in isolated cell bodies of identified colonic afferent neurons. Indeed, colonic nociceptors that are located at the thoracolumbar and sacral levels (19,20,32,33) were both found to express the Ca V 3.2 channels and to display small whole-cell T-type currents under control conditions. In contrast, in animals with induced colonic hypersensitivity, T-type current density was significantly increased, supporting their role as major pain signal amplifiers in primary afferent neurons.…”

Section: Discussionmentioning

confidence: 99%

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome

Marger

Gelot²,

Alloui³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

132

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The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca V 3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyratemediated rodent model of IBS. Both the selective genetic inhibition of Ca V 3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca V 3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca V 3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca V 3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.analgesia | visceral nociceptor | sensitization | trafficking I rritable bowel syndrome (IBS) is one of the most prevalent lower gastrointestinal (GI) tract disorders, affecting ∼20% of the population in developed countries. Despite high prevalence and considerable impairment of quality of life, current treatments for IBS are empirical and often poorly effective, and the disorder remains a challenge to clinicians (1). IBS is characterized by abdominal pain and discomfort associated with abnormal bowel functions. Although different etiologies have been proposed, it is generally accepted that IBS is multifactorial and that there are likely multiple molecular targets relevant to innovative drug development strategies (2). Among these, there is considerable interest in dysregulation of the brain-gut pain neuraxis and specific subtypes of ion channels in primary afferent neurons that mediate the detection of nociceptive stimuli and transmission to the CNS (3). Moreover, in a number of animal models of chronic pain, the pathological remodeling of ion channel expression patterns has been linked to the hyperexcitability of primary afferent nociceptors (4, 5).A number of ionic conductances contribute to neuronal firing, including voltage-gated calcium channels, which uniquely both shape action potentials and influence neuronal excitability. In mammals, 10 pore-forming calcium channel α 1 subunit genes have been identified, three of which, Ca V 3.1, Ca V 3.2, and Ca V 3.3, form low-voltage-activated (LVA) T-type calcium channels that are activated by weak depolarizations and generally act to control excitability (6, 7). Al...

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“…In pathological conditions such as duodenal or gastric ulcer, and gastroesophageal reflux disease, acid secretion can be associated with severe pain. In one study where gastric ulcers were induced in mice by short exposure of the gastric mucosa to acetic acid, gastric afferents in the DRG and nodose ganglia exhibited ASIC-like currents, which were attributed to expression of ASIC1 and ASIC2 subunits, based on the response to inhibitors (372). Signaling along the brain-gut axis was also disrupted in ASIC3 knockout mice which had been exposed to iodoacetamide to induce a mild gastritis (416).…”

Section: Asics and Painmentioning

confidence: 99%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

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The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach

Cited by 97 publications

References 63 publications

Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse

Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome

ENaCs and ASICs as therapeutic targets

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