Distension‐sensitive vagal afferent fibres from the cardiac region of the guinea‐pig stomach were recorded extracellularly, then filled with biotinamide, using an anterograde tracing technique. Most of the stretch‐sensitive units of the guinea‐pig stomach (41 out of 47; number of animals N= 26) had low thresholds (less than 1 mm) to circumferential stretch and showed slow adaptation. Twenty of these units fired spontaneously under resting conditions (mean: 1.9 ± 0.3 Hz, n = 20, N = 14). Adaptation of firing during slow or maintained stretch correlated closely with accommodation of intramural tension, but tension‐independent adaptation was also present. Nicardipine (3 μm) with hyoscine (3 μm) reduced stretch‐evoked firing of gastric vagal afferents, by inhibiting smooth muscle contraction. Gadolinium (1 mm) blocked distension‐evoked firing. Focal stimulation of the stomach muscle wall with a von Frey hair (0.4 mN) identified one to six punctate receptive fields in each low threshold vagal distension‐sensitive afferent. These were marked on the serosal surface of the stomach wall. Anterograde filling of recorded nerve trunks revealed intraganglionic laminar endings (IGLEs) within 142 ± 34 μm (n = 38; N = 10) of marked receptive fields. The mean distance from randomly generated sites to the nearest IGLE was significantly greater (1500 ± 48 μm, n = 380, N = 10, P < 0.0001). Viscerofugal nerve cell bodies, intramuscular arrays and varicose axons were not associated with receptive fields. The results indicate that IGLEs are the mechanotransduction sites of low threshold, slowly adapting vagal tension receptors in the guinea‐pig upper stomach.

Vagal mechanoreceptors to the guinea-pig oesophagus, recorded extracellularly, in vitro, fired spontaneously at 3.3 ± 0.2 Hz, (n = 75, from 57 animals), and had low thresholds to circumferential stretch. In this study, we have investigated whether mechanotransduction by intraganglionic laminar endings (IGLEs) directly relies on mechano-gated ion channels, or whether it is due to chemical activation by neurotransmitters (

Background & Aims-Large distensions reliably evoke sensation from the non-inflamed, nonischemic bowel, but the specialized afferent axonal structures responsible have not been

Non-technical summary The endothelin-3 (ET-3) gene is essential for the development of the enteric nervous system in the gastrointestinal tract of mammals, including humans and mice. Loss of the ET-3 gene leads to the formation of an aganglionic colorectum and impaired bowel function. Endogenous endothelin peptides and their receptors also play a major role in nociception in a variety of organs and species, including humans. However, whether nociception is altered in the aganglionic region of the colorectum is unknown. We show that in ET-3 deficient mice, there is a loss of nociception from the aganglionic rectum, but not other visceral organs. This loss of nociception is due to a reduction in spinal afferent innervation and a selective deficiency in specific classes of rectal afferent nerve fibres, which are necessary for detection of noxious stimuli from this region.Abstract Endothelin peptides and their endogenous receptors play a major role in nociception in a variety of different organs. They also play an essential role in the development of the enteric nervous system. Mice with deletions of the endothelin-3 gene (lethal spotted mice, ls/ls) develop congenital aganglionosis. However, little is known about how nociception might be affected in the aganglionic rectum of mice deficient in endothelin-3. In this study we investigated changes in spinal afferent innervation and visceral pain transmission from the aganglionic rectum in ls/ls mice. Electromyogram recordings from anaesthetized ls/ls mice revealed a deficit in visceromotor responses arising from the aganglionic colorectum in response to noxious colorectal distension. Loss of visceromotor responses (VMRs) in ls/ls mice was selective, as no reduction in VMRs was detected after stimulation of the bladder or somatic organs. Calcitonin gene related peptide (CGRP) immunoreactivity, retrograde neuronal tracing and extracellular afferent recordings from the aganglionic rectum revealed decreased colorectal spinal innervation, combined with a reduction in mechanosensitivity of rectal afferents. The sensory defect in ls/ls mice is primarily associated with changes in low threshold wide dynamic range rectal afferents. In conclusion, disruption of endothelin 3 gene expression not only affects development and function of the enteric nervous system, but also specific classes of spinal rectal mechanoreceptors, which are required for visceral nociception from the colorectum.

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