Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

P2X receptors

Extracellular adenosine 5′-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2X receptors have a widespread tissue distribution. On some smooth muscle cells, P2X receptors mediate the fast excitatory junction potential that leads to depolarization and contraction. In the central nervous system, activation of P2X receptors allows calcium to enter neurons and this can evoke slower neuromodulatory responses such as the trafficking of receptors for the neurotransmitter glutamate. In primary afferent nerves, P2X receptors are critical for the initiation of action potentials when they respond to ATP released from sensory cells such as taste buds, chemoreceptors or urothelium. In immune cells, activation of P2X receptors triggers the release of pro-inflammatory cytokines such as interleukin 1β. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in the management of cough, pain, inflammation and certain neurodegenerative diseases. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

Primary Afferent Stimulation Differentially Potentiates Excitatory and Inhibitory Inputs to Spinal Lamina II Outer and Inner Neurons

Spinal lamina II (substantia gelatinosa) neurons play an important role in processing of nociceptive information from primary afferent nerves. Anatomical studies suggest that neurons in the outer (lamina IIo) and inner (lamina IIi) zone of lamina II receive distinct afferent inputs. The functional significance of this preferential afferent termination in lamina II remains unclear. In this study, we examined the differential synaptic inputs to neurons in lamina IIo and IIi in response to primary afferent stimulation. Whole cell voltage-clamp recordings were performed on neurons in lamina IIo and IIi of the rat spinal cord slice under visual guidance. Capsaicin (1 μM) significantly increased the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in all 27 lamina IIo neurons and significantly increased the amplitude of mEPSCs in 12 of 27 lamina IIo neurons. However, capsaicin only significantly increased the frequency of mEPSCs in 9 of 22 (40.9%) lamina IIi neurons and increased the amplitude of mEPSCs in 6 of these 9 neurons. Furthermore, the peak amplitude of EPSCs, evoked by electrical stimulation of the attached dorsal root, in 40 lamina IIo neurons was significantly greater than that [160.5 ± 16.7 vs. 87.0 ± 10.4 (SE) pA] in 37 lamina IIi neurons. On the other hand, the peak amplitude of evoked inhibitory postsynaptic currents (IPSCs) in 40 lamina IIo neurons was significantly smaller than that (103.1 ± 11.6 vs. 258.4 ± 24.4 pA) in 37 lamina IIi neurons. In addition, the peak amplitudes of both EPSCs and IPSCs, evoked by direct stimulation of lamina II, were similar in lamina IIo and IIi neurons. This study provides new information that stimulation of primary afferents differentially potentiates synaptic inputs to neurons in lamina IIo and IIi. The quantitative difference in excitatory and inhibitory synaptic inputs to lamina IIo and IIi neurons may be important for integration of sensory information from primary afferent nerves.

Modeling an electrosensory landscape

SUMMARYMost biological sensory systems benefit from multiple sensors. Elasmobranchs (sharks, skates and rays) possess an array of electroreceptive organs that facilitate prey location, mate location and navigation. Here, the perceived electrosensory landscape for an elasmobranch approaching prey is mathematically modeled. The voltages that develop simultaneously in dozens of separate sensing organs are calculated using electrodynamics. These voltages lead directly to firing rate modifications in the primary afferent nerves. The canals connecting the sense organs to an elasmobranch's surface exhibit great variation of location and orientation. Here, the voltages arising in the sense organs are found to depend strongly on the geometrical distribution of the corresponding canals. Two applications for the modeling technique are explored: an analysis of observed elasmobranch prey-capture behavior and an analysis of morphological optimization. For the former, results in specific predator-prey scenarios are compared with behavioral observations, supporting the approach algorithm suggested by A. Kalmijn. For the latter, electrosensory performance is contrasted for two geometrical models of multiple sense organs,a rounded head and a hammer-shaped head.

Arteriolar dilation mediated by capsaicin and calcitonin gene-related peptide in rats

In addition to altering vascular tone by stimulating primary afferent nerves and acting through reflex pathways, capsaicin acts locally. We examined effects of topically applied capsaicin on arteriolar diameter in striated muscle and tested the hypothesis that capsaicin can alter microvascular tone by releasing substance P (SP) or calcitonin gene-related peptide (CGRP). In anesthetized rats, the right cremaster muscle was exposed and suspended in a tissue bath filled with a physiological salt solution. Diameters of third-order arterioles were displayed and measured using in vivo video microscopy. In 17 of 20 rats, addition of capsaicin (3 x 10(-7) M) to the bath dilated arterioles (85 +/- 14% above control). Failure of a second administration of capsaicin to produce a sustained dilation in 6 of 7 arterioles that had previously dilated to capsaicin is consistent with the hypothesis that this agent causes depletion of an endogenous vasodilator. Pretreatment with an SP inhibitor did not alter capsaicin-induced dilation. CGRP (1 x 10(-10) to 2 x 10(-8) M) caused dilation similar to that caused by capsaicin. Pretreatment with a CGRP inhibitor to the bath prevented capsaicin-induced dilation, but not constriction. These results suggest that capsaicin can dilate microvessels by releasing CGRP, which can modulate tone.