TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus

2009 ◽  
Vol 296 (2) ◽  
pp. G255-G265 ◽  
Author(s):  
Shaoyong Yu ◽  
Ann Ouyang
Keyword(s):  
Guinea Pig ◽  
Action Potentials ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Sensory Nerves ◽  
Peripheral Sensitization ◽  
Nerve Terminals ◽  
Mechanical Hypersensitivity ◽  
C Fibers

Bradykinin (BK) activates sensory nerves and causes hyperalgesia. Transient receptor potential A1 (TRPA1) is expressed in sensory nerves and mediates cold, mechanical, and chemical nociception. TRPA1 can be activated by BK. TRPA1 knockout mice show impaired responses to BK and mechanical nociception. However, direct evidence from sensory nerve terminals is lacking. This study aims to determine the role of TRPA1 in BK-induced visceral mechanical hypersensitivity. Extracellular recordings of action potentials from vagal nodose and jugular neurons are performed in an ex vivo guinea pig esophageal-vagal preparation. Peak frequencies of action potentials of afferent nerves evoked by esophageal distension and chemical perfusion are recorded and compared. BK activates most nodose and all jugular C fibers. This activation is repeatable and associated with a significant increase in response to esophageal distension, which can be prevented by the B2 receptor antagonist WIN64338. TRPA1 agonist allyl isothiocyanate (AITC) activates most BK-positive nodose and jugular C fibers. This is associated with a transient loss of response to mechanical distensions and desensitization to a second AITC perfusion. Desensitization with AITC and pretreatment with TRPA1 inhibitor HC-030031 both inhibit BK-induced mechanical hypersensitivity but do not affect BK-evoked activation in nodose and jugular C fibers. In contrast, esophageal vagal afferent Aδ fibers do not respond to BK or AITC and fail to show mechanical hypersensitivity after BK perfusion. This provides the first evidence directly from visceral sensory afferent nerve terminals that TRPA1 mediates BK-induced mechanical hypersensitivity. This reveals a novel mechanism of visceral peripheral sensitization.

scholarly journals Effect of synthetic cationic protein on mechanoexcitability of vagal afferent nerve subtypes in guinea pig esophagus

2011 ◽  
Vol 301 (6) ◽  
pp. G1052-G1058 ◽  
Author(s):  
Shaoyong Yu ◽  
Ann Ouyang
Keyword(s):  
Action Potentials ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Vagal Afferents ◽  
Spontaneous Discharge ◽  
Cationic Protein ◽  
C Fibers ◽  
Potentiation Effect ◽  
Before And After ◽  
Evoke Action Potential

Eosinophilic esophagitis is characterized by increased infiltration and degranulation of eosinophils in the esophagus. Whether eosinophil-derived cationic proteins regulate esophageal sensory nerve function is still unknown. Using synthetic cationic protein to investigate such effect, we performed extracellular recordings from vagal nodose or jugular neurons in ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Nerve excitabilities were determined by comparing action potentials evoked by esophageal distensions before and after perfusion of synthetic cationic protein poly-l-lysine (PLL) with or without pretreatment with poly-l-glutamic acid (PLGA), which neutralized cationic charges of PLL. Perfusion with PLL did not evoke action potentials in esophageal nodose C fibers but increased their responses to esophageal distension. This potentiation effect lasted for 30 min after washing out of PLL. Pretreatment with PLGA significantly inhibited PLL-induced mechanohyperexcitability of esophageal nodose C fibers. In esophageal nodose Aδ fibers, perfusion with PLL did not evoke action potentials. In contrast to nodose C fibers, both the spontaneous discharges and the responses to esophageal distension in nodose Aδ fibers were decreased by perfusion with PLL, which can be restored after washing out PLL for 30–60 min. Pretreatment with PLGA attenuated PLL-induced decrease in spontaneous discharge and mechanoexcitability of esophageal nodose Aδ fibers. In esophageal jugular C fibers, PLL neither evoked action potentials nor changed their responses to esophageal distension. Collectively, these data demonstrated that synthetic cationic protein did not evoke action potential discharges of esophageal vagal afferents but had distinctive sensitization effects on their responses to esophageal distension.

scholarly journals Effects of acid on vagal nociceptive afferent subtypes in guinea pig esophagus

2014 ◽  
Vol 307 (4) ◽  
pp. G471-G478 ◽  
Author(s):  
Xiaoyun Yu ◽  
Youtian Hu ◽  
Shaoyong Yu
Keyword(s):  
Guinea Pig ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Acid Reflux ◽  
Motor Dysfunction ◽  
Nerve Endings ◽  
Noncardiac Chest Pain ◽  
C Fibers ◽  
Acid Perfusion ◽  
C Fiber

Acid reflux-induced heartburn and noncardiac chest pain are processed peripherally by sensory nerve endings in the wall of the esophagus, but the underlying mechanism is still unclear. This study aims to determine the effects of acid on esophageal vagal nociceptive afferent subtypes. Extracellular single-unit recordings were performed in guinea pig vagal nodose or jugular C fiber neurons by using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. We recorded action potentials (AP) of esophageal nodose or jugular C fibers evoked by acid perfusion and compared esophageal distension-evoked AP before and after acid perfusion. Acid perfusion for 30 min (pH range 7.4 to 5.8) did not evoke AP in nodose C fibers but significantly decreased their responses to esophageal distension, which could be recovered after washing out acid for 90 min. In jugular C fibers, acid perfusion not only evoked AP but also inhibited their responses to esophageal distension, which were not recovered after washing out acid for 120 min. Lower concentration of capsaicin perfusion mimicked acid-induced effects in nodose and jugular C fibers. Pretreatment with TRPV1 antagonist AMG9810, but not acid-sensing ion channel (ASIC) inhibitor amiloride, significantly inhibited acid-induced effects in nodose and jugular C fiber. These results demonstrate that esophageal vagal nociceptive afferent nerve subtypes display distinctive responses to acid. Acid activates jugular, but not nodose, C fibers and inhibits both of their responses to esophageal distension. These effects are mediated mainly through TRPV1. This inhibitory effect is a novel finding and may contribute to esophageal sensory/motor dysfunction in acid reflux diseases.

scholarly journals The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mariska P. M. van den Berg ◽  
Susan Nijboer-Brinksma ◽  
I. Sophie T. Bos ◽  
Maarten van den Berge ◽  
David Lamb ◽  
...  
Keyword(s):  
Pilot Study ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Chronic Respiratory Disease ◽  
The Novel ◽  
Airway Narrowing

Abstract Background Asthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma. Methods First, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann–Whitney U test or One-way nonparametric Kruskal–Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate. Results A dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips. Conclusions TRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.

scholarly journals The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs

2021 ◽  
Author(s):  
Mariska van den Berg ◽  
Susan Nijboer - Brinksma ◽  
Sophie Bos ◽  
Maarten van den Berge ◽  
David Lamb ◽  
...  
Keyword(s):  
Pilot Study ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Chronic Respiratory Disease ◽  
The Novel ◽  
Airway Narrowing

Abstract Background: Asthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 in against AHR and inflammation guinea-pig models of asthma.Methods: First, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann-Whitney U test or One-way nonparametric Kruskal-Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate.Results: A dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips.Conclusions: TRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.

Capsaicin-sensitive afferent nerves activate submucosal secretomotor neurons in guinea pig ileum

1995 ◽  
Vol 269 (2) ◽  
pp. G203-G209 ◽  
Author(s):  
S. Vanner ◽  
W. K. MacNaughton
Keyword(s):  
Guinea Pig ◽  
Ion Transport ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Sensory Nerves ◽  
Guinea Pig Ileum ◽  
Secretomotor Neurons

This study examined whether capsaicin-sensitive sensory nerves regulate intestinal ion transport using both Ussing chamber and intracellular recording techniques in in vitro submucosal preparations from the guinea pig ileum. In Ussing chamber studies, serosal application of capsaicin (20 nM-20 microM) evoked a biphasic dose-dependent increase in short-circuit current (Isc) (maximal effective concentration 200 nM and 2 microM, respectively). In chloride-free buffer, capsaicin responses were significantly reduced. Capsaicin evoked little or no response when extrinsic sensory nerve fibers had been surgically removed and tetrodotoxin and low-calcium and high-magnesium solutions blocked responses to capsaicin. In epithelial preparations devoid of submucosal neurons, capsaicin had virtually no effect, suggesting that responses evoked by capsaicin-sensitive nerves result from activation of submucosal secretomotor neurons. Intracellular recordings from single submucosal neurons demonstrated that superfusion with capsaicin (2 microM) depolarized neurons with an associated decreased conductance. Depolarizations were completely desensitized when capsaicin was reapplied, but synaptic inputs were unaffected. This study suggests that capsaicin-sensitive nerves can regulate ion transport in the gastrointestinal tract by release of neurotransmitter(s) that activate submucosal secretomotor neurons.

scholarly journals The Effects of Polarizing Current on Nerve Terminal Impulses Recorded from Polymodal and Cold Receptors in the Guinea-pig Cornea

2002 ◽  
Vol 120 (3) ◽  
pp. 395-405 ◽  
Author(s):  
Richard W. Carr ◽  
Svetlana Pianova ◽  
James A. Brock
Keyword(s):  
Guinea Pig ◽  
Nerve Terminal ◽  
Sensory Nerve ◽  
Outward Current ◽  
Nerve Terminals ◽  
Functional Difference ◽  
Inward Current ◽  
Cold Receptor ◽  
Cold Receptors

It was reported recently that action potentials actively invade the sensory nerve terminals of corneal polymodal receptors, whereas corneal cold receptor nerve terminals are passively invaded (Brock, J.A., S. Pianova, and C. Belmonte. 2001. J. Physiol. 533:493–501). The present study investigated whether this functional difference between these two types of receptor was due to an absence of voltage-activated Na+ conductances in cold receptor nerve terminals. To address this question, the study examined the effects of polarizing current on the configuration of nerve terminal impulses recorded extracellularly from single polymodal and cold receptors in guinea-pig cornea isolated in vitro. Polarizing currents were applied through the recording electrode. In both receptor types, hyperpolarizing current (+ve) increased the negative amplitude of nerve terminal impulses. In contrast, depolarizing current (−ve) was without effect on polymodal receptor nerve terminal impulses but increased the positive amplitude of cold receptor nerve terminal impulses. The hyperpolarization-induced increase in the negative amplitude of nerve terminal impulses represents a net increase in inward current. In both types of receptor, this increase in inward current was reduced by local application of low Na+ solution and blocked by lidocaine (10 mM). In addition, tetrodotoxin (1 μM) slowed but did not reduce the hyperpolarization-induced increase in the negative amplitude of polymodal and cold nerve terminal impulses. The depolarization-induced increase in the positive amplitude of cold receptor nerve terminal impulses represents a net increase in outward current. This change was reduced both by lidocaine (10 mM) and the combined application of tetraethylammomium (20 mM) and 4-aminopyridine (1 mM). The interpretation is that both polymodal and cold receptor nerve terminals possess high densities of tetrodotoxin-resistant Na+ channels. This finding suggests that in cold receptors, under normal conditions, the Na+ conductances are rendered inactive because the nerve terminal region is relatively depolarized.

scholarly journals TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus

2015 ◽  
Vol 308 (6) ◽  
pp. G489-G496 ◽  
Author(s):  
Xiaoyun Yu ◽  
Youtian Hu ◽  
Fei Ru ◽  
Marian Kollarik ◽  
Bradley J. Undem ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Sensory Transduction ◽  
Dependent Manner ◽  
Preferential Expression ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor

Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.

scholarly journals Mechanisms of the adenosine A2Areceptor-induced sensitization of esophageal C fibers

2016 ◽  
Vol 310 (3) ◽  
pp. G215-G223 ◽  
Author(s):  
M. Brozmanova ◽  
L. Mazurova ◽  
F. Ru ◽  
M. Tatar ◽  
Y. Hu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Mechanical Response ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Receptor Potential ◽  
P2x Receptor ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor ◽  
Stimulation Of

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2Areceptor. Here we addressed the hypothesis that stimulation of the adenosine A2Areceptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2Areceptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10–60 mmHg) in a concentration-dependent fashion (1–100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2Aantagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031 . Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2Areceptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

scholarly journals Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus

2015 ◽  
Vol 308 (6) ◽  
pp. G482-G488 ◽  
Author(s):  
Zhenyu Liu ◽  
Youtian Hu ◽  
Xiaoyun Yu ◽  
Jiefeng Xi ◽  
Xiaoming Fan ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Allergen Challenge ◽  
Nerve Endings ◽  
Mast Cell Activation ◽  
Antigen Challenge ◽  
Esophageal Mucosa ◽  
C Fibers ◽  
C Fiber

Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE.

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