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Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers.
Am J Physiol Gastrointest Liver Physiol. 2016 Feb 01; 310(3):G215-23.AJ

Abstract

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 A2A receptor. Here we addressed the hypothesis that stimulation of the adenosine A2A receptor 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 A2A receptor-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 A2A antagonist 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 A2A receptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

Authors+Show Affiliations

Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and.Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and.Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and.Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland kollarik@jhmi.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26564719

Citation

Brozmanova, M, et al. "Mechanisms of the Adenosine A2A Receptor-induced Sensitization of Esophageal C Fibers." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 310, no. 3, 2016, pp. G215-23.
Brozmanova M, Mazurova L, Ru F, et al. Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers. Am J Physiol Gastrointest Liver Physiol. 2016;310(3):G215-23.
Brozmanova, M., Mazurova, L., Ru, F., Tatar, M., Hu, Y., Yu, S., & Kollarik, M. (2016). Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers. American Journal of Physiology. Gastrointestinal and Liver Physiology, 310(3), G215-23. https://doi.org/10.1152/ajpgi.00350.2014
Brozmanova M, et al. Mechanisms of the Adenosine A2A Receptor-induced Sensitization of Esophageal C Fibers. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 1;310(3):G215-23. PubMed PMID: 26564719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers. AU - Brozmanova,M, AU - Mazurova,L, AU - Ru,F, AU - Tatar,M, AU - Hu,Y, AU - Yu,S, AU - Kollarik,M, Y1 - 2015/11/12/ PY - 2014/09/22/received PY - 2015/11/09/accepted PY - 2015/11/14/entrez PY - 2015/11/14/pubmed PY - 2016/6/4/medline KW - C fibers KW - adenosine KW - esophagus KW - nociceptor KW - vagus nerve SP - G215 EP - 23 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 310 IS - 3 N2 - 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 A2A receptor. Here we addressed the hypothesis that stimulation of the adenosine A2A receptor 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 A2A receptor-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 A2A antagonist 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 A2A receptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/26564719/Mechanisms_of_the_adenosine_A2A_receptor_induced_sensitization_of_esophageal_C_fibers_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00350.2014?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -