title: Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers.
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.affiliation: Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and.
authors.forename: M
authors.initials: M
authors.lastname: Brozmanova
authors.affiliation: Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and.
authors.forename: L
authors.initials: L
authors.lastname: Mazurova
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: F
authors.initials: F
authors.lastname: Ru
authors.affiliation: Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and.
authors.forename: M
authors.initials: M
authors.lastname: Tatar
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Kollarik
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004947:Esophagus / Q000187:drug effects* / Q000294:innervation*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D010627:Phenethylamines; D047428:Protein Kinase Inhibitors; D058911:Purinergic P2X Receptor Agonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D013449:Sulfonamides; D050051:Transient Receptor Potential Channels; D014230:Triazoles; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: C fibers; adenosine; esophagus; nociceptor; vagus nerve