TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus.
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 Adelta 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.
Yu
Shaoyong
S
Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. suy13@psu.edu
Ouyang
Ann
A
D000200:Action Potentials; D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D065094:Bradykinin B2 Receptor Antagonists; D004947:Esophagus / Q000294:innervation*; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000378:metabolism*; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D040542:Mechanotransduction, Cellular; D009281:Naphthalenes / Q000494:pharmacology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism; D009620:Nodose Ganglion / Q000187:drug effects / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011312:Pressure; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D013268:Stimulation, Chemical; D050051:Transient Receptor Potential Channels / Q000187:drug effects / Q000378:metabolism*; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*
D065094:Bradykinin B2 Receptor Antagonists; D017879:Isothiocyanates; D009281:Naphthalenes; D009943:Organophosphorus Compounds; D043782:Receptor, Bradykinin B2; D050051:Transient Receptor Potential Channels; C087374:WIN 64338; C004471:allyl isothiocyanate; D001920:Bradykinin