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This Article Free via Open Access: OA OA Full Text Full Text (PDF) OA All Versions of this Article: 580/3/977    most recent jphysiol.2006.126599v2 jphysiol.2006.126599v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kayssi, A. Articles by Vanner, S. Search for Related Content PubMed PubMed Citation Articles by Kayssi, A. Articles by Vanner, S. Related Collections Alimentary

¹ Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
² Departments of Surgery and Physiology, University of California, San Francisco, CA, USA

Agonists of protease-activated receptor 2 (PAR₂) evoke hyperexcitability of dorsal root ganglia (DRG) neurons by unknown mechanisms. We examined the cellular mechanisms underlying PAR₂-evoked hyperexcitability of mouse colonic DRG neurons to determine their potential role in pain syndromes such as visceral hyperalgesia. Colonic DRG neurons were identified by injecting Fast Blue and DiI retrograde tracers into the mouse colon. Using immunofluorescence, we found that DiI-labelled neurons contained PAR₂ immunoreactivity, confirming the presence of receptors on colonic neurons. Whole-cell current-clamp recordings of acutely dissociated neurons demonstrated that PAR₂ activation with a brief application (3 min) of PAR₂ agonists, SLIGRL-NH₂ and trypsin, evoked sustained depolarizations (up to 60 min) which were associated with increased input resistance and a marked reduction in rheobase (50% at 30 min). In voltage clamp, SLIGRL-NH₂ markedly suppressed delayed rectifier I_K currents (55% at 10 min), but had no effect on the transient I_A current or TTX-resistant Na⁺ currents. In whole-cell current-clamp recordings, the sustained excitability evoked by PAR₂ activation was blocked by the PKC inhibitor, calphostin, and the ERK_1/2 inhibitor PD98059. Studies of ERK_1/2 phosphorylation using confocal microscopy demonstrated that SLIGRL-NH₂ increased levels of immunoreactive pERK_1/2 in DRG neurons, particularly in proximity to the plasma membrane. Thus, activation of PAR₂ receptors on colonic nociceptive neurons causes sustained hyperexcitability that is related, at least in part, to suppression of delayed rectifier I_K currents. Both PKC and ERK_1/2 mediate the PAR₂-induced hyperexcitability. These studies describe a novel mechanism of sensitization of colonic nociceptive neurons that may be implicated in conditions of visceral hyperalgesia such as irritable bowel syndrome.

(Received 13 December 2006; accepted after revision 6 February 2007; first published online 8 February 2007)
Corresponding author S. Vanner: Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario, Canada K7L 5G2. Email: vanners{at}hdh.kari.net

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