Mechanisms of protease-activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon

Ahmed Kayssi, Silvia Amadesi, Francisco Bautista, Nigel Bunnett, Stephen Vanner

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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 IK currents (55 at 10 min), but had no effect on the transient IA 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 ERK1/2 inhibitor PD98059. Studies of ERK1/2 phosphorylation using confocal microscopy demonstrated that SLIGRL-NH2 increased levels of immunoreactive pERK1/2 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 IK currents. Both PKC and ERK1/2 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.
Original languageEnglish
Pages (from-to)977 - 991
Number of pages15
JournalThe Journal of Physiology
Issue number3
Publication statusPublished - 2007

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