Received for publication August 13, 2007.
Revised November 12, 2007.
Accepted for publication November 13, 2007.

Prostaglandin-induced activation of nociceptive neurons via direct interaction with TRPA1

Abstract

Inflammation contributes to pain hypersensitivity through multiple mechanisms. Among the most well-characterized of these is the sensitization of primary nociceptive neurons by arachidonic acid metabolites such as prostaglandins through G protein-coupled receptors. However, in light of the recent discovery that the nociceptor-specific ion channel TRPA1 can be activated by exogenous electrophilic irritants through direct covalent modification, we reasoned that electrophilic carbon-containing A- and J- series prostaglandins, metabolites of prostaglandin E₂ and D₂ (PGE₂ and PGD₂), respectively, would excite nociceptive neurons through direct activation of TRPA1. Consistent with this prediction, the PGD₂ metabolite 15-deoxy-^12,14-prostaglandin J₂ (15dPGJ₂), activated activated heterologously expressed human TRPA1 (hTRPA1-HEK), as well as a subset of chemosensitive mouse trigeminal neurons. 15dPGJ₂'s effects on neurons were blocked by both the non-selective TRP channel blocker ruthenium red and the TRPA1 inhibitor HC-030031, but unaffected by the TRPV1 blocker iodo-resiniferatoxin. In whole-cell patch clamp studies on hTRPA1-HEK cells, 15dPGJ₂ evoked currents similar to equimolar AITC in the nominal absence of calcium, suggesting a direct mechanism of activation. Consistent with the hypothesis that TRPA1 activation required reactive electrophilic moieties, A- and J-series prostaglandins and the isoprostane 8-iso prostaglandin A₂ evoked calcium influx in hTRPA1-HEK cells with similar potency and efficacy. Notably, this effect was not mimicked by their non-electrophilic precursors, PGE₂ and PGD₂, or PGB₂, which differs from prostaglandin A₂ (PGA₂) only in that its electrophilic carbon is rendered unreactive through steric hindrance. Taken together, these data suggest a novel mechanism through which reactive prostanoids may activate nociceptive neurons independent of prostaglandin receptors.

Key words: Prostanoid, Capsaicin/vanilloid, Ion channel regulation, Ca imaging

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