• Stefan Herrmann, Hamsa Rajab, Irina Christ, Christoph Schirdewahn, and Daniel Höfler.
• aInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanybInstitut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanycCenter for Integrated Protein Science Munich CiPSM at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, München, Germany.
• Pain. 2017 Oct 1; 158 (10): 2012-2024.

AbstractSeveral studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. A near-complete lack of sensitization was observed in both mutant strains when peripheral inflammation was induced by an intradermal injection of 8br-cAMP. The lack of HCN2 as well as the inhibition of PKA eliminated the cAMP-mediated increase of calcium transients in dorsal root ganglion neurons. Facilitation of Ih via cAMP, a hallmark of the Ih current, was abolished in neurons without PKA activity. Collectively, these results show a significant contribution of both genes to inflammatory pain and suggest that PKA-dependent activation of HCN2 underlies cAMP-triggered neuronal sensitization.

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