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Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory

Stefan Herrmann1, Hamsa Rajab1, Irina Christ1

  • 1Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Pain
|August 3, 2017
PubMed

Insights

Cyclic adenosine monophosphate (cAMP) triggers inflammatory pain by activating protein kinase A (PKA) and HCN2 channels in nociceptors. Disabling these targets reduces pain sensitization, revealing a key pathway in pain signaling.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • Cyclic adenosine monophosphate (cAMP) is a key second messenger in nociceptor sensitization.
  • Downstream targets of cAMP signaling in neuronal plasticity remain incompletely understood.

Purpose of the Study:

  • To investigate the roles of HCN2 and protein kinase A (PKA) in cAMP-mediated nociceptor sensitization.
  • To elucidate the downstream mechanisms of cAMP in inflammatory pain.

Main Methods:

  • Utilized a Cre/loxP strategy to selectively disable HCN2 or PKA in peripheral nociceptive neurons.
  • Analyzed nociceptive responses in transgenic mouse lines following inflammatory stimuli.
  • Measured calcium transients and Ih current facilitation in dorsal root ganglion neurons.

Main Results:

  • Both HCN2 and PKA disruption nearly abolished sensitization to inflammatory pain induced by 8br-cAMP.
  • Lack of HCN2 or PKA inhibition prevented cAMP-mediated calcium increases in neurons.
  • cAMP-induced facilitation of the Ih current was abolished in neurons lacking PKA activity.

Conclusions:

  • HCN2 and PKA significantly contribute to inflammatory pain.
  • PKA-dependent activation of HCN2 is a critical mechanism underlying cAMP-triggered neuronal sensitization in inflammatory pain.

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