Maturation of nociceptive neurons depends on changes of transcription factors, ion channels, and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. If sensitization signaling also changes during development and aging remains so far unknown.
Using a novel automated microscopy approach, we quantified changes of intracellular signaling protein expression, of their signaling dynamics, as well as of intracellular signaling cascade wiring in sensory neurons from newborn to senescent rats.
We found nociceptive subgroups defined by the signaling components PKA-RIIβ and CaMKIIα to develop around postnatal day 10, the time of nociceptor maturation. The integrative nociceptor marker, PKA-RIIβ, allowed subgroup segregation earlier than the classical markers TRPV1 and Nav1.8. Signaling kinetics remained constant over lifetime despite in part strong changes of the expression levels. Strikingly, we found a crosstalk from cAMP/PKA to ERK1/2, which is important for neuronal memory, to emerge postnatally.
Thus, maturation of nociceptors is closely accompanied by altered expression, activation, and connectivity of signaling pathways known to be central for pain sensitization and neuronal memory formation.
- Received September 9, 2016.
- Accepted May 10, 2017.
- © 2017. Published by The Company of Biologists Ltd