Prostaglandin E2 (PGE2) and epinephrine act directly on nociceptors to produce mechanical hyperalgesia through protein kinase A (PKA) alone or through a combination of PKA, protein kinase C epsilon (PKCε), and extracellular signal-regulated kinase (ERK), respectively. Disruptors of the cytoskeleton (microfilaments, microtubules, and intermediate filaments) markedly attenuated the hyperalgesia in rat paws caused by injection of epinephrine or its downstream mediators. In contrast, the hyperalgesia induced by PGE2 or its mediators was not affected by any of the cytoskeletal disruptors. These effects were mimicked in vitro, as measured by enhancement of the tetrodotoxin-resistant sodium current. When PGE2 hyperalgesia was shifted to dependence on PKCε and ERK as well as PKA, as when the tissue is "primed" by prior treatment with carrageenan, it too became dependent on an intact cytoskeleton. Thus, inflammatory mediator-induced mechanical hyperalgesia was differentially dependent on the cytoskeleton such that cytoskeletal dependence correlated with mediation by PKCε and ERK.
Dina, O. A., McCarter, G. C., De Coupade, C., & Levine, J. D. (2003). Role of the sensory neuron cytoskeleton in second messenger signaling for inflammatory pain. Neuron, 39(4), 613–624. https://doi.org/10.1016/S0896-6273(03)00473-2