eIF4E phosphorylation regulates ongoing pain, independently of inflammation, and hyperalgesic priming in the mouse CFA model.

Mitogen activated protein kinase-interacting kinase (MNK)-mediated phosphorylation of the mRNA cap binding protein eIF4E controls the translation of a subset of mRNAs that are involved in neuronal and immune plasticity. MNK-eIF4E signaling plays a crucial role in the response of nociceptors to injury and/or inflammatory mediators. This signaling pathway controls changes in excitability that drive acute pain sensitization as well as the translation of mRNAs, such as brain-derived neurotrophic factor (BDNF), that enhance plasticity between dorsal root ganglion (DRG) nociceptors and second order neurons in the spinal dorsal horn. However, since MNK-eIF4E signaling also regulates immune responses, we sought to assess whether decreased pain responses are coupled to decreased inflammatory responses in mice lacking MNK-eIF4E signaling. Our results show that while inflammation resolves more quickly in mice lacking MNK-eIF4E signaling, peak inflammatory responses measured with infrared imaging are not altered in the absence of this signaling pathway even though pain responses are significantly decreased. We also find that inflammation fails to produce hyperalgesic priming, a model for the transition to a chronic pain state, in mice lacking MNK-eIF4E signaling. We conclude that MNK-eIF4E signaling is a critical signaling pathway for the generation of nociceptive plasticity leading to acute pain responses to inflammation and the development of hyperalgesic priming.