Translation Control of Pain Plasticity

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 DESCRIPTION (provided by applicant): Chronic pain affects tens of millions of Americans and its inadequate treatment creates an enormous burden on our health care system, its patients and its clinicians. Gaining a better understanding of the basic mechanisms driving chronic pain has the potential to lead to therapeutics that can reverse chronic pain as opposed to currently available palliative treatments. Changes in gene expression in peripheral sensory neurons link initial injury to the development of chronic pain. Work in this area has focused on transcriptionally-mediated events. However, sensory neurons are large cells with peripheral terminals at great distances from the site of transcription, the nucleus. Hence, control of protein translation potentially affords these cells a mechanism to rapidly change gene expression in direct response to local signaling factors. We have demonstrated, through the previous period of grant support, that translation control indeed plays a vital role in changes in gene expression driving the transition to chronic pain. This discovery creates an important therapeutic opportunity because translation is controlled by a number of kinases (e.g. MNK1/2) which signal to proteins (e.g. eIF4E) involved in the rate-limited step of protein synthesis, translation initiation. We wil test the central hypothesis that translation control signaling is crucial for changes in nociceptor excitability after exposure to pain promoting compounds and for mediating phenotypic changes in nociceptors during the transition to chronic pain. Specifically we will examine a novel signaling pathway for pain plasticity: MNK1/2 kinase phosphorylation of eIF4E. Our hypotheses will be tested through 3 specific aims: 1) MNK1/2 signaling to eIF4E as a key signaling hub for behavioral plasticity leading to chronic pain, 2) MNK1/2 signaling to eIF4E as a critical step for plasticity in nociceptor excitability and 3) BDNF as a key translational target of MNK1/2 - eIF4E signaling in nociceptor phenotypic changes that promote chronic pain. The outcome of the completion of these aims will be an in-depth understanding of how translation regulation promotes nociceptive plasticity, the identification of a specific mechanism (eIF4E phosphorylation) and target (MNK1/2 kinase) as a potential pain therapeutic and novel regulatory mechanisms of BDNF translation and the role of this process in the transition to chronic pain.