Acute pain in the wake of peripheral injury is an important, adaptive physiological response. Pain helps to reduce re-injury, thus hastening recovery. Acute pain normally resolves when the injury heals. However, in many cases involving damage to peripheral nerves, acute pain transforms into chronic pain, which persists long after wounds have fully healed, and can be severely debilitating. Injury to peripheral nerves elicits a regenerative response and may also lead to long-term sensitization that contributes to the development of chronic pain. Protein synthesis in sensory neurons is required for both axon regeneration and for the development and maintenance of sensitization and pain following injury. Our goal is to gain new insights into the signaling pathways controlling protein synthesis in response to nerve injury to develop strategies that stimulate neurological recovery without coincidently promoting the development of chronic pain. The evolutionarily conserved mammalian Target Of Rapamycin (mTOR), a master regulator of the protein synthesis machinery, and the extracellular signal-regulated kinase (ERK) pathway are linked to both axon regeneration and to the development of neuropathic pain. Activation of mTOR by conditional deletion of the negative regulator tuberin (TSC2) in sensory neurons is sufficient to sustain regenerative growth, but whether it affects the development of nerve injury-induced pain is not known. ERK1/2 signaling is a major upstream regulator or mTOR activity. Although sensitization and regenerative axon growth are two processes known to require protein synthesis, the role or ERK1/2 signaling in regulating protein synthesis in sensory neurons has not been explored. Furthermore, in the studies performed to date, no discrimination was made regarding which ERK isoform, ERK1 or ERK2, is involved in sensitization and regenerative axon growth. Our preliminary data reveal ERK2 as the critical isoform for nociceptor sensitization and as a negative regulator of axon regeneration. This provocative result challenges the current model of the role of ERK1/2 signaling in axon regeneration. We propose here to identify the overlapping molecular events that regulate axon regeneration and the conversion from acute to chronic pain after nerve injury. Specifically, we will determine if ERK signaling regulates protein synthesis in naive or injured primary sensory neurons. We will determine which ERK isoform affects the regenerative ability of sensory neurons and if this effect is dependent on ERK-mediated regulation of protein synthesis. Finally, we will evaluate the effect of TSC2, ERK1 and ERK2 deletion on the development and maintenance of nerve injury-induced pain. Together, these experiments will test whether TSC2 and ERK signaling converge to mTOR-dependent protein translation to regulate nerve regeneration and the development of injury-induced chronic pain.

Public Health Relevance

Recovery from peripheral nerve injury can be relatively good, but the damage can also lead to permanent neurological deficits including failure of reinnervation and the development of chronic pain. Here we propose to understand how the molecular mechanisms that help to promote axonal regeneration interact with the molecular pathways that result in the conversion from acute to chronic neuropathic pain after peripheral nerve injury. The ultimate goal is to identify approaches whereby one can selectively promote axon repair after injury without simultaneously promoting the development of chronic neuropathic pain.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE022000-04
Application #
8704123
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wan, Jason
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Cho, Yongcheol; Sloutsky, Roman; Naegle, Kristen M et al. (2013) Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell 155:894-908
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