Following injury to nerves in the peripheral nervous system, regeneration readily occurs oftentimes with some functional recovery depending on the severity of the injury; however, aberrant regenerative responses after nerve injury could lead to neuropathic pain. Research has suggested that collateral sprouting of central sensory axons in pain receptive lamina of the spinal cord occurs after peripheral nerve injury and this may contribute to the development of neuropathic pain. Recent works from our laboratory and others have shown that mRNAs translated directly within peripheral nerves are needed for regeneration after injury. However, the possibility that peripheral stimuli can alter mRNA transport or translation in centrally projecting DRG axons has not been explored. I hypothesize that injury to peripheral nerves triggers changes in sensory neuron gene expression and subsequent transport of mRNAs into centrally projecting axons that result in changes in the growth capacity of those axons. I will use RT-PCR and in situ hybridization to quantify axonal mRNAs encoding growth-associated and neuronal signaling proteins in centrally projecting axons before and after peripheral nerve injury. To determine if any changes in axonal mRNA levels in centrally projecting DRG axons are driven by injury-induced transcription I will use Importin ?1 3?-UTR knockout mice in which transcriptional regulation is attenuated. I will also use viral-mediated gene transfer to increase or decrease the axonal levels of mRNAs encoding growth associated proteins to examine how this influences sprouting of centrally projecting sensory axons and the development of neuropathic pain. Overall, the work in this proposal will provide training in molecular neurobiology techniques and will serve to tell us if transport of mRNAs into central sensory axons with localized generation of proteins contributes to sprouting in the spinal cord and progression to neuropathic pain.
Neuropathic pain is a debilitating and frequent complication from injury to the peripheral and central nervous system. The research proposed here will determine newly recognized mechanisms of axon regeneration that may also contribute to the development or perpetuation of neuropathic pain.
