PROJECT SUMMARY/ABSTRACT
Chronic pain is both highly prevalent and a major cause of disability, affecting approximately 20.4% of the U.S.
Despite this prevalence, there are still limited therapeutic options. These issues are particularly true for pain
associated with trigeminal nerve injury. Recent comparative analyses support the presence of differences
between trigeminal and somatic nerves regarding the response to injury, and also point to voltage-gated sodium
channels (VGSCs) as a potential mechanism accounting for both the pain and differences in the efficacy of
available therapeutic interventions. Furthermore, VGSCs accumulation at the site of nerve injury and changes
in the relative density of subtypes in sensory neuron cell bodies have been implicated in the ongoing pain and
hypersensitivity associated with peripheral nerve injury. There is no consensus in the literature as to which of
the VGSC subtype(s) underlie action potential (AP) propagation along peripheral nerves, or which subtypes
underlie AP propagation following injury. However, there is evidence that the redistribution of VGSC subunits
along peripheral axons enables the nerve injury-induced pain and hypersensitivity, and therefore may serve as
a viable therapeutic target. In this regard, we have preliminary data suggesting that trigeminal but not the somatic
nerve injury is associated with an increase in functional NaV1.1 channels in trigeminal nerve axons that when
blocked, reverse nerve injury-induced mechanical sensitivity. Two general mechanisms have been implicated in
changes in axonal VGSC channels: protein trafficking and local translation of mRNA. While both mechanisms
are possible, at least two lines of evidence suggest local translation may underly the nerve injury-induced
increase in NaV1.1 in trigeminal axons. Thus, I hypothesize that the change in distribution of NaV1,1 in trigeminal
nerves following injury is due to local translation, and that the increase in functional NaV1.1 axonal protein
contributes to injury-induced hypersensitivity. To test this hypothesis, I will use a combination of techniques that
will elucidate the contribution of local translation and protein trafficking to nerve-injury induced hypersensitivity
in a series of experiments described under three specific aims involving anatomical and biochemical techniques
(Aim 1), functional endpoints (Aim 2), and behavioral endpoints (Aim 3). Results from these aims will determine
the basis for the nerve injury-induced increase in NaV1.1 in trigeminal nerve axons and their contribution to
changes in nociception. Future studies will address the implications for these results for novel therapeutic
approaches to the treatment of neuropathic pain. Along with the state-of-the-art facilities available, the highly
collaborative environment in the Center for Neuroscience at the University of Pittsburgh will ensure the
successful completion of the experiments proposed. These studies will also provide me with the technical and
intellectual training required to become an independent investigator in the field of pain, while the commitment to
diversity in the CNUP will allow me to pursue my career goal of promoting inclusion in science.
