Neurological recovery following peripheral nerve damage can be relatively good, but can also lead to permanent neurological deficits including chronic pain. Peripheral nerve injury affects both motor and primary sensory axons and elicits two types of responses. One is the regenerative growth, which depends upon initiation of a regenerative transcriptional program and the second is long-term hyperexcitability in nociceptive neurons, which contributes to the development of chronic pain. Initiation of a regeneration program requires that injury signals alter transcription of multiple genes. While changes in gene expression in most peripheral neurons include transcription factors necessary for survival and growth, others, restricted to nociceptor neurons, lead to long-term pathological changes associated with neuropathic pain. Injury signals may thus contribute to both regenerative responses and the development of pain. Alterations in gene expression lead to changes in protein expression following injury. Recently, the mTOR- dependent translational regulation was shown to be involved in both promoting regeneration and chronic pain after peripheral nerve injury. Our preliminary data indicate that conditional deletion of TSC2, a key regulator of protein synthesis that acts by inhibiting the activation of mTOR, increased dorsal root ganglia (DRG) neurons growth capacity in vitro. This effect is likely due to activation of the mTOR pathway, since our preliminary data show that TSC2 deletion leads to activation of mTOR in DRG neurons in vivo. The proposed revision expands on the goals of the parent grant (in vitro studies of TSC2) to examine the role of TSC2 in vivo in promoting peripheral nerve regeneration and in the development of injury-induced neuropathic pain. We will first determine whether loss of TSC2 affects the development of DRG neurons by examining the anatomy of sensory nerve fibers projections in the hind paw skin of mice lacking TSC2. We will then determine if DRG neurons lacking TSC2 possess an enhanced regenerative ability in vivo. Using two widely used models for neuropathic pain we will then determine the contribution of TSC2 to mTOR activity specifically in nociceptive neurons, a subset of DRG neurons, and its role in the development of- and recovery from- nerve injury-induced persistent pain. The effects of lack of TSC2 in nociceptive neurons on baseline heat, cold and touch perception will be determined, as well as the time-course of the induction and resolution of persistent pain after injury. Given the apparent dual role of protein synthesis in promoting both regeneration and pain, it is important to better define the molecular mechanisms controlled by mTOR activity after nerve injury. TSC2, having multiple functions in addition to regulating the mTOR pathway, may represent a useful candidate to enhance nerve regeneration without coincidently promoting neuropathic pain. By understanding the interrelationships between nerve regeneration and pain sensitization, we hope to be able to devise strategies that selectively enhance regeneration after injury and limit the development of neuropathic pain.
Despite recent advances in understanding peripheral nerve regenerative abilities, recovery remains suboptimal and the development of chronic pain is often a major problem. Promoting extensive neurological recovery requires simultaneously providing protection to injured neurons, increasing the numbers of neurons that extend axons and limiting the development of pain. Defining the mechanisms by which the protein TSC2 enhances the growth capacity of peripheral neurons may enable or suggest new strategies to enhance nerve regeneration following injury and limit the development of pain.
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