Peripheral neuropathic pain results from maladaptive changes in the central nervous system that are initiated by abnormal activity of injured sensory neurons. Increasing evidence indicates that neuroplasticity in the spinal cord depends on glial-neuronal interactions. In neuropathic pain, glial cells play a critical role in both the development and maintenance of hypersensitivity. Our data suggest that the neuropeptide precursor protein VGF (non-acronymic) and the peptides derived from it may represent novel injury-induced glial activators. We have shown that 1) VGF is rapidly and robustly upregulated in sensory neurons at the onset of nerve injury, and 2) VGF-derived peptides activate spinal microglia. VGF peptides also evoke thermal hyperalgesia, and mechanical and cold allodynia, and potentiate the activity of dorsal horn neurons. These results strongly implicate VGF peptides as sensory neuron signals that initiate microglial activation after nerve injury and participate in spinal neuroplasticity. Furthermore, VGF remains upregulated for the duration of the behavioral hypersensitivity, indicating that VGF peptides may participate both in the initiation of neuropathic pain and also in its maintenance. Our long-term research goal is to delineate the role that VGF-derived neuropeptides play in conditions of chronic pain. Our objective in this application is to determine how VGF peptides drive the spinal neuroplasticity that leads to neuropathic pain, and to establish whether they are required for its maintenance. The central hypothesis of this proposal is that VGF peptides serve as key mediators of the transition from acute to chronic pain.
In Specific Aim 1, we will determine the role of VGF peptides in the spinal neuroplasticity that leads to neuropathic pain. We hypothesize that VGF peptides are required for microglial activation and the development of nerve injury-induced hypersensitivity, and that VGF ablation or immunoneutralization of VGF peptides will prevent these events.
In Specific Aim 2, we will determine the contribution of VGF to the maintenance of the neuropathic pain state. We hypothesize that the levels and/or processing of VGF peptides in spinal cord and CSF are altered for the duration of neuropathic pain and that neuropathic pain will be abolished by VGF ablation.
In Specific Aim 3, we will delineate the mechanisms responsible for VGF regulation of spinal neuroplasticity. We hypothesize that VGF peptides regulate the neuromodulatory activity of microglia that drives maladaptive neuroplasticity in dorsal horn neurons. Characterization of biologically active VGF-derived peptides, which may additionally establish novel CSF biomarkers of the neuropathic state, the VGF signaling system, and the peptide receptors that mediate VGF actions, has the potential to identify new therapeutic approaches to control spinal neuroplasticity, providing insight into the development and progression of neuropathic pain.
Increased effort to understand what causes pain has motivated a multi-decade global research effort to identify new molecular players that communicate the perception of pain to the brain. The proposed research will investigate the activity of a novel spinal pain signaling system, that of the neuropeptide precursor protein VGF (non-acronymic). We have recently shown that under conditions of chronic pain, this protein increases in sensory neurons. We hypothesize that this protein contributes to injury signals that mediate the development of chronic pain. Understanding how VGF drives pain signaling may lead to new approaches for diagnosing and treating chronic pain conditions.
