Modulation of BDNF Signaling by the Neurosecretory Protein VGF Mediates Spinal Neuroplasticity
Abstract
Initial injuries, including those often sustained in service to our country, typically heal with treatment and/or time. However, sometimes, even after the healing has occurred, pain can remain for the long term (chronic pain). The reason for this is not well understood, and we are not currently able to predict which injuries will transition to long-term pain. Currently, treatments for chronic pain can present risks (such as addiction and overdose), and living in chronic pain is often distressing and can significantly impact quality of life. Understanding how and why chronic pain develops is important for both prediction and prevention of this form of pain. Nerve injury initiates chronic neuropathic pain in part by changing the communication between neurons in the spinal cord. A wealth of evidence points to a role for the signaling molecule BDNF and its receptor TrkB in the changes that follow nerve injury. Importantly, it has been shown that continuous BDNF/TrkB signaling is necessary for sustained increase of excitatory communication, but the mechanisms responsible for continuous spinal BDNF release are unknown. Understanding these mechanisms will help the development of treatments that prevent the transition to chronic pain. TLQP-62 is another signaling molecule in spinal cord, which we have shown to also participate in increased excitatory communication. TLQP-62 is known to increase BDNF/TrkB signaling in regions of the brain important for memory and depression. Our preliminary data suggest that in the spinal cord there is a similar relationship between TLQP-62 and BDNF. We propose to test the hypothesis that this relationship is important for maladaptive changes in BDNF/TrkB signaling in spinal cord after nerve injury. Using mouse models, we will test the hypotheses that: (Aim 1) after nerve injury TLQP-62 increases the excitability of spinal neurons and this effect depends on BDNF/TrkB signaling; (Aim 2) after nerve injury TLQP-62 increases the excitatory sensory input to spinal neurons from the periphery and this effect depends on BDNF/TrkB signaling; (Aim 3) TLQP-62 augments BDNF release from primary sensory neurons. In Aim 4, we will investigate if TLQP-62 affects human primary sensory neurons and modulates BDNF release from these neurons. This proposal addresses the knowledge gap in understanding the mechanisms of transition from acute to chronic pain. The completion of these studies will elucidate how the relationship of TLQP-62 to BDNF contributes to an environment in the spinal cord that can result in short-term pain becoming long-term chronic pain. This will help us understand why some acute injuries that are associated with nerve damage transition to chronic neuropathic pain. We expect that the proposed mechanistic studies will establish TLQP-62 as a new therapeutic target and provide proof-of-concept for future development of TLQP-62 neutralizing antibodies as a potential biologic treatment that could prevent or reverse this transition. Such an advancement would have significant impact to our military personnel living with chronic pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010509
Entities
People
- Lyudmila Vulchanova-hart
Organizations
- United States Army
- University of Minnesota