Fc Gamma Receptor Signaling: A New Pathway for Sustained Neuropathic Pain
Abstract
The prevalence of chronic pain among Service members and Veterans is more than twice that of the general public. This disproportionate burden is largely due to the frequency of traumatic injuries. Nearly half of all Service members sustain a traumatic injury to the nervous system during combat, which can devolve in to a type of chronic pain known as neuropathic pain. Such pain is exceedingly difficult to treat as the available drugs are only minimally effective. In addition, the risk of abuse posed by opioids that are also used to treat neuropathic pain has caused a national crisis. Therefore, effective and opioid-free pain management is a major unmet need for Service members, Veterans, and the general public alike. The lack of effective treatments reflects the fact that the mechanisms underlying neuropathic pain are incompletely understood. Therefore, gaining further insight into the mechanisms that maintain neuropathic pain is expected to reveal new therapeutic targets for disease-modifying treatment. Studies have shown that astrocytes, immune-like cells in the spinal cord and brain, contribute to the maintenance of neuropathic pain by releasing signals that activate neurons in pain pathways. However, it is not known how astrocytes remain activated during neuropathic pain. We have new evidence to suggest that antibodies are generated against cell components that are released by damaged neurons after peripheral nerve injury. In turn, the antibodies signal at receptors expressed by astrocytes. Using a rat model of neuropathic pain that mimics nerve injury to limbs (e.g., due to blasts or high velocity projectiles), this proposal aims to characterize the antibodies that are generated after peripheral nerve injury. It also aims to identify the signaling pathways that are engaged in astrocytes upon recognition of the antibodies, and to learn how they maintain pain signaling at neurons in pain pathways. The short-term impact of these activities will be to add to our scientific understanding of how astrocytes remain activated and therefore maintain neuropathic pain after peripheral nerve injury — a current knowledge gap. The long-term impact is that the identified signaling axis is expected to offer new, non-opioid pharmacological targets for neuropathic pain. Preliminary data that we have obtained strongly suggest that targeting this pathway will be effective in attenuating immune-like signaling by astrocytes and the subsequent propagation of pain, opening new research horizons for neuropathic pain, particularly in drug development. Possible targets include the source of antibodies or antigens or the maladaptive signaling pathways that will be discovered as a consequence of this work. Furthermore, these targets may be tractable by repurposing existing non-opioid drugs to almost immediately treat Service members and Veterans with neuropathic pain. Improved treatments for neuropathic pain are critically needed, as highlighted in a recent meta-analysis, which concluded that “inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain.” The limited treatment options diminish the quality of life for pain patients, as they typically experience concomitant depression, sleep disturbance, fatigue, and decreased overall physical functioning. By elucidating a fundamental mechanism that sustains chronic neuropathic pain, the proposed project relates to the Chronic Pain Management Topic Area.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910160
Entities
People
- Peter M. Grace
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army