Synaptic Retinoic Acid Signaling in Spinal Cord Homeostatic Plasticity and Mechanical Allodynia
Abstract
Fiscal Year 2022 Chronic Pain Management Research Program Investigator-Initiated Research Award Focus Areas to be addressed by the proposed research: Chronification of pain: (1) Understanding mechanisms of the transition from acute to chronic pain following physical trauma; (2) Development of mechanistically based therapies to prevent and treat chronification of pain. Perception of pain to harmful stimuli is a protective mechanism essential for survival. However, neuropathic pain, a major form of chronic pain, plagues 7%-10% of the general population long after the recovery from an initial injury. This state of prolonged hypersensitivity is a debilitating condition resistant to analgesics and surgical intervention. Characteristics of neuropathic pain include spontaneous pain (stimulus-independent pain), allodynia (pain in response to an innocuous stimulus such as a light touch), and hyperalgesia (exaggerated pain responses to minimally painful stimuli). Despite a relatively large investment in chronic pain research, the mechanisms underlying the transformation of acute pain into persistent pain remain incompletely understood. Our research aims to develop therapeutic means to prevent neuropathic pain development by focusing on the neurological basis of pain chronification. Specifically, we tackle the following fundamental questions: (1) How do the synaptic communications between neurons in the spinal cord neural circuits change after peripheral nerve injury? (2) How do these changes alter tactile information processing so that it becomes painful? (3) What are the key molecules present in spinal cord neurons that mediate such changes? (4) Can we prevent the development of neuropathic pain after acute injury by inhibiting the functions of these key molecules? We use three mouse models of neuropathic pain to answer these questions: the spared-nerve injury model (a partial injury of the sciatic nerve), the chemotherapy-induced peripheral neuropathy model, and a diabetic neuropathy model. These three models are well established in the neuropathic pain field as valid animal models with strong clinical relevance to a broad range of human neuropathic pain conditions. We chose these three models because they share one critical aspect of disease-causing condition -- the neuropathic pain is caused by damages to peripheral nerves, either by acute trauma (e.g., in amputation), chemotherapy drugs, or prolonged hyperglycemia. These peripheral nerve damages invariably lead to reduced neuronal activity in spinal cord circuits, thus driving similar compensatory changes in the spinal cord circuit that misdirects the tactile information to the pain-sensing pathway, causing the pain percept. In our previous work studying a similar compensatory process in cortical circuits that respond to sensory deprivation, we discovered several molecules within a key signaling pathway that are mediators for such circuit changes. In the current study, we will investigate the requirement of this signaling pathway and the key molecules involved in the spinal cord circuit changes after peripheral nerve injury, and explore the possibility of preventing neuropathic pain development by blocking the functions of this pathway. Our preliminary experiments show promising results in that mechanical allodynia after spared-nerve injury can be prevented by blocking the function of one of these molecules, RARalpha. The proposed study will dive deeper into the mechanistic aspects of this result and extend the investigation of other neuropathic pain models. Results from our study will contribute to our understanding of the molecular and cellular mechanisms underlying neuropathic pain development. Importantly, our project differs from and complements most studies in the neuropathic pain field in that, instead of aiming to treat existing pain that has become chronic, it focuses on preventing the chronification of neuropathic pain. This is the first tim
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310715
Entities
People
- Lu Chen
Organizations
- Stanford University
- United States Army