Prevention of Pain Chronification and Neuroinflammation After Traumatic Brain Injury by Neuroprotectin D1 and GPR37 Signaling
Abstract
This proposal aims to test the beneficial effects of neuroprotection D1 (NPD1) for protecting against neuropathic pain and neuroinflammation after mild traumatic brain injury (mTBI) in mice of both sexes. Specifically, we will test the hypothesis that NPD1 is highly effective in preventing the development of chronic pain after mTBI(s). We will also test the hypothesis that NPD1 is potent in treating chronic pain in the late-phase of mTBI(s). We recently identified GPR37 as a novel receptor for NPD1. We will further test the hypothesis that NPD1 can protect against neuropathic pain and neuroinflammation via GPR37 signaling through three specific aims. Aim 1 will characterize mTBI models and examine the duration of pain and the effects of stress in both sexes. Aim 2 will test the hypothesis that NPD1 can prevent acute pain and chronic pain following mTBI(s) and further alleviate established neuropathic pain in the late phase. Aim 3 will test the hypothesis that NPD1 can protect against neuroinflammation and neurodegeneration after TBI. This project addresses several priorities emphasized by the Chronic Pain Management Research Program (CPMRP). (1) The proposed work addresses the Focus Area “Chronification of pain” and will provide new mechanistic insights into transition from acute pain to chronic pain.” Per the FY19 CPMRP Congressional appropriation, chronic pain is defined as pain that occurs on at least half the days for 6 months or more. We will test the following specific hypotheses related to the transition from acute pain to chronic pain: • mTBI produces transient periorbital and cutaneous allodynia, which is associated with hyperactivity of TG and DRG primary sensory neurons. • Chronification of pain can be induced by multiple mTBIs or by single mTBI combined with stress. • Females exhibit longer duration of pain after TBI. • Duration of pain is prolonged after GPR37 deficiency. (2) This proposal also addresses the Focus Area “Development of novel non-µ-opioid receptor-targeted therapies for the treatment of chronic pain.” • We will test neuroprotectin D1 (NPD1) as a novel therapy for preventing and treating TBI-induced acute and chronic pain. NPD1 is bio-synthesized from fish oil DHA and acts as a specialized pro-resolving mediator (SPM). Our previous studies have demonstrated that NPD1 can potently inhibit inflammatory pain and nerve injury-induced neuropathic pain, as well as nerve injury-induced neuroinflammation in the spinal cord. Furthermore, NPD1 can block TRPV1 and TNF-alpha-induced neuronal sensitization. Since GPR37 is a newly identified receptor of NPD1, we will test the hypothesis that NPD1 can effectively prevent and treat TBI-induced neuropathic pain and neuroinflammation via GPR37 signaling. • For comparison with NPD1, we will also test docosahexaenoic acid (DHA), a complementary and integrative health non-pharmacological intervention. DHA is an omega-3 fatty acid present in fish oil and dietary supplements and serves as an important precursor of NPD1. We will test similar and distinct effects of NPD1 and DHA through the following hypotheses: (1) DHA is effective in preventing TBI-induced pain and neuroinflammation; (2) NPD1 is more potent (1000-fold) than DHA in producing beneficial effects; and (3) NPD1 but not DHA is effective in treating chronic pain. Our previous study has shown that NPD1 is 500 times more potent than gabapentin, a current treatment for neuropathic pain, in attenuating nerve injury-induced neuropathic pain in the maintenance phase. The incidence of chronic pain after mTBI is very high in military and civilian populations. Unfortunately, current efforts to prevent and treat acute and chronic pain after TBI have achieved limited success, in part due to our incomplete understanding of the molecular and cellular mechanisms underlying the pathogenesis of chronic pain. Thus, there is an urgent need to identify the new mechanisms and develop novel therapeutic approaches fo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110885
Entities
People
- Ru-Rong Ji
Organizations
- Duke University
- United States Army