In this BIRT application, we establish a new collaboration to substantially expand ongoing activities under the Parent Grant to define the mechanistic relationships between neuronal plasticity and spinal immune activation in chronic pain in the spine. In particular, this application addresses the spinal disorder of facet joint injury-mediated chronic pain, which is a soft tissue and joint injury in the spine that can lead to chronic neck and low back pain, encompassing a major musculoskeletal disorder, with far-reaching clinical implications. The proposed research represents a new interdisciplinary collaboration between an engineer (PI, Dr. Winkelstein) in the School of Engineering and Applied Sciences, who has expertise in injury biomechanics and development of painful injury models in the rodent, and a clinician (Dr. Golder) in the School of Veterinary Medicine who has both clinical and research expertise in neural electrophysiological recording techniques and clinical assessment and management of pain in veterinary species. This collaboration represents a first step in building a new interdisciplinary research team through a new formal collaboration to study spinal neuron activity in response to painful injury. Our proposal combines two complementary researchers who have not worked together formally in any way but have the necessary scientific backgrounds and skills to enable making a major contribution to the area of orthopaedic pain, and its diagnosis and treatment. In addition, the proposed activities are far-removed from the primary research activities underway in either lab so they are not possible without such an integrative approach. A significant challenge exists in treating painful musculoskeletal disorders owing to the research challenges that exist in simultaneously investigating the neuronal and immune contributions that drive the development and maintenance of chronic pain. This challenge is due in part to the fact that truly interdisciplinary teams, with the appropriate expertise and specialization, are needed to attack this problem. The Parent Grant focuses on defining the relationships between biomechanics of tissue injury and the inflammatory contributions to the resulting pain responses. Proposed supplemental studies in this application expand those investigations via aims that utilize elextrophysiological techniques to map the spatial and temporal responses of nociceptive spinal neurons to identify the mechanisms responsible for the development of chronic pain after spinal injury. We also expand the scope of studies in the Parent Grant by assessing glutamate activity in neuronal and glial cells in the thalamus, where pain signals are amplified and translated to the somatosensory cortex of the brain. Both of these scientific approaches are a direct result of a new collaboration for the PI with a neuroscientist and veterinarian. Our innovative research proposal leverages several separate fields to develop an integrated understanding of the complex problem of pain. The proposed experiments are designed to overcome difficult technical and analytical challenges and to provide integrated mechanisms leading to chronic pain in order to help inform clinical treatment strategies. Accordingly, we propose three novel interdisciplinary specific aims to expand the Parent Grant activities through a new collaboration:
Aim 1. Measure extracellular voltage recordings of sensory neurons in the dorsal horn of the spinal cord at day 1 and day 14 following whiplash injuries that produces persistent pain.
Aim 2. Define the relative contributions of afferent fiber types in the facet joint to the development of spinal cord neuronal plasticity following whiplash injury, using toxins to selectively ablate nerve fibers and measuring extracellular voltage recordings in the spinal cord.
Aim 3. Quantify pain symptoms and extracellular voltage recordings of spinal neurons after whiplash injury followed by injection of the sodium channel blocker, bupivacaine, to block sensory fiber activity from the injured joint. Neuronal responses will be measured after injection to define the contributions of sensory inputs from the joint to the maintenance of chronic pain. This interdisciplinary collaboration will begin to characterize the integrated relationships between neuronal- inflammatory cascades in the CNS that lead to whiplash pain. Our research team is uniquely-suited to address the challenges with implementing the required techniques to test our hypothesis, owing to our collective expertise in engineering and injury biomechanics (Winkelstein), electrophysiology (Golder), animal modeling and pain (Winkelstein &Golder). Activities proposed in this BIRT application are substantively different from aims in the Parent Grant and are highly relevant to research areas in NIAMS.
The aims of the Parent Grant focus on defining the glial cell activation and neurotrophin responses in the dorsal root ganglia and spinal cord, and defining local inflammatory responses in the facet joint for whiplash pain. However, that proposal does not address neuronal responses explicitly. We have a recent interest in expanding assessment of cellular responses to include the brain, where pain signals are processed and perceived. Certainly, through the establishment of these interdisciplinary research activities, our ongoing efforts to understand whiplash pain will be greatly expanded in directions beyond the scope of the Parent Grant. Indeed, the investigators will continue to collaborate after the period of the BIRT and will develop future proposals focused on developing targeted pharmacologic treatments for joint pain, clinical interventions for back pain and methods for improved tissue healing.
Chronic pain is a significant public health problem and continues to present a variety of challenges in its clinical management. Among current obstacles is an inadequate ability to effectively treat patients with pain from musculoskeletal injuries because the mechanisms of chronic pain in these syndromes are not well-defined. This research proposal will define neuronal firing patterns in the spinal cord and patterns of cellular pain responses in the brain after whiplash-mediated joint injury in the spine, a common injury in the neck. The overall goal of this work is to identify characteristic temporal neuronal profiles involved in the development of chronic pain. Findings from these studies have the potential to identify and enable development of effective treatments and clinical management approaches for this chronic pain syndrome, as well as for facet joint- mediated low back pain.
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