Principal Investigators: Wade S. Kingery, MD and David Clark, MD, PhD Co-Investigator: Christopher R. Jacobs, PhD Collaborators: David Yeomans, PhD and Steven Wilson, PhD Objectives: Limb trauma causing fractures and/or nerve injuries can lead to the development of a complex regional pain syndrome (CRPS). At onset this syndrome presents a baffling array of clinical findings, including changes in skin temperature, distal limb edema, increased spontaneous protein extravasation, periarticular osteopenia, pain, and allodynia. Persistent CRPS can lead to chronic edema, pain, weakness, contractures, and osteoporosis, resulting in serious disability in over 80% of patients. Currently there is no consensus on either the pathophysiology or treatment for CRPS and there is a need for translational studies to identify therapeutic targets and novel pharmacologic approaches. We have recently developed a rat fracture model resembling CRPS. After distal tibia fracture rats develop chronic unilateral hind limb warmth, edema, facilitated spontaneous protein extravasation, periarticular osteoporosis, hind limb unweighting, and allodynia, changes resembling those observed in CRPS I patients. We have also described a sciatic nerve transection model in rats resembling CRPS type II in man. Chronic glucocorticoid treatment in the tibia fracture and sciatic section rat models inhibited vascular and nociceptive abnormalities, similar to the clinical response. Since glucocorticoid treatment also blocked substance P (SP) mediated neurogenic extravasation responses in the rat, we postulated that the therapeutic activity of glucocorticoids in the CRPS models are mediated by inhibitory effects on SP signaling. This hypothesis was confirmed with studies using a selective SP receptor antagonist, demonstrating that the chronic edema, warmth, spontaneous extravasation, and nociceptive sensitization observed in these trauma models was at least partially mediated by SP signaling. Substance P promotes the production of various cytokines in the skin, including tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-6, and these inflammatory cytokines are believed capable of inducing pathologic changes in the vascular, nervous, and bone organ systems similar those observed in CRPS. These cytokines are up-regulated in the skin of the CRPS limb and we have observed that TNF-alpha expression in the hindpaw skin is chronically increased after tibia fracture in rats. Tibia fracture rats treated with the cytokine inhibitor pentoxifylline failed to develop allodynia or hind limb unweighting, indicating an important role for cytokine signaling in trauma induced chronic pain. Intriguingly, several recent controlled trials have demonstrated that bisphosphonates can also alleviate CRPS symptoms and associated bone loss and these drugs are potent modulators of cytokine activity. Another mediator of inflammatory pain is nerve growth factor (NGF) and SP signaling also stimulates NGF expression in skin. NGF is upregulated by bone and soft tissue trauma and anti-NGF therapy can reverse pain behavior and neurochemical changes associated with pain in animal models of bone tumor, neuropathic, and inflammatory pain. Research Plan: 1) determine whether SP, inflammatory cytokines, and NGF signaling are chronically upregulated in hind limb skin, nerve, and bone of the CRPS limb trauma models, 2) determine whether SP signaling mediates the up-regulation of inflammatory cytokines and NGF observed in the trauma models, 3) establish the efficacy of cytokine inhibitors, bisphosphonates, and anti-NGF therapy in reducing chronic pain behavior, nociceptive neurochemical changes, and the vascular and bone abnormalities observed in the limb trauma models. Work Accomplished: Funding has not started on this project yet. Expected Outcome: It is anticipated that this project will characterize chronic changes in cytokine and NGF signaling after limb trauma, determine the role cytokines and NGF play in the development and maintenance of post-traumatic CRPS-like sequelae, and demonstrate the feasibility of promising new treatments for post-traumatic pain and inflammation. These studies should provide translational evidence supporting future clinical CRPS trials, with the potential for improving the efficacy and safety of the pharmacologic management of this debilitating condition. Funding Source: Department of Veterans Affairs - Merit Review
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