Principal Investigator: Wade S. Kingery, MD Project Staff: Christopher R. Jacobs, PhD; David Yeomans; and Martin Schmelz Project Category: Bone & Joint - 2003 Objective: Fractures and nerve injuries can lead to the development of a complex regional pain syndrome (CRPS). This syndrome presents with a baffling array of clinical findings, including increased cutaneous blood flow, increased skin temperature, spontaneous protein extravasation, limb edema, periarticular osteopenia, spontaneous pain, hyperalgesia and allodynia. The mechanism underlying this pathophysiology is unknown and most CRPS patients with persistent symptoms are permanently disabled. This proposal tests the hypothesis that the injuries that most frequently cause CRPS Type I (distal limb fractures) and Type II (incomplete nerve injuries) in man evoke similar syndromes in rats, including changes in cutaneous vascular function (increased skin temperature, vasodilatation, and spontaneous extravasation), bony tissue (periarticular osteopenia measured by radiographs and absorptiometry), and nociceptive thresholds (hindpaw hyperalgesia and allodynia). This proposal will also examine the role of facilitated substance P signaling in the development of CRPS-like sequelae of bone and nerve injuries. Research Plan: After establishing that the fracture and incomplete nerve injury rat models resemble CRPS Type I and II, the next step will be to test the hypothesis that facilitated substance P signaling mediates the vascular, bony and nociceptive changes observed in these injury models. To confirm this hypothesis, neurotoxic lesioning of the substance P containing neurons will be used to prevent the development of vascular, bony, and nociceptive changes in the injury models, while substance P receptor antagonists will be used to reverse CRPS pathophysiology in these models. Finally, this proposal will utilize the CRPS models to develop invasive and noninvasive techniques for measuring facilitated cutaneous neurogenic inflammatory responses, techniques which can be used in future investigations examining facilitated substance P signaling in CRPS patients. These techniques include using cutaneous microdialysis and laser Doppler blood flow measurements to determine protein extravasation and vasodilatation responses to electrical stimulation and substance P microinfusion. A less invasive method will use cutaneous iontophoresjs of substance P to evoke a facilitated vasodilatation response measured by laser Doppler. Work Accomplished: We have now established animal models for CRPS types I and II and can use these models to further define the mechanisms for the constellation of vascular, bony, and nociceptive abnormalities that ensue after trauma. The neuropeptide substance P probably contributes to the edema, warmth, and increased spontaneous extravasation, mechanical hyperalgesia and allodynia that develop after trauma and immobilization and these changes are partially reversed with the substance P receptor antagonist LY303870, data supporting this novel therapeutic approach to the treatment of CRPS. Paradoxically both substance P and CGRP levels declined in the bilateral hindpaw nerve and skin in the trauma and immobilization models. We are currently performing cutaneous microdialysis studies that will hopefully shed light on the mechanisms underlying these discordant results. Another remarkable finding is that unilateral sciatic section, tibial fracture and casting all caused loss of cancellous bone ipsilateral and contralateral to the injury and caused the bilateral loss of substance P and CGRP in bone, evidence suggesting that neurotransmitters in bone contribute to the maintenance of normal bone metabolism and that trauma or immobilization disrupts this signaling. This could be a novel therapeutic target for the treatment of osteoporosis. Expected Outcome: The information collected during the course of these studies will greatly contribute tour understanding of the role of facilitated substance P signaling in the vascular, bony, and nociceptive CRPS sequelae, and will contribute to the ultimate goal of improving the efficacy and safety of the pharmacologic management of these diverse consequences of injury. Furthermore, we expect that the by defining the interactions between neurons and bone cells we will advance the bone field and potentially generate novel pharmacologic approaches for the treatment of osteoporosis. Funding Source: NIH Funding Status: Funded |
