Principal Investigator: Wade S. Kingery, MD Co-Investigators: Christopher R. Jacobs, PhD and David Yeomans, PhD Collaborator: Martin Schmelz, MD Objectives: 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. 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. The inhibitory effects of glucocorticoid treatment on CRPS edema, hyperalgesia and spontaneous extravasation will also be determined and the mechanisms investigated. Work Accomplished: The animal models for CRPS types I and II and a hindpaw immobilization model were established and being used to define the mechanisms for the constellation of vascular, bony, and nociceptive abnormalities that ensue after trauma or immobilization. The edema, warmth, increased spontaneous extravasation, and allodynia that develop in these models are partially reversed with the substance P receptor antagonist LY303870, data supporting a role substance P in the maintenance of the vascular and nociceptive sequelae of trauma and immobilization. Paradoxically both substance P and CGRP levels declined in the sciatic nerves in the trauma and immobilization models. SP perfusion studies demonstrated a facilitated SP evoked protein extravasation response in the CRPS hindpaw indicating a post-junctional enhancement of substance P signaling. We have also examined the effects of chronic glucocorticoid administration in the CRPS I rat model. Methylprednisolone (1mg/kg/day) for 14 days inhibited the development of hindpaw edema and warmth, but had no effect on allodynia or osteoporosis. This inhibitory effect appears to be caused by a post-junctional reduction in substance P signaling. We are further investigating the mechanisms for these effects in the CRPS I model, looking at the effects of glucocorticoids on neuropeptide gene expression, protein synthesis, and metabolism. 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 nerve and bone, evidence suggesting that neurotransmitters in bone contribute to the maintenance of normal bone metabolism and that trauma or immobilization disrupts this signaling. We have now performed capsaicin lesioning of sensory neurons in rats and demonstrated a loss of trabecular integrity, reduced bone mass and strength, and depleted neuropeptides in nerve and bone. These data suggest that capsaicin-sensitive sensory neurons contribute to trabecular bone integrity. Expected Outcome: The information collected during the course of these studies will greatly contribute to our understanding of the role of facilitated sensory neurotransmitter signaling in the vascular, bony, and nociceptive sequelae of trauma and immobilization, 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 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. Publications Kingery, W. S., Agashe, G.S., Clark, J.D. An NK1 antagonist can reverse vascular and nociceptive abnormalities in a rodent model of complex regional pain syndrome (CPRS). Abstracts 10th World Congress on Pain, IASP Press, 2002, 39: P35. Guo, T.Z., Wei, T. Kingery, W.S., Glucocorticoid inhibition of vascular abnormalities in a tibia fracture rat model of complex regional pain syndrome type I, Pain, 2006, 121: 158-167. Kingery, W.S., Davies, M.F., Clark, J.D., A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II, Pain, 2003,104: 75-84. Kingery, W.S., Offley, S.C., Guo, T.Z., Davies, M.F., Clark, J.D., Jacobs, C.R., A substance P receptor (NK1) antagonist enhances the widespread osteoporotic effects of sciatic nerve section, Bone, 2003, 33: 927-936. Guo, T.Z., Offley, S.C., Boyd, E.A., Jacobs, C.R, Kingery, W.S., Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I, Pain, 2004, 108: 95-107. Kingery, W.S., Agashe, G.S., Guo, T.Z., Davies, M.F., Clark, J.D., Maze, M., Capsaicin sensitive afferents mediate the development of heat hyperalgesia and hindpaw edema after sciatic section. Neurosci. Lett. 2002, 318: 39-43. Funding Source: NIH
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