Complex Regional Pain Syndrome Type I (CRPS I) is a frequent sequela of distal tibia and radius fractures and limb surgery though it can occur even after minor injuries. Pain is a prominent feature of this syndrome, and disability in the setting of CRPS is very common. Recently our group described a tibia fracture model that exhibits the principal stigmata of CRPS I including chronic edema, allodynia, epidermal thickening, keratinocyte proliferation and periarticular osteoporosis. Unfortunately, the mechanisms supporting these changes remain highly enigmatic, and available clinical treatments have limited efficacy. Activation of the innate system of immunity in skin initiates the cascade of changes supporting this chronic disease. This research proposal outlines a vertically integrated set of experiments all focused on the central hypothesis that neural activation of keratinocyte inflammasomes is required for the production of IL-12, downstream mediators such as nerve growth factor (NGF), and ultimately the development of CRPS-like features in our rodent model. The project's specific aims are as follows: 1. We will test the hypothesis that substance P (SP), calcitonin gene related peptide (CGRP) and beta 2 adrenergic receptor agonists stimulate the production of key inflammasome components, and the activation of caspase-1 resulting in enhanced cytokine production. 2. We will test the hypothesis that inflammasome activation occurs after fracture, and is required for expression of the CRPS-like syndrome after tibial fracture in mice. 3. We will test the hypothesis that intact peripheral nervous system signaling is required for the activation of inflammasomes in skin after fracture, and that this activation is, in turn, required for the expression of CRPS-related biomarkers as well as edema, warmth and nociceptive sensitization. These experiments will use both cell culture and whole animal experiments. We will measure gene expression, mediator levels, enzymatic activity and behavioral indices of CRPS. In the short term we will refine the model of neuro-cutaneous signaling as it supports specific dimensions of CRPS I. In the longer run we hope to translate these findings into clinical trials involving CRPS I patients which will be made possible by the clinical orientation of the investigative team and the advent of pharmaceutical agents targeted at the regulation of inflammation.
Complex Regional Pain Syndrome (CRPS) is a common neurological condition causing chronic pain and disability. The recent discovery that CRPS-related inflammation is supported by the innate system of immunity, and that this system may control the onset and maintenance of CRPS is very novel. The proposed detailed studies of the neuropeptide and sympathetically mediated activation of inflammasomes will both further our understanding of neuro-cutaneous signaling and possibly suggest new approaches to the treatment of CRPS.
|Wei, Tzuping; Guo, Tian-Zhi; Li, Wen-Wu et al. (2016) Acute versus chronic phase mechanisms in a rat model of CRPS. J Neuroinflammation 13:14|
|Clark, J David (2016) Preclinical Pain Research: Can We Do Better? Anesthesiology 125:846-849|
|Tajerian, Maral; Clark, John David (2016) New Concepts in Complex Regional Pain Syndrome. Hand Clin 32:41-9|
|Tajerian, Maral; Clark, J David (2015) Novel cytogenic and neurovascular niches due to blood-brain barrier compromise in the chronic pain brain. Mol Pain 11:63|
|Li, W-W; Guo, T-Z; Shi, X et al. (2015) Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture. Neuroscience 310:73-90|
|Shi, Xiaoyou; Guo, Tian-Zhi; Wei, Tzuping et al. (2015) Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization. Pain 156:1852-63|
|Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-Wu et al. (2014) Immobilization contributes to exaggerated neuropeptide signaling, inflammatory changes, and nociceptive sensitization after fracture in rats. J Pain 15:1033-45|
|Tajerian, Maral; Leu, David; Zou, Yani et al. (2014) Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome. Anesthesiology 121:852-65|
|Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou et al. (2014) Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome. Pain 155:2377-89|
|Birklein, Frank; Drummond, Peter D; Li, Wenwu et al. (2014) Activation of cutaneous immune responses in complex regional pain syndrome. J Pain 15:485-95|
Showing the most recent 10 out of 20 publications