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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Palo Alto Veterans Institute for Research
Palo Alto
United States
Zip Code
Shi, Xiaoyou; Guo, Tian-Zhi; Li, Wenwu et al. (2018) Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model. Anesthesiology 129:557-575
Guo, Tian-Zhi; Wei, Tzuping; Huang, Ting-Ting et al. (2018) Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain 19:1147-1156
Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou et al. (2018) Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome. J Neuroinflammation 15:105
Tajerian, Maral; Hung, Victor; Nguyen, Huy et al. (2018) The hippocampal extracellular matrix regulates pain and memory after injury. Mol Psychiatry 23:2302-2313
David Clark, J; Tawfik, Vivianne L; Tajerian, Maral et al. (2018) Autoinflammatory and autoimmune contributions to complex regional pain syndrome. Mol Pain 14:1744806918799127
Guo, Tian-Zhi; Shi, Xiaoyou; Li, Wen-Wu et al. (2017) Passive transfer autoimmunity in a mouse model of complex regional pain syndrome. Pain 158:2410-2421
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
Tajerian, Maral; Clark, John David (2016) New Concepts in Complex Regional Pain Syndrome. Hand Clin 32:41-9
Clark, J David (2016) Preclinical Pain Research: Can We Do Better? Anesthesiology 125:846-849
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

Showing the most recent 10 out of 27 publications