Complex regional pain syndrome (CRPS) is a condition characterized by pain, autonomic abnormalities and profound disability generally involving a limb. Surgery, trauma and immobilization are the most common causes of this syndrome. Though once considered a purely neurological problem, recent evidence from humans and laboratory animals indicates that activation of the innate system of immunity particularly in the skin of affected individuals may initiate and sustain the symptoms. Our own experiments demonstrate that the activation of multi-protein containing inflammasomes in skin generates IL-12 which is particularly important to the pain related aspects of CRPS. The existence of a readily available human model of CRPS would facilitate translational studies on this condition, and would greatly enhance our ability to study alternative analgesic and rehabilitative strategies. This application is a pilot proposal with 4 main objectives: 1) to identify which components of CRPS are well modeled in the setting of human hand surgery/cast immobilization, 2) to acquire sufficient preliminary data to allow estimation of effect size and variance in our assays allowing more accurate prediction of sample size requirements in subsequent studies, 3) to determine the likelihood that the basic observations concerning activation of IL-12 and the innate system of immunity in our rodent model can be translated to humans, and 4) to assemble a team of investigators on a focused project who will work together efficiently in subsequent larger scale efforts. To meet the study's objectives we will recruit 30 patients from a hand surgery clinic having undergone replacement of the first carpometacarpal (CMC) joint and subsequent cast immobilization of the limb for 4 weeks. At the time of cast removal the patients will be assessed carefully using both subjective and objective measures for the presence of CRPS-like changes. These assessments will determine which dimensions of CRPS are represented in this patient population. Biopsies from the skin of the hands ipsi- and contralateral to the surgery/immobilization will be collected. These samples will be analyzed for the expression of inflammation related genes both at the level of mRNA and subsequently using immunohistochemistry. We hypothesize that significant up-regulation of inflammasome proteins and IL-12 will be observed. At the conclusion of these studies we hope to have collected the data required for our team to design more in depth analyses of the mechanisms supporting CRPS. The bidirectional flow of information between animal models and this newly characterized human system would represent a major advancement in this field.
