Peripheral Sensitization as a Novel Mechanism for Pain in Sickle Cell Disease

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DESCRIPTION (provided by applicant): The goal of this proposal is to provide the applicant a pathway to independence as a clinical investigator and expert in the field of pain in sickle cell disease (SCD). Pain causes significant morbidity for patients with SCD and currently there is a gap in knowledge in the understanding of SCD pain. This knowledge gap has hindered the development of new treatments for SCD pain. Thus, the overarching career goals of the applicant are to begin to close this knowledge gap by dedicating her career to the study of SCD pain. The applicant strives to become an expert in SCD pain and to develop and apply novel interventions for SCD pain management and/or prevention. She will begin to achieve these goals by performing patient-oriented research focused on SCD pain and engaging in career development activities focused on training in pain from clinical, biological, and research perspectives. Specifically, she will require additional training in the fundamental concepts of pain neurobiology, methodology of pain research, and further training in the management of both acute and chronic pain. Her career development plan is specifically tailored to her training needs in pediatric pain and will be guided by mentors and a scientific advisory committee at the Medical College of Wisconsin. The training plan takes advantage of training opportunities at the Medical College of Wisconsin and will also take advantage of opportunities outside of the institution to supplement her on-site pain training. The research activities will include investigation into the underlying neurobiology of SCD pain by exploration into mechanisms of peripheral sensitization and its contribution to SCD pain. Peripheral sensitization occurs when damage to or change in peripheral nerves result in features of neuropathic pain which can clinically present as hypersensitivity to mechanical or thermal stimuli. Preliminary data in both mice and patients with SCD reveal they both display hypersensitivity to heat and cold stimuli when in baseline state of health. In mice, this hypersensitivity worsens with hypoxia-reoxygenation, a laboratory-induced method that induces sickling phenomenon. It is not known whether this worsening sensitivity occurs in patients with SCD and the underlying reason for this hypersensitivity is not known. Chronic inflammation, including leukotrienes, has been shown to sensitize pain sensing nociceptors in non-SCD models. In addition, leukotrienes have been shown to be elevated in SCD patients compared to controls, increase further during acute pain, and higher levels have been associated with more frequent pain. The contribution of leukotrienes to peripheral sensitization in SCD has not been studied. Thus, this proposal aims to further study peripheral sensitization in humans with SCD using a validated methodology called quantitative sensory testing (QST) where thermal (heat, cold) pain thresholds can be safely and feasibly measured and will explore the association of leukotrienes with this sensitivity. We will use QST to evaluate heat and cold pain thresholds during an acute pain event and determine the relationship of leukotriene levels to these thermal pain thresholds at baseline and during pain. Results of this proposal have the potential to provide a mechanistic-based guide for further studies into the neurobiology of SCD pain and ultimately may contribute to the discovery of novel targets for therapeutics to prevent or treat SCD pain and relieve the suffering that patients with SCD experience.