Sarah M. Sweitzer - US grants

DESCRIPTION Chronic neuropathic pain is debilitating both physically and emotionally to the patient and to their family. This form of pain is often refractory to current pain therapies and costs this country billions of dollars a year. Current pain theory upholds that glial activation, increase expression of pro- inflammatory cytokines, and neuronal hypersensitivity all may contribute to long term potentiation of nociceptive pathways. The proposed project will utilize a spinal nerve transection animal model of neuropathic pain and mechanically lesioned mixed human neuronal and astrocytes cultures to determine the mechanism of action through which a new potentially indirect adenosine agonist produces anti-nociception (analgesia). My hypothesis is that this new potential therapeutic produces analgesia in neuropathic pain by simultaneously decreasing glial activation, pro-inflammatory cytokine expression and neuronal glutamate release. Immunohistochemistry, RT- PCR, and ELISA will be used to determine the effects of our potential indirect adenosine agonist on glial activation, pro-inflammatory cytokine expression and glutamate distribution in both an in vivo and in vitro model. This proposed study may uncover a new approach to treating neuropathic pain that employs therapeutics which target several molecular phenomenon simultaneously.

DESCRIPTION (provided by applicant): Pain processing in infants and children is not well understood. As recently as 20 years ago, major surgery was performed on neonates without the use of anesthetics. This is distressing because neonates have lower pain thresholds than adults and early painful experiences influence later pain responses. For example, boys who have been circumcised without anesthetics demonstrate significantly greater pain responses to immunization injections than do boys circumcised with the use of anesthetics. This amplification of pain responses is termed central sensitization and involves 'rewiring' of the nervous system. We propose that the developmental regulation of signal transduction protein kinase C isozymes and neuromodulatory astrocytes within the spinal cord predispose infants to develop central sensitization and that this manifests as increased pain sensitivity. Postnatal rats provide a model for studying the developmental regulation of pain. Postnatal rat pups have been shown to be more sensitive than adults to hind paw application of formalin (an irritant) that produces quantifiable short-term pain behaviors (paw licks and flinches). The present work will study pain processing in the neonatal central nervous systems at the behavioral, electrophysiological, cellular and molecular levels. We will examine the contribution of protein kinase C isozymes and astrocytes to the developmental regulation of formalin-induced central sensitization. The long-term goal is to provide therapeutic targets for the rational discovery and application of non-opioid analgesics in children.

[unreadable] DESCRIPTION (provided by applicant): A little over 10 years ago a series of clinical studies were published showing that untreated pain in the neonatal period (circumcision in male infants) enhanced subsequent pain responses in infancy and childhood. Basic science responded with a number of rodent studies but the majority of these studies used animals that are equivalent in age to a pre-term human infant and used inflammatory pain models. In contrast, the majority of under-treated pain in the hospital setting involves full-term infants and young children who are experiencing acute nociceptive pain. To this end, this proposal will use endothelin-1, an endogenous peptide released at sites of injury and disease, to model an acute nociceptive pain experience in a rat that is equivalent in development to a full-term human infant. We postulate that pain experience early in development decreases endothelin B receptor expression on keratinocytes in a testosterone-dependent manner. The end result of these changes is that early pain experiences sensitize males to subsequent pain. A combination of behavior, histological and pharmacological methods will be used to determine the mechanisms by which exposure to endothelin-1 early in life down-regulates the endothelin B receptor pathway. By determining the mechanism of endothelin-induced sensitization this work will lay the foundation for the development of therapeutic strategies to minimize pain and prevent pain-induced sensitization in infants and children. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Understanding how a pain experience early in life changes pain sensations experienced later in life is important to adequately assess pain and treat pain in infants and children. This proposal will define the mechanism by which one pain experience can enhance a subsequent pain experience. The goal of this proposal is to identify novel therapeutic targets for the development of therapies to prevent pain sensitization. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): With the addition of a graduate-level medical professional program, a strong research requirement for faculty, and the expectation that both graduate and undergraduate faculty will seek grant support, the PIs propose to establish an Office of Sponsored Projects (OSP) for Presbyterian College. The PIs will initially focus on building the administrative support necessary for the Pharmacy School and subsequently expand their efforts to support the undergraduate campus. Upon completion of the project, the goal is to have a centralized OSP that serves both the graduate and undergraduate faculty and programs successfully. This is a new function for the organization with three primary objectives (1) Develop and implement a formal administrative structure (FAS) for Pre- to Post-award grants management and reporting, (2) Create a research development initiative (RDI) to assist faculty in finding grant funding opportunities, developing proposals, post-award mentorship, and support, and (3) Evaluate the program to ensure the proposed structure and processes implemented meet the dynamic needs of an expanding faculty and administration and develop a sustainability plan. Working with the PIs' mentors at the Medical University of South Carolina and with the institution-wide support of their presidentially appointed steering committee, the PIs will establish a centralized office overseeing all grant activity; develop policies, procedures, an communication methods governing faculty grant development, from funding source identification to grants administration; develop institutional policies and procedures to govern facilities management and safety policies related to federal funding source requirements; provide education for existing staff, particularly in the area of grants management and accounting and reporting; add and train new staff in order to more efficiently and effectively manage and grow grant volume; develop policies and make provisions for technology transfer and intellectual property development needs, IRB, IACUC, and biohazard policies and procedures; and utilize evaluation methodology to ensure that the proposed processes and procedures designed and implemented meet the needs of the faculty and administration. Increasing ethnic diversity by continuing the Presbyterian College School of Pharmacy's (PCSP's) emphasis on recruiting students to pharmacy from Historically Black Colleges and Universities (HBCUs) and encouraging them to participate in faculty-directed research will be emphasized.