This application proposes a program of training and research to expand the candidate's future prospects in achieving independence in pain research. The candidate has demonstrated his dedication to research and his initiative and high productivity in prior investigations, but he requires familiarity with a broader range of experimental approaches to fully explore pain pathophysiology and to be competitive in independent funding. The mentor. Dr. Hogan is a well-established clinician/scientist, and the dynamic research surrounding at Medical College of Wisconsin provides an ideal environment for the candidate to become a highly productive independent researcher. The program will help the candidate to accomplish the following goals: 1) establish modern scientific knowledge, acquire the newest research skills, and refine critical analytical abilities;2) provide coursework and interactive settings that will expand independence as a scientist;3) apply this new knowledge to examine the role of sigma receptors (aR) in traumatic painful neuropathy and inflammatory pain. Sensory neurons, including their somata in the dorsal root ganglion (DRG), develop abnormal function following nerve trauma and inflammation that contributes to pain. Although numerous triggers have been proposed for initiating these debilitating conditions, none has been established as a clinically relevant pathway. The proposed studies will examine the central hypothesis that activation of alR receptors in nociceptive sensory neurons contributes to neuropathic and inflammatory pain through inhibition of calcium signaling.
Specific Aim 1 will determine the effects of olR ligands on behavioral hyperalgesia after nerve injury and injection of complete Freund's adjuvant.
Specific Aim 2 will define the expression of olR in primary sensory neurons under baseline conditions.
Specific Aim 3 will examine functional consequences of olR activation in vitro, including effects on inward Ca2+ currents, neuronal excitability, and intracellular Ca2+ signaling.
Specific Aim 4 will identify expression and functional contributions of alR activity to changes after nerve injury and inflammation. These proposed experiments will employ convergent approaches including molecular and cell biological methods, immunohistochemical and live cell imaging, electrophysiological recording, and behavioral evaluation. The program will establish the candidate's new expertise in electrophysiology, molecular biology, and neuropharmacology and provide the foundation for establishing an independent research program considering olR in pain, opioid tolerance, and addiction.
Exploration of the contributions of alR in primary sensory neurons to pain sensation may provide a new therapeutic pathway for pain conditions that are resistant to currently available treatments.
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