Primary Faculty/Secondary Faculty

Ron Wiley, M.D., Ph.D.

Professor of Neurology

VA TVHS, Neurology Service (127) 1310 24th Avenue, South, Nashville, TN, 37212

Research Description

The Laboratory of Experimental Neurology in the ACRE building of the Nashville VA Medical Center is devoted to the neurobiology of pain. A key feature of our approach is the use of targeted cytotoxins to selectively destroy specific types of neurons. This strategy has evolved in our laboratory from initial use of the toxic lectins, ricin, abrin, modeccin and volkensin, as suicide transport agents that kill any neuron they are applied to. We subsequently developed selective agents such as immunotoxins that consist of a monoclonal antibody directed against a neuronal surface molecule, armed to kill by conjugation with the ribosome inactivating protein, saporin. The immunotoxins, 192 IgG-saporin, anti-DBH-saporin, anti-DAT-saporin, etc. are effective immunolesioning agents that destroy specific classes of neurons determined by the presence of target molecules on the cell surface. These immunotoxins have been used extensively for studies of learning and memory, and now, are also of interest in pain experiments. More recently, neuropeptides have been used to target saporin, including substance P and dermorphin, which are toxic to cells expressing substance P receptors or mu opiate receptors, respectively.
Our approach includes the development, validation and use of operant behavioral tests of thermal pain perception in addition to standard reflex assays (hotplate, tail flick) in order to assess the affective/motivation component of pain. Animals trained on the operant tests are injected with targeted toxin to eliminate a specific class of neurons in a specific location such as the dorsal horn of the lumbar spinal cord and then retested to detect changes in behavioral responses to noxious heat and responses to analgesic drugs or other agents that alter pain sensitivity. At the completion of behavioral testing, the toxin-induced cell loss is assessed using immunohistochemistry and image analysis techniques to quantitatively relate the extent of lesion in each animal to the behavioral observations from the same animal. Functional anatomic analyses are also performed using induction of c-fos expression as an indication of neuronal activation by noxious stimuli. The goal is better understanding of the role(s) of specific types of neurons in nociception and analgesic drug action, and discovery of new approaches to treat chronic pain. .

Selected Publications