This is an application for a K award (Research Career Development Award) from NIDA. The applicant is an anesthesiologist who is interested in studying the role of Ca2+ channels in sensory transmission including nociception with the long term goal being to determine the potential of Ca2+ channel blockers for better management of chronic pain. The applicant has chosen for his primary sponsor Charles F. Zorumski, M.D., a psychiatrist and neuroscientist who is a leader in the fields of glutamate research and CNS synaptic physiology. He will be co-sponsored by Christopher J. Lingle, Ph.D., an established neuroscientist and biophysicist who is pursuing research studies of Ca2+ channels that are relevant to the applicant's career goals. Additionally, one consultant will offer help in applicant's training and guidance. Min Zhuo, Ph.D., a neuroscientist with expertise in cellular electrophysiology, will provide training in spinal cord slice preparation. The applicant's goal is to acquire expertise to launch an independent career in pain research in the future. The applicant's research proposal addresses the role of multiple Ca2+ channels in sensory and nociceptive pathways in DRG and spinal cord. Even though voltage gated Ca2+ channels have long been recognized as targets for analgesic, anesthetic and anticonvulsant agents, progress in understanding the action of these channels on specific targets within sensory pathways has been impeded by the lack of selective tools to study their pharmacology. In the past two years, working on acutely dissociated rat DRG cells, the applicant has identified a novel selective antagonist for T-type Ca2+ channels, a neurosteroid (+)-ECN, which has minimal effects on other voltage- and receptor-gated channels. Another neurosteroid, (+)-ACN, shows remarkable selectivity for Q-, and R-subtypes of HVA Ca2+ channels and is a promising new tool to study HVA channels. Additionally, one of the most effective agents for treatment of neuropathic pain, the anticonvulsant phenytoin, blocks T-type current in DRG neurons in clinically relevant concentrations. The applicant proposes to follow up these findings with additional studies aimed at further clarifying the mechanisms and targets for these agents in acutely dissociated labeled spinothalamic dorsal horn neurons, isolated dendrites of dissociated dorsal horn neurons and their effects on synaptic transmission in DRG-dorsal horn co-cultures.

K08DA000428

2000-08-16

2001-08-31