This is an application for a K award (Research Career development Award). The applicant is an anesthesiologist who is interested in studying the role of glutamate and the NMDA glutamate transmitter system in nociception and cognitive functions with the long term goal being to develop better therapeutic approaches to the management of chronic pain- -approaches that take advantage of the unique analgesic properties of NMDA antagonists while avoiding the serious side effects of these agents which include psychosis and cognitive impairment. The applicant has chosen for her primary sponsor John Olney, MD, a psychiatrist and neuroscientist who has been a pioneering leader in the glutamate research filed for the past 30 years. She will also be co-sponsored by Dr. John Newcomer, MD, an established clinical investigator who is pursuing clinical studies that are relevant to the applicant's career goals. Therefore, although the research projects described in the application all pertain to animal research that will be performed under Dr. Olney's guidance, the applicant will simultaneously be collaborating with Dr. Newcomer on human studies which will provide the training and expertise required to launch her own clinical studies in the future. The applicant's research addresses a pressing clinical problem as follows: Recent evidence implicates glutamate as a transmitter in nociceptive pathways and documents that antagonists of NMDA glutamate receptors can alleviate neuropathic pain (NPP), a type of pain that is not responsive to other known analgesics. However, NMDA antagonists have potentially serious side effects, including toxic degeneration of cortical neurons and psychotic, cognitive and motor disturbances that are thought to relate to excessive release of acetylcholine (ACh) in the cerebral cortex. Dr. Olney and colleagues have found that certain classes of drugs, including a2 adrenergic agonists such as clonidine, can suppress the ACh-releasing action of NMDA antagonists while also suppressing their neurotoxic side effects. The applicant has found that clonidine not only suppresses these side effects but enhances the NPP- relieving action of the NMDA antagonist, MK801. The applicant proposes to follow up these findings with additional studies aimed at further clarifying the mechanisms involved and identifying specific NMDA antagonist and a2 adrenergic agonists which, when used in combination can provide both a high degree of safety and superior relief from NPP in animal studies, with the eventual goal being to test the safety and therapeutic efficacy of this treatment regimen in a human pain clinic setting.
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