Daniela Salvemini, Ph.D. was awarded a grant from NIH/NIDA for 5 years for $1,771,000 for research entitled, “Role of peroxynitrite in morphine hyperalgesia and tolerance”. Opioid drugs such as morphine are the most effective analgesics for treating acute/severe chronic pain, but their pain-relieving action is often diminished during chronic administration, necessitating dose escalation that reduces quality of life for the patient.  This work will help elucidate the mechanisms and pathways in which the toxic by-product of superoxide and nitric oxide, peroxynitrite, negatively impacts opioid-induced analgesia. The outcome of this research will provide a novel mechanistic rationale for development of potent peroxynitrite-targeted therapies to maintain adequate pain relief during repetitive dosing for chronic pain, without engendering tolerance or unacceptable side-effects, thus addressing a large unmet medical need with major socioeconomic consequences.

Daniel Scott Zahm, Ph.D. was awarded a grant from NIH/NINDS for 5 years for $1,442,174. The proposed research entitled, “Convergent Versus Parallel Striatal Afferents,” addresses a brain system concerned with mechanisms that underlie decision-making by investigating its neuroanatomical relationships, the behavioral correlates of stimulating and inactivating it and the mechanisms by which it influences the reward system. The results should lead to better means to address how brain mechanisms subserving decision-making are affected by stress, alcohol and drugs, and, hopefully, to improved approaches to countering maladaptive decision-making, which, to a significant extent, underlies many of the chronic problems experienced by American individuals, families and society, including various forms of addiction and the seemingly inevitable cascades of relapse. 

Mary Ellsworth, Randy Sprague, Alan Stephenson and Christopher Ellis were awarded an Exploratory Program in Systems Biology (R33) grant. The regulation of oxygen supply to match oxygen demand in skeletal muscle is a fundamental physiological process, yet because of its complexity, attempts to describe it have been generally inadequate. It has become increasingly obvious that because processes like these cannot be understood merely by reducing them to their component parts, they must be studied as intact, functioning systems using a systems biology approach with computational modeling. In this proposal we use a systems biology approach to determine whether the release of ATP from red blood cells in response to metabolic need is responsible for local regulation of oxygen supply within skeletal muscle and test the predictions of the model by examining it using a system (type 2 diabetes) in which there is a defect in that regulatory system, i.e., ATP release from RBCs of type 2 diabetics is compromised.