This is an application for a Small Grant Award under the priority category of newer, less experienced investigators. Opioids are the most important drugs used in pain treatment. However, in addition to desirable analgesic properties, opioids have undesirable side effects such as the development of tolerance, physical dependence and the risk of addicition. We propose that tolerance development involves a series of layered events that result in a complex clinical picture. Very little is known about the signaling mechanisms underlying the development of acute tolerance and cross tolerance to opioids or the temporal sequence of these adaptations. The long term goals of this research are to understand signaling mechanisms responsible for the development of tolerance to, cross tolerance to, and physical dependence on opioids. The short term goals of this proposal are to characterize the role of extracellular signal related kinase (ERK) in the development of acute tolerance and cross tolerance, and to determine the relevance of these findings in behaving animals. We shall achieve these goals by using molecular and behavioral techniques to test the following hypotheses: A) Opioid tolerance may be mediated by the extracellular signal regulated kinase (ERK) cascade. B) Desensitization of ERK responses may be responsible for the development of cross-tolerance. To test these hypotheses, we propose studies with the following specific aims:
Aim 1 : To correlate ERK activation by mu opioid agonists to their receptor binding affinity, efficacy, or in vitro potency.
Aim 2 : To characterize trhe effects of acut mu opioid administration on ERK activation by subsequent doses of agonists or potential cross-tolerating agents.
Aim 3 : To assess the effects of ERK cascade inhibitors on the development of acute opioid tolerance in behaving animals. Taken together, these studies will correlate ERK activation with other indices of agonist efficacy and potency, and assess the role of ERK in the development of acute opioid tolerance. These experiments could lead to the identification of novel therapeutic targets that may eventually enable physicians to sustain the effectiveness of opioid analgesics while diminishing their undesirable side effects and addictive potential.
