Opioids have become a mainstay of treatment for moderate to severe pain. Direct healthcare costs of pain treatment together with pain-related disability cost the US economy tens of billions annually. While opioids are indisputably effective for acute pain and pain due to malignancies, the use of these drugs is often problematic for more chronic pain states. Abuse, dependence, tolerance and a host of physiological side effects may complicate long-term opioid management. Recently it has been demonstrated both in humans and in animal models that sensitization to painful stimuli develops after the sustained administration of opioids thereby reducing the efficacy of the drugs in achieving long term pain relief. This opioid-induced hyperalgesia (OIH) has no clinically available treatments, and there exist no validated strategies to prevent its occurrence. Our long term goals are to provide such treatments and strategies thus improving our ability to control serious pain. Work completed as part of our Stage I CEBRA award has documented a strong heritable component to OIH in mice, and we have been able to map these genetic differences to specific genes using new in silico mapping techniques. The gene most strongly associated with the mechanical dimension of OIH was the beta-2 adrenergic receptor. The studies to be completed as part of this proposal will confirm (or refute) a functional role for this gene in OIH, document the anatomical location of expression of this gene relevant to its role in OIH and determine the mechanism by which this gene helps to support OIH. A host of selective pharmacological agents as well as transgenic animals and biochemical assays will be employed. In addition, quantitative PCR, immunoblotting, immunohistochemistry and other techniques will assist us in determining basal and morphine-induced changes in levels of expression of this gene in specific central and peripheral nervous system tissues. Finally, we will evaluate hypothesized interactions between the beta-2 adrenergic receptor and pathways already well established to modulate OIH in rodents. The importance of this research with respect to public health is in addressing a fundamental problem limiting the utility of our most powerful pain relieving medications, the opioids. In doing so, we will be in position to design and test strategies which may limit OIH. The molecules on which this research focuses are particularly amenable to translational studies which could be completed in the future.