14-3-3 gamma regulation of peripheral kappa opioid receptor function

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ABSTRACT Nearly one third of the population of the United States suffers from chronic pain. This pain causes major activity restrictions in nearly 11 million people. Opioids are used for the treatment of pain, but have many negative effects such as respiratory depression, addiction, and sedation. As these negative effects are mediated by the central nervous system, a promising approach for the safe and effective treatment of pain is to target the peripheral nervous system. Signals are sent by the peripheral nervous system to the brain and are interpreted as pain. By specifically inhibiting the transmission of these signals, pain can be alleviated. The value of this approach is illustrated by the pronounced analgesic effectiveness of local anesthetics. Peripherally restricted opioids can target peripheral neurons and overcome the limitations of local anesthetics, such as motor neuron inhibition. However, opioid receptors in the periphery are uniquely regulated, and poorly understood mechanisms of long-term inhibition reduce the effectiveness of peripherally restricted opioids. This study has preliminary evidence that the regulatory molecule 14-3-3γ mediates long-term inhibition of antinociception through the kappa opioid receptor (KOR). Further, 14-3-3γ appears to bias KOR signaling towards the pronociceptive mitogen-activated protein kinase (MAPK) pathways. This fellowship will: (1) establish that 14-3-3γ directly interacts with KOR, (2) identify KOR signaling pathways mediated by 14-3-3γ, and (3) evaluate the changes in KOR nociceptive signaling in vivo. These proposed studies will elucidate the role of 14-3-3γ in regulating KOR-mediated antinociception in peripheral sensory neurons. As a result, these studies will have significant impact on the use of peripherally restricted opioids for the safe and effective treatment of pain. Additionally, these studies will serve as an outstanding training vehicle for the applicant. The innovative research approach combines a heterologous expression system, rat primary neuronal culture, and behavioral nociception assays, which will ensure comprehensive training in the fields of pharmacology, cellular signaling, and rodent behavior. With the guidance of the applicant’s postdoctoral advisory committee, the training goals of developing new techniques, expanding understanding in a new field, refining communications, and producing research products will be realized. Ultimately, this fellowship will lay the foundation for a successful career as an independent investigator studying opioid receptor signaling in human disease.