Project Summary Normal pain promotes health by warning us of potential tissue damage, but abnormal pain reduces the quality of life for millions around the world. Available treatment for pain is currently inadequate, in part because of the deleterious side effects of our best analgesics, the opioids. Better treatments for abnormal pain are badly needed. We propose to reveal novel targets for pain medications by exploiting the powerful genetic toolkit of the Drosophila model. Fruit fly larvae react to noxious stimuli using an escape behavior consisting of an unmistakable corkscrew roll. This model system has been used to identify dozens of components that regulate nociceptive sensitivity. Many signaling components identified in the fly are very similar to their mammalian counterparts. Preliminary results indicate that the fly homolog of B-catenin, called Armadillo (Arm) regulates nociceptive sensitivity but the mechanism of this regulation is currently unclear. Aim 1 will test the hypothesis that Arm regulates sensitivity by exerting its influence in the well-known Wnt/Wg transcriptional control pathway. This testing will be accomplished by targeting RNAi silencing and/or overexpression constructs of key pathway genes specifically to the nociceptor neurons using the Gal4/UAS system. Any resulting changes to nociceptive sensitivity will be observed in thermo- and mechanonociception assays that focus on the escape behavior. Aim 2 will test the independent hypothesis that Arm and related components regulate nociceptive sensitivity through Arm's cell adhesion function. We will cause the nociceptors to express tagged forms of Arm and other components that can be analyzed by immunofluorescent microscopy to study neuronal Arm's contribution to neuronal-epidermal adhesive junctions called sheaths and to synapses with CNS interneurons. We will under- and overexpress Arm and other components and correlate any changes in sheath or synapse formation with nociceptive sensitivity using our behavioral assays. The proposed studies have the potential to identify novel mechanisms and components that affect nociceptive sensitivity. Because of the high degree of functional conservation between fly and mammalian signaling molecules, components identified by these experiments may represent targets for novel medications for the treatment of abnormal pain in humans.

Project Narrative: Available pain medications are inadequate to fully address the problem of intractable pain affecting some 10% of the US population. The proposed investigation aims to identify targets for effective new pain treatments by analyzing a pathway known to regulate nociceptive sensitivity in Drosophila. Drosophila is a powerful genetic model in which to efficiently identify the well-conserved genes that underlie basic processes like pain, allowing translation of these findings to mammals like rodents and humans.