Characterization of the signaling pathways that produce nociceptor sensitization in Drosophila

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Normal pain promotes health by warning us of potential tissue damage, but abnormal pain reduces the quality of life for millions around the world. Pain sensitization after injury also promotes health by reducing re-injury during healing. Some types of abnormal pain, including chronic pain, result from dysregulation of the pain sensitization system. Available treatment for chronic pain is inadequate, in part because the deleterious side effects of our best analgesics, the opioids, are made more hazardous by longer use. 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. When the fruit fly larva is injured by a controlled dose of ultraviolet (UV) radiation, the animal exhibits allodynia, a manifestation of nociceptive sensitization. This means that the injured animal will react with a nocifensive avoidance behavior in the form of an unmistakable corkscrew roll, in response to a thermal stimulus that most uninjured animals find innocuous. This injury induced sensitization paradigm has previously been used to demonstrate that the nociceptor neuron requires signaling by the Bone Morphogenetic Proteins (BMP) pathway to produce allodynia. BMP signaling components in the fly are very similar to their mammalian orthologs. Preliminary results indicate that a transcriptional and translational response is necessary in the nociceptor neurons in order to produce allodynia following injury. Aim 1 will examine the necessity of a set of BMP related transcriptional regulators like brinker, yorkie and bantam. This will be accomplished by targeting an RNAi silencing construct of each gene specifically to the nociceptor neurons using the Gal4/UAS system. Aim 2 will bring additional BMP pathway and other components to light by identifying transcriptional and translationally regulated genes, again using Gal4/UAS gene targeting, ribosome-tagging and immunopurification tools, RNA sequencing and bioinformatics. Aim 3 will begin to translate the discoveries made in Drosophila into mammalian systems by testing BMP pathway inhibiting drugs for efficacy in providing relief from injury-induced pain sensitization. The proposed studies have the potential to identify all components regulated by transcription and translation in the signaling pathways required for allodynia. Because of the high degree of functional conservation between fly and mammalian BMPs, components identified by these experiments may represent targets for novel medications for the treatment of abnormal pain in humans.