Glypicans Dally and Dally-like control injury-induced allodynia in Drosophila

Over 100 million people are challenged by the effects of chronic pain in the United States alone. This burden also impacts the U.S. economy; 600 billion dollars annually is spent on medical care, medications, and lost productivity in the workplace. Current opioid treatments cause adverse effects including nausea, constipation, tolerance, and addiction liability. Nociceptive sensitization is thought to perpetuate chronic pain, but too little is known about its mechanisms. Components of the pathways that sensitize the nociceptors after injury are likely to be valuable targets for novel medications for the relief or prevention of chronic pain. Utilizing the Drosophila melanogaster cell targeting and RNA interference toolkit, we are investigating the bone morphogenetic protein pathway and its role in ultraviolet light injury-induced nociceptive sensitization. Bone morphogenetic proteins are well known as secreted developmental morphogens that control development, but other functions are known. We have previously identified bone morphogenetic protein signaling components used in nociceptors to modulate injury-induced allodynia, including Decapentaplegic (Dpp, orthologous to mammalian bone morphogenetic protein 2/4), and its downstream signaling components. The morphogen Hedgehog has also been shown to be necessary for allodynia following injury. Here, we show that two membrane-embedded regulators of the Dpp and Hedgehog pathways, Dally and Dally-like, are necessary for injury-induced thermal allodynia, as the formation of sensitization was reduced when either component was suppressed. These bone morphogenetic protein components are highly conserved and, because dysregulation of nociceptor sensitization underlies chronic pain, the homologs of Dally and Dally-like may represent novel therapeutic targets in humans challenged by chronic pain. Furthermore, because of their extracellular location, Dally and Dally-like represent attractive therapeutic drug targets because such drugs would not need to cross the plasma membrane.