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. 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 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 avoidance 'jump', in response to a thermal stimulus with a reduced delay, compared with uninjured animals. This injury induced sensitization paradigm has previously been used in larval flies 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. However, studies on larval flies are limited to the short time available before the larva pupariates, becoming insensitive while metamorphosis reorganizes the larval tissues to produce an adult. This project seeks to establish similar methods that can be applied to adult flies, which live for 35 or more days, a much longer time window for studying processes like chronic pain. Preliminary results indicate that UV-injured adults, like larvae, do indeed become hypersensitive to noxious stimuli. We are now ready to map out the time required for injured adults to become sensitized and then return to normal sensitivity, so that we can test the roles of genes that my serve to prolong pain sensitization, while others may shorten the hypersensitive period. The roles of sex and aging in pain sensitization will also be examined. Because of the high degree of functional conservation between fly and mammalian genes, components identified by these experiments may represent targets for novel medications for the treatment of abnormal pain in humans.

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 treatment by analyzing the process by which the neurons that sense noxious stimuli in both flies and mammals become sensitized after injury and then recover. 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.