Billions of people suffer worldwide from chronic pain, with little relief as most patients do not respond to current therapies. These patients experience a range of symptoms including sensitisation to non-painful stimuli as well as persistent sleep disruption. Flies have been used for decades to understand both the molecular and neuronal pathways that control complex behaviours such as pain and sleep, and many of these have been shown to be conserved across phyla. Here we use UV radiation to induce inflammatory chronic pain in fly.
We found UV injury causes long term increases in thermal nociception sensitisation and poor sleep, including decreased sleep time and more fragmented sleep. Interestingly, we found it is possible to genetically uncouple sleep and pain as mutant dTrpA1 (fly pain receptor) flies displayed no thermal sensitisation, but still showed defective sleep. Since UV light damages DNA, we evaluated p53 mutant flies which were sufficient to induce a pain-like sleep phenotype without injury.
Mechanistically, we show that Drosophila Tumour Necrosis Factor (TNF) signalling was required for the maintenance of sleep-loss. The TNF receptor was not required in neurons, but instead in astrocyte-like glia. Downstream, we identify taurine transport by EAAT2 to be critical in the regulation of the late-stage sleep-loss after injury. Together, we describe a new chronic pain model in Drosophila, which genetically uncouples pain from sleep, with pain being mediated by peripheral sensation, while sleep changes are driven via inflammatory modulation of glial function.