Nociceptor sensitivity and plasticity in Drosophila larvae is regulated by translation initiation factors

Nociception is the process of detecting noxious thermal, mechanical, or chemical stimuli by specialized sensory neurons known as nociceptors. Following tissue damage or inflammation, nociceptors may become sensitized, leading to increased pain perception and nociceptive behavior. Aberrant or prolonged nociceptor sensitization may underly many chronic pain conditions, highlighting the importance of understanding the mechanisms that underly the process of nociceptor sensitization. In Drosophila larvae, Class IV multidendritic neurons act as nociceptors that are activated by noxious thermal, mechanical, and UV stimuli in order to generate a nocifensive escape locomotion behavior. When larvae experience UV-induced tissue damage, they undergo nociceptor sensitization controlled by Eiger, Hedgehog, and Tachykinin signaling pathways that results in heightened nociceptive responses to noxious thermal stimuli. We show that nociceptor sensitivity under basal conditions and nociceptor sensitization is regulated by the function of the eukaryotic translation initiation factors (eIFs) of the eIF4F complex, the assembly of which is the rate-limiting step of translation initiation. Knockdown of eIF4A, eIF4G, and eIF4E subunits in the nociceptors results in decreased nociceptive responses to noxious thermal stimuli and a loss of nociceptive sensitization following UV-induced tissue damage. Loss of eIF4A specifically results in severe branching defects in Class IV neuron dendrites, suggesting that eIF4F subunits may have differing roles in nociceptor development and morphogenesis. These results suggest that regulation of gene expression during Drosophila nociceptor sensitization may be controlled at the level of translation initiation. Ongoing experiments will characterize the cellular mechanisms that translational regulators use to shape nociceptor function and also identify the molecular targets subject to translational regulation.