Neuropeptide signaling is required for tissue damage-induced nociceptive sensitization in Drosophila larvae. Seol-Hee Im¹, Daniel Babcock¹, Felona Gunawan², Michael Galko¹. 1) Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX; 2) Department of Biochemistry Cell and Molecular Biology, Rice University, Houston, TX.

   Nociception is the sensory perception of noxious stimuli. It serves the adaptive function of protecting organisms from potential tissue damage. When tissue is damaged, organisms display a subsequent reduction in their detection threshold for noxious stimuli, a phenomenon called nociceptive sensitization or allodynia. To understand the genetic basis of nociceptive sensitization, we combined an assay for tissue damage-induced thermal allodynia with a tissue specific in vivo RNAi screen for genes required within nociceptive sensory neurons for the development of thermal allodynia. We found that knock-down of the Drosophila tachykinin receptor (DTKR) inhibited UV-induced thermal allodynia. DTKR encodes the Drosophila homolog of the mammalian G-Protein-Coupled Receptor (Neurokinin receptor) for Substance P, a prominent nociceptive peptide neurotransmitter. Mutant alleles of DTKR also exhibit strong sensitization defects suggesting that the in vivo RNAi results are on-target. Pan-neuronal, but not nociceptive sensory neuron-specific RNAi targeting tachykinin (dTk), which encodes the neuropeptide ligands for DTKR, also resulted in a decrease in thermal allodynia. Importantly, no DKTR or dTk knockdowns or mutants gave defects in baseline nociception, suggesting a specific function in damage-induced sensitization. Furthermore, overexpression of DTKR in the nociceptive sensory neurons induced an ectopic sensitization in the absence of tissue damage. Genetic epistasis analysis using larvae with hyperactivated neuropeptide signaling suggested that Tachykinin signaling is upstream of Hedgehog signaling but independent of TNF signaling (two other nociceptive modulators) in pain sensitization. Our study suggests that Tachykinin, a Drosophila homolog of Substance P, plays a conserved role in nociceptive sensitization that will be amenable to genetic dissection using the powerful genetics and nociception assays available in Drosophila.