Nociceptive (pain) sensitization occurs when tissue damage leads to an adaptive lowering of the threshold for pain behavior. We have developed a platform for studying the genetic basis of adaptive and maladaptive pain modulation. Our unique platform combines UV radiation with quantitative behavioral assessment of thermal or mechanical nociception. To identify conserved genetic players underlying nociceptive sensitization we used tissue-specific RNAi, electrophysiology, cell-based assays, and behavior analysis to discover that Drosophila Substance P (Tachykinin) signaling modulates injury-induced nociceptive sensitization by controlling Hedgehog signaling (Im et al., eLife, 2015). This is a novel genetic interaction regulating acute sensitization.
While injury-induced nociceptive sensitization is an adaptive modulation of pain, when misregulated it can lead to maladaptive, debilitating chronic pain. To identify regulators of the transition from acute to chronic pain, we performed a tissue-specific RNAi screen looking for genes that led to persistent thermal hypersensitivity when specifically knocked down in multidendritic sensory neurons. Among 150 RNAi lines targeting conserved kinase-encoding genes, we found multiple hits that represent potential regulators of the elusive acute-chronic pain transition. The most striking candidate to emerge from this pilot screen was the insulin receptor (InR). InR knockdown caused prolonged hypersensitivity toward thermal and mechanical stimulation that was not accompanied by defects in baseline nociception (no injury) or acute adaptive sensitization to injury. Thus, the defect in InR knockdown larvae is specific to the transition from acute to chronic pain. The identification of InR as a regulator of the acute to chronic pain transition prompted us to model painful diabetic neuropathy (PDN), one of the most prevalent complications of diabetes with disabling pain syndromes. Similar to knockdown of InR, Drosophila models of both type I and type II diabetes exhibited prolonged PDN-like thermal pain hypersensitivity. This data suggest that diabetic conditions in Drosophila lead to pathological pain hypersensitivity similar to that experienced by diabetic patients, advocating that our genetically tractable platform is useful for dissecting genetic/molecular mechanisms of PDN pain syndromes. This discovery suggests a completely novel hypothesis not yet investigated in the field, namely that Insulin signaling is required within nociceptive sensory neurons to prevent PDN. We are currently investigating how this PDN-like chronic pain is achieved.