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Updated: Jan 12, 2026
An Improved Assay and Tools for Measuring Mechanical Nociception in Drosophila Larvae
Published on: October 29, 2020
ILP4 and InR regulate paclitaxel-induced hypersensitivity differently in Drosophila larvae
Sreepradha Sridharan1,2,3, Yogesh Srivastava1,4, Ashleigh Ogg1
1Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Abstract:
Paclitaxel (PTX), a chemotherapeutic that stabilizes microtubules, induces nociceptive hypersensitivity and sensory neuron damage in humans, mice, and flies. To enhance our basic understanding of PTX-induced effects, we undertook a molecular/genetic dissection of PTX-induced nociceptive hypersensitivity. Larvae fed viable doses of PTX exhibited dose-dependent hypersensitivity to subnoxious thermal stimuli. Hypersensitivity developed rapidly and did not completely resolve at the larval stage. Live imaging of peripheral thermal nociceptors showed that lower doses of PTX (< 10 µM) caused hyper-sprouting of tertiary dendritic branches. At 10 µM and above, dendritic beading was observed. PTX-induced hypersensitivity does not depend on signaling pathways previously implicated in acute injury-induced nociceptive sensitization. However, the insulin-like peptide 4 (ILP4) was required for PTX-induced thermal hypersensitivity at 10 µM PTX. Surprisingly, RNAi targeting the insulin receptor (InR) in nociceptors increased PTX-induced hypersensitivity, suggesting that ILP4 does not activate InR in this context. The salivary gland is likely the primary tissue source of functional ILP4. ILP4 mutant larvae did not exhibit PTX-induced beading (10 µM) but did exhibit hypersprouting at lower PTX concentrations. In summary, our model of PTX-induced hypersensitivity reveals a disconnect between hypersensitivity and neuronal morphology and a genetic separation of ILP4 and InR in PTX-induced hypersensitivity.
Insights
Paclitaxel causes pain hypersensitivity by affecting sensory neurons. This study reveals the insulin-like peptide 4 (ILP4) is crucial for this effect, independent of the insulin receptor (InR) in neurons.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Paclitaxel (PTX) is a chemotherapy drug known to cause nerve damage and pain hypersensitivity.
- The precise molecular mechanisms underlying PTX-induced nociceptive hypersensitivity are not fully understood.
Purpose of the Study:
- To investigate the molecular and genetic basis of paclitaxel-induced nociceptive hypersensitivity.
- To explore the role of specific signaling pathways and molecules in PTX effects on sensory neurons.
Main Methods:
- Dose-dependent administration of PTX to Drosophila larvae.
- Live imaging of peripheral thermal nociceptors to observe dendritic morphology.
- Genetic manipulation using RNA interference (RNAi) and gene mutants (ILP4, InR).
Main Results:
- PTX induced dose-dependent thermal hypersensitivity and altered dendritic morphology (hyper-sprouting and beading) in nociceptors.
- PTX-induced hypersensitivity was independent of previously known acute injury pathways.
- Insulin-like peptide 4 (ILP4) was required for PTX hypersensitivity, but the insulin receptor (InR) in nociceptors did not mediate this effect.
- Salivary glands were identified as a likely source of ILP4.
Conclusions:
- PTX-induced hypersensitivity involves a complex interplay of neuronal and molecular factors, including ILP4.
- There is a dissociation between hypersensitivity and neuronal structural changes (dendritic morphology) in response to PTX.
- The findings suggest a novel signaling pathway involving ILP4, separate from InR in nociceptors, contributes to PTX-induced pain sensitization.
