Drosophila Insulin receptor regulates the persistence of injury-induced nociceptive sensitization.

Seol Hee Im,Michael J Galko,Atit A Patel,Daniel N Cox

doi:10.1242/dmm.034231

Abstract

ABSTRACTDiabetes-associated nociceptive hypersensitivity affects diabetic patients with hard-to-treat chronic pain. Because multiple tissues are affected by systemic alterations in insulin signaling, the functional locus of insulin signaling in diabetes-associated hypersensitivity remains obscure. Here, we used Drosophila nociception/nociceptive sensitization assays to investigate the role of Insulin receptor (Insulin-like receptor, InR) in nociceptive hypersensitivity. InR mutant larvae exhibited mostly normal baseline thermal nociception (absence of injury) and normal acute thermal hypersensitivity following UV-induced injury. However, their acute thermal hypersensitivity persists and fails to return to baseline, unlike in controls. Remarkably, injury-induced persistent hypersensitivity is also observed in larvae that exhibit either type 1 or type 2 diabetes. Cell type-specific genetic analysis indicates that InR function is required in multidendritic sensory neurons including nociceptive class IV neurons. In these same nociceptive sensory neurons, only modest changes in dendritic morphology were observed in the InRRNAi-expressing and diabetic larvae. At the cellular level, InR-deficient nociceptive sensory neurons show elevated calcium responses after injury. Sensory neuron-specific expression of InR rescues the persistent thermal hypersensitivity of InR mutants and constitutive activation of InR in sensory neurons ameliorates the hypersensitivity observed with a type 2-like diabetic state. Our results suggest that a sensory neuron-specific function of InR regulates the persistence of injury-associated hypersensitivity. It is likely that this new system will be an informative genetically tractable model of diabetes-associated hypersensitivity.

Highlights

Drosophila has emerged as a useful system for the study of insulin signaling/diabetes and nociception
InR mutant larvae exhibit persistent thermal hyperalgesia To explore the possibility that larvae with alterations in insulin signaling might exhibit nociceptive phenotypes, we first tested whether InR mutant larvae exhibited changes in baseline thermal nociception and thermal hyperalgesia, using assays standard in the field (Chattopadhyay et al, 2012) (Fig. 1A,B)
In InR mutants, this acute sensitization failed to resolve over the normal time course (Fig. 1E), and continued as persistent thermal hyperalgesia at a time (24 h post-injury) when acute sensitization has resolved in controls

Summary

Introduction

Drosophila has emerged as a useful system for the study of insulin signaling/diabetes and nociception. Dysregulation of Ilp production leads to a type 1-like diabetic state in Drosophila larvae (Rulifson et al, 2002), while a high-sugar diet leads to insulin resistance and a type 2-like diabetic state (Morris et al, 2012; Musselman et al, 2011; Skorupa et al, 2008). Insulin signaling and diabetic states in Drosophila regulate systemic glucose metabolism and organ-specific metabolic programs that impact muscle/cardiac function (Demontis and Perrimon, 2010; Na et al, 2013) and immunity (Musselman et al, 2017). Whether diabetic larvae exhibit the types of sensory phenotypes often associated with diabetic patients remains unclear

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Conclusion