Nerve injury drives a heightened state of vigilance and neuropathic sensitization in Drosophila

Abstract

Injury can lead to devastating and often untreatable chronic pain. While acute pain perception (nociception) evolved more than 500 million years ago, virtually nothing is known about the molecular origin of chronic pain. Here we provide the first evidence that nerve injury leads to chronic neuropathic sensitization in insects. Mechanistically, peripheral nerve injury triggers a loss of central inhibition that drives escape circuit plasticity and neuropathic allodynia. At the molecular level, excitotoxic signaling within GABAergic (γ-aminobutyric acid) neurons required the acetylcholine receptor nAChRα1 and led to caspase-dependent death of GABAergic neurons. Conversely, disruption of GABA signaling was sufficient to trigger allodynia without injury. Last, we identified the conserved transcription factor twist as a critical downstream regulator driving GABAergic cell death and neuropathic allodynia. Together, we define how injury leads to allodynia in insects, and describe a primordial precursor to neuropathic pain may have been advantageous, protecting animals after serious injury.

Evolution of mechanisms and behaviour important for pain

“…This feature has long been assumed to contribute to chronic pain conditions and to involve transcriptionally dependent neuronal alterations [33,34]. Until now, the longest-lasting sensitizing effects of noxious stimulation in any invertebrate had been reported for Aplysia, where nociceptor sensitization after nerve injury persisted for over a month [35], a duration similar to that of behavioural alterations recently reported after leg amputation in Drosophila [11,32]. For the first time in any invertebrate, Howard et al [12] describe lifelong (13 weeks) sensitization of probable primary afferent neurons.…”

The Genetics of Neuropathic Pain from Model Organisms to Clinical Application

“…High-throughput genetic and phenotypic analysis (e.g., nociception) can be achieved in flies, as well as fish and worms, whereas complex behavioral traits such as cognitive affect can be assessed in rodents. Appreciation of plasticity in the fly nervous system has led to the application of several injury and chemically induced neuropathy models to this organism (Khuong et al., 2019). Adult flies are also capable of learned conditioning to thermal stimuli such that they subsequently avoid that area of the chamber even in the absence of heat (Wustmann et al., 1996).…”

Loss of Pseudouridine Synthases in the RluA Family Causes Hypersensitive Nociception inDrosophila

“…Drosophila larvae respond to noxious thermal and mechanical stimuli through stereotyped rolling escape locomotion (in which the larva rotates around its long body axis) which is easily distinguishable from other forms of locomotion (Tracey et al 2003). Combined with the unparalleled genetic tools available for Drosophila melanogaster, this behavioral readout provides an excellent system to study the genetics of nociception and pain (Tracey et al 2003;Caldwell and Tracey 2010;Milinkeviciute et al 2012;Im and Galko 2012;Khuong et al 2019).…”