Pokes, sunburn, and hot sauce: Drosophila as an emerging model for the biology of nociception

Abstract

The word "nociception" is derived from the Latin "nocere," which means "to harm." Nociception refers to the sensory perception of noxious stimuli that have the potential to cause tissue damage. Since the perception of such potentially harmful stimuli often results in behavioral escape responses, nociception provides a protective mechanism that allows an organism to avoid incipient (or further) damage to the tissue. It appears to be universal in metazoans as a variety of escape responses can be observed in both mammalian and non-mammalian vertebrates, as well as diverse invertebrates such as leeches, nematodes, and fruit flies (Sneddon [2004] Brain Research Review 46:123-130; Tobin and Bargmann [2004] Journal of Neurobiology 61:161-174; Smith and Lewin [2009] Journal of Comparative Physiology 195:1089-1106). Several types of stimuli can trigger nociceptive sensory transduction, including noxious heat, noxious chemicals, and harsh mechanical stimulation. Such high-threshold stimuli induce the firing of action potentials in peripheral nociceptors, the sensory neurons specialized for their detection (Basbaum et al. [2009] Cell 139:267-284). In vertebrates, these action potentials can either be relayed directly to a spinal motor neuron to provoke escape behavior (the so-called monosynaptic reflex) or can travel via spinal cord interneurons to higher-order processing centers in the brain. This review will cover the establishment of Drosophila as a system to study various aspects of nociceptive sensory perception. We will cover development of the neurons responsible for detecting noxious stimuli in larvae, the assays used to assess the function(s) of these neurons, and the genes that have been found to be required for both thermal and mechanical nociception. Along the way, we will highlight some of the genetic tools that make the fly such a powerful system for studies of nociception. Finally, we will cover recent studies that introduce new assays employing adult Drosophila to study both chemical and thermal nociception and provide an overview of important unanswered questions in the field.

Fig. 1

Classes of larval multidendritic neurons and the nociceptive sensory modalities they mediate. The top diagrams show the characteristic dendritic morphologies of the four classes of Multidendritic (Md) neurons that arborize over the larval barrier epidermis (adapted from Grueber et al., 2007 with the permission of the publisher). Below is a table that indicates which nociceptive sensory modalities each neuronal class subserves (data derived from Hwang et al., 2007). Boxes with question marks indicate where the assays for these modalities (noxious cold and chemical) have yet to be developed with Drosophila larvae and thus the neurons that mediate these potential responses have yet to be determined. +++, fully required for responsiveness. +, partially required for responsiveness. −, not required for responsiveness. See text for a discussion of the possible roles of the Class-I–III Md neurons.

Fig. 2

Assays for the different nociceptive sensory modalities in Drosophila larvae and adults. The table shows the different nociceptive sensory modalities and representative assays for assessing behavioral responses. Boxes with question marks indicate modalities/stages where assays have yet to be developed. Only noxious heat has been studied so far at both stages, using a custom-designed heat probe that can be dialed to a particular setpoint temperature (larvae) or a heated chamber that allows adults to choose between a noxious 46°C or non-noxious 32°C temperature range (diagram adapted from Neely et al., 2010, with permission from the publisher). Other thermal assays have been developed and are discussed in the text. The mechanical nociception assay in larvae involves a quick poke with a stiff fiber that delivers a ~ 50-mN force. The behavioral response to this stimulus, a corkscrew-like body roll, is very similar to that observed upon focal presentation of a noxious heat probe. For chemical nociception, one adult-based assay involves presenting the adult with a liquid laced with a presumably noxious compound (see text for details) and measuring the willingness of the adult to extend its proboscis and sample and resample the proffered nourishment. Other adult-based assays are discussed in the text. Proboscis extension pictures were adapted from Gordon and Scott (2009) with permission from the publisher.