Abstract
Steroid hormones organize many aspects of development, including that of the nervous system. Steroids also play neuromodulatory and other activational roles, including regulation of sensitivity to painful stimuli in mammals. In Drosophila, ecdysteroids are the only steroid hormones, and therefore the fly represents a simplified model system in which to explore mechanisms of steroid neuromodulation of nociception. In this report, we present evidence that ecdysteroids, acting through two isoforms of their nuclear ecdysone receptor (EcR), modulate sensitivity to noxious thermal and mechanical stimuli in the fly larva. We show that EcRA and EcRB1 are expressed by third instar larvae in the primary nociceptor neurons, known as the class IV multidendritic neurons. Suppression of EcRA by RNA interference in these cells leads to hyposensitivity to noxious stimulation. Suppression of EcRB1 leads to reduction of dendritic branching and length of nociceptor neurons. We show that specific isoforms of the ecdysone receptor play critical cell autonomous roles in modulating the sensitivity of nociceptor neurons and may indicate human orthologs that represent targets for novel analgesic drugs.
Highlights
Seeking treatment for pain is one of the top reasons patients visit their physicians [1]
The results indicate that the EcRB1 and EcRA isoforms of the nuclear ecdysone receptor are required, in an otherwise wild-type animal, for normal dendritic morphology and for maximal behavioral response to noxious stimulation, respectively
Both EcRA and EcRB1 isoforms can be detected in the class IV multidendritic neurons (Fig 1) via immunohistochemistry
Summary
Seeking treatment for pain is one of the top reasons patients visit their physicians [1]. For many years researchers have investigated the mechanisms of ailments that may be causing pain, but have in some ways neglected to consider pain as a treatable malady itself. The incidence of idiopathic acute and chronic pain is almost as prevalent as pain associated with a different causative ailment, suggesting that pain should be viewed as a symptom, and as a condition on its own. The fruit fly represents a simplified model in which to study pain, and one with important similarities to mammalian systems. The Drosophila model is free of placebo-induced analgesia [2,3], making it ideal for the investigation of baseline nociceptive behavior.
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