A descending inhibitory mechanism of nociception mediated by an evolutionarily conserved neuropeptide system in Drosophila

Author:

Oikawa Izumi1,Kondo Shu2,Hashimoto Kao3,Yoshida Akiho1ORCID,Hamajima Megumi4ORCID,Tanimoto Hiromu5,Furukubo-Tokunaga Katsuo6,Honjo Ken46ORCID

Affiliation:

1. Graduate School of Life and Environmental Sciences, University of Tsukuba

2. Faculty of Advanced Engineering, Tokyo University of Science, Katsushika-ku

3. College of Life and Environmental Sciences, University of Tsukuba

4. Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology

5. Graduate School of Life Sciences, Tohoku University

6. Faculty of Life and Environmental Sciences, University of Tsukuba

Abstract

Nociception is a neural process that animals have developed to avoid potentially tissue-damaging stimuli. While nociception is triggered in the peripheral nervous system, its modulation by the central nervous system is a critical process in mammals, whose dysfunction has been extensively implicated in chronic pain pathogenesis. The peripheral mechanisms of nociception are largely conserved across the animal kingdom. However, it is unclear whether the brain-mediated modulation is also conserved in non-mammalian species. Here, we show that Drosophila has a descending inhibitory mechanism of nociception from the brain, mediated by the neuropeptide Drosulfakinin (DSK), a homolog of cholecystokinin (CCK) that plays an important role in the descending control of nociception in mammals. We found that mutants lacking dsk or its receptors are hypersensitive to noxious heat. Through a combination of genetic, behavioral, histological, and Ca2+ imaging analyses, we subsequently revealed neurons involved in DSK-mediated nociceptive regulation at a single-cell resolution and identified a DSKergic descending neuronal pathway that inhibits nociception. This study provides the first evidence for a descending modulatory mechanism of nociception from the brain in a non-mammalian species that is mediated by the evolutionarily conserved CCK system, raising the possibility that the descending inhibition is an ancient mechanism to regulate nociception.

Funder

Japan Society for the Promotion of Science

National Center for Geriatrics and Gerontology

Uehara Memorial Foundation

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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