Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans

In order to thrive in constantly changing environments, animals must adaptively respond to threatening events. Noxious stimuli are not only processed according to their absolute intensity, but also to their context. Adaptation processes can cause animals to habituate at different rates and degrees i...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Filipe Marques, Laurent Falquet, Elke Vandewyer, Isabel Beets, Dominique A. Glauser
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/6e8b22aed558406b9f6d7fd8a4ec92e2
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6e8b22aed558406b9f6d7fd8a4ec92e2
record_format	dspace
spelling	oai:doaj.org-article:6e8b22aed558406b9f6d7fd8a4ec92e22021-11-25T05:52:24ZSignaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans1553-73901553-7404https://doaj.org/article/6e8b22aed558406b9f6d7fd8a4ec92e22021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601619/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404In order to thrive in constantly changing environments, animals must adaptively respond to threatening events. Noxious stimuli are not only processed according to their absolute intensity, but also to their context. Adaptation processes can cause animals to habituate at different rates and degrees in response to permanent or repeated stimuli. Here, we used a forward genetic approach in Caenorhabditis elegans to identify a neuropeptidergic pathway, essential to prevent fast habituation and maintain robust withdrawal responses to repeated noxious stimuli. This pathway involves the FRPR-19A and FRPR-19B G-protein coupled receptor isoforms produced from the frpr-19 gene by alternative splicing. Loss or overexpression of each or both isoforms can impair withdrawal responses caused by the optogenetic activation of the polymodal FLP nociceptor neuron. Furthermore, we identified FLP-8 and FLP-14 as FRPR-19 ligands in vitro. flp-14, but not flp-8, was essential to promote withdrawal response and is part of the same genetic pathway as frpr-19 in vivo. Expression and cell-specific rescue analyses suggest that FRPR-19 acts both in the FLP nociceptive neurons and downstream interneurons, whereas FLP-14 acts from interneurons. Importantly, genetic impairment of the FLP-14/FRPR-19 pathway accelerated the habituation to repeated FLP-specific optogenetic activation, as well as to repeated noxious heat and harsh touch stimuli. Collectively, our data suggest that well-adjusted neuromodulation via the FLP-14/FRPR-19 pathway contributes to promote nociceptive signals in C. elegans and counteracts habituation processes that otherwise tend to rapidly reduce aversive responses to repeated noxious stimuli. Author summary We all rapidly habituate to persistent or repeated innocuous sensory stimuli, for example when we go swimming and quickly accustom to cool water. In contrast, plasticity mechanisms in the nociceptive pathways tend to produce habituation for painful sensations only on longer time scales. Rapidly ignoring persistent innocuous stimuli, but remaining sensitive to potentially damaging stimuli is hence a strategy universally applied in animals. However, little is known about the molecular mechanisms acting to prevent rapid habituation in nociceptive pathways, despite understanding these mechanisms may provide important clues for developing new therapeutic approaches in pain management. Here, we identify a neuropeptide-based positive feedback signaling in a nociceptive pathway, which is essential to maintain its activity in a paradigm of repeated noxious stimulations.Filipe MarquesLaurent FalquetElke VandewyerIsabel BeetsDominique A. GlauserPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Filipe Marques Laurent Falquet Elke Vandewyer Isabel Beets Dominique A. Glauser Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans
description	In order to thrive in constantly changing environments, animals must adaptively respond to threatening events. Noxious stimuli are not only processed according to their absolute intensity, but also to their context. Adaptation processes can cause animals to habituate at different rates and degrees in response to permanent or repeated stimuli. Here, we used a forward genetic approach in Caenorhabditis elegans to identify a neuropeptidergic pathway, essential to prevent fast habituation and maintain robust withdrawal responses to repeated noxious stimuli. This pathway involves the FRPR-19A and FRPR-19B G-protein coupled receptor isoforms produced from the frpr-19 gene by alternative splicing. Loss or overexpression of each or both isoforms can impair withdrawal responses caused by the optogenetic activation of the polymodal FLP nociceptor neuron. Furthermore, we identified FLP-8 and FLP-14 as FRPR-19 ligands in vitro. flp-14, but not flp-8, was essential to promote withdrawal response and is part of the same genetic pathway as frpr-19 in vivo. Expression and cell-specific rescue analyses suggest that FRPR-19 acts both in the FLP nociceptive neurons and downstream interneurons, whereas FLP-14 acts from interneurons. Importantly, genetic impairment of the FLP-14/FRPR-19 pathway accelerated the habituation to repeated FLP-specific optogenetic activation, as well as to repeated noxious heat and harsh touch stimuli. Collectively, our data suggest that well-adjusted neuromodulation via the FLP-14/FRPR-19 pathway contributes to promote nociceptive signals in C. elegans and counteracts habituation processes that otherwise tend to rapidly reduce aversive responses to repeated noxious stimuli. Author summary We all rapidly habituate to persistent or repeated innocuous sensory stimuli, for example when we go swimming and quickly accustom to cool water. In contrast, plasticity mechanisms in the nociceptive pathways tend to produce habituation for painful sensations only on longer time scales. Rapidly ignoring persistent innocuous stimuli, but remaining sensitive to potentially damaging stimuli is hence a strategy universally applied in animals. However, little is known about the molecular mechanisms acting to prevent rapid habituation in nociceptive pathways, despite understanding these mechanisms may provide important clues for developing new therapeutic approaches in pain management. Here, we identify a neuropeptide-based positive feedback signaling in a nociceptive pathway, which is essential to maintain its activity in a paradigm of repeated noxious stimulations.
format	article
author	Filipe Marques Laurent Falquet Elke Vandewyer Isabel Beets Dominique A. Glauser
author_facet	Filipe Marques Laurent Falquet Elke Vandewyer Isabel Beets Dominique A. Glauser
author_sort	Filipe Marques
title	Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans
title_short	Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans
title_full	Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans
title_fullStr	Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans
title_full_unstemmed	Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans
title_sort	signaling via the flp-14/frpr-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in c. elegans
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/6e8b22aed558406b9f6d7fd8a4ec92e2
work_keys_str_mv	AT filipemarques signalingviatheflp14frpr19neuropeptidepathwaysustainsnociceptiveresponsetorepeatednoxiousstimuliincelegans AT laurentfalquet signalingviatheflp14frpr19neuropeptidepathwaysustainsnociceptiveresponsetorepeatednoxiousstimuliincelegans AT elkevandewyer signalingviatheflp14frpr19neuropeptidepathwaysustainsnociceptiveresponsetorepeatednoxiousstimuliincelegans AT isabelbeets signalingviatheflp14frpr19neuropeptidepathwaysustainsnociceptiveresponsetorepeatednoxiousstimuliincelegans AT dominiqueaglauser signalingviatheflp14frpr19neuropeptidepathwaysustainsnociceptiveresponsetorepeatednoxiousstimuliincelegans
_version_	1718414407151648768

Signaling via the FLP-14/FRPR-19 neuropeptide pathway sustains nociceptive response to repeated noxious stimuli in C. elegans

Ejemplares similares