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

Abstract

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.