Mechanical forces are detected and processed by the somatosensory system. Mechanosensation encompasses the distinct submodalities of touch, proprioception, and mechanical nociception. Touch plays an important discriminative role and contributes to social interactions (Abraira and Ginty, 2013; McGlone et al., 2014). Nociception reports incipient or potential tissue damage. It triggers protective behaviours and can give rise to pain sensations (Basbaum et al., 2009). Thus, physically similar signals can carry fundamentally different physiological information, depending on stimulus intensity. Whereas innocuous touch sensations rely on low-threshold mechanosensory neurons, noxious mechanical stimuli activate high-threshold mechanosensory neurons, i.e. nociceptors. While mechanisms to differentiate these mechanosensory submodalities are essential for survival, little is known how this is achieved at cellular and molecular levels.

The activity of nociceptors can be increased through sensitization, e.g. upon inflammation, and decreased through antinociceptive processes, leading to pain relief. In both cases, G protein-coupled receptors (GPCRs) play an important modulatory role. Receptors that couple to heterotrimeric G_q/11 or G_s proteins, like the prostaglandin EP₂ receptor, increase the excitability of nociceptors by activating phospholipase C and adenylyl cyclase pathways, respectively. In contrast, G_i/o-coupled receptors, which are gated by soluble ligands like morphine and endogenous opioid neuropeptides generally inhibit nociceptor signalling. In mammalian nociceptors, cell surface receptors that couple to G_i/o proteins are located at presynaptic sites in the dorsal horn of the spinal cord, where they reduce glutamate release, at somata in dorsal root ganglia (DRG), and at peripheral processes, where they suppress receptor potential generation (Yudin and Rohacs, 2018).

Research on mechanosensation has focussed mainly on receptors that transduce mechanical force into electrical current, and the function of such mechanosensing ion channels is currently the subject of detailed investigations. In contrast, evidence for mechano-metabotropic signal transfer and compelling models of force conversion into an intracellular second messenger response are limited, despite the vital role of metabotropic modulation in all corners of physiology (Mederos y Schnitzler et al., 2008; Hoffman et al., 2011). Adhesion-type GPCRs (aGPCRs), a large molecule family with over 30 members in humans, operate in diverse physiological settings. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies and cancer (Hamann et al., 2015; Scholz et al., 2016). In contrast to most members of the GPCR phylum, aGPCRs are not activated by soluble ligands. Instead, aGPCRs interact with partner molecules tethered to membranes or fixed to the extracellular matrix via their long, adhesive N-terminal domain. This arrangement positions aGPCRs as metabotropic mechanosensors, which translate a relative displacement of the receptor-bearing cell into an intracellular second messenger signal (Langenhan et al., 2016).

CIRL (ADGRL/Latrophilin, Lphn), one of the oldest members of the aGPCR family, is expressed in the neuronal dendrites and cilia of Drosophila larval chordotonal organs (ChOs), mechanosensory structures that respond to gentle touch, sound, and proprioceptive input (Kernan, 2007; Scholz et al., 2015). Here, mechanical stimulation of CIRL triggers a conformational change of the protein and activation via its tethered agonist (Stachel) (Liebscher et al., 2014; Stoveken et al., 2015). Signalling by the activated receptor reduces intracellular cAMP levels, which in turn sensitizes ChO neurons and potentiates the mechanically-evoked receptor potential (Scholz et al., 2017). In the current study, we show that CIRL also adjusts the activity of nociceptors, which respond to strong mechanical stimuli. Here, too, its function is consistent with G_i/o coupling. However, in contrast to touch-sensitive ChO neurons, nociceptors are sensitized by elevated cAMP concentrations and toned down by an antinociceptive and Stachel-independent action of CIRL. As a result of curtailing cAMP production, CIRL modulates neural processing of noxious harsh and innocuous gentle touch bidirectionally. This elegant signalling logic serves signal discrimination by helping to separate mechanosensory submodalities.

Drosophila larvae possess two major types of peripheral sensory neurons. Monociliated type one neurons, including ChOs and external sensory organs, and type two neurons with multiple dendritic (md) projections, classified as tracheal dendrite (md-td), bipolar dendrite (md-bd), and dendritic arborization (md-da). Md-da neurons are further subdivided into four classes: C1da-C4da (Ghysen et al., 1986; Bodmer and Jan, 1987; Grueber et al., 2002). Previous work demonstrated prominent expression of Cirl in ChOs, where it modulates sensory processing of innocuous mechanical stimuli (Scholz et al., 2015; Scholz et al., 2017). In addition, Cirl transcription was also noted in md neurons. Motivated by this observation, we now turned our attention to C4da neurons: polymodal nociceptors, which respond to noxious temperatures, intense light and, importantly, harsh mechanical touch (Tracey et al., 2003; Xiang et al., 2010; Zhong et al., 2010; Zhong et al., 2012; Kim et al., 2012; Kim and Johnson, 2014). Degenerin/epithelial sodium channels (DEG/ENaCs) contribute to nociceptive mechanotransduction in invertebrates and mammals (Price et al., 2001; Chatzigeorgiou et al., 2010; Zhong et al., 2010; Gorczyca et al., 2014; Guo et al., 2014; Mauthner et al., 2014). Placing a fluorescent reporter under transcriptional control of the DEG/ENaC subunit pickpocket (ppk) reliably marks C4da neurons (Grueber et al., 2003; Han et al., 2011). We therefore combined a direct GFP-ppk promoter fusion (ppk-CD4::tdGFP) with binary expression of the red photoprotein Tomato by a Cirl promoter element in the UAS/GAL4 system (dCirlp^GAL4 >UAS-CD4::tdTomato) (Brand and Perrimon, 1993; Scholz et al., 2015). This setting revealed Cirl transcription in both ppk-negative ChOs and ppk-positive C4da neurons (Figure 1). Thus, Cirl is expressed in different sensory neurons, including proprioceptors and nociceptors.

Figure 1

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Given CIRL’s role in mechanosensation, we next tested for a specific contribution of the aGPCR to mechanical nociception. Drosophila larvae display a stereotyped response to noxious mechanical insult. Importantly, this innate nocifensive behaviour, characterized by a ‘corkscrew’ body roll, can be quantified and is distinct from the animals’ reaction to innocuous touch (Figure 2A; Video 1; Tracey et al., 2003; Zhong et al., 2010). Mechanical stimulation with a 40 mN von Frey filament triggered nocifensive behaviour in 53% of control larvae. In contrast, Cirl null mutants (dCirl^KO) showed significantly increased nocifensive behaviour and responded in 75% of the trials (Figure 2B; Table 1). Knocking-down Cirl levels specifically in C4da neurons via RNA-interference (RNAi; ppk-GAL4 >UAS-dCirl^RNAi) delivered a mutant phenocopy and re-expressing Cirl in nociceptors rescued the mutant phenotype. Notably, Cirl overexpression had the opposite effect resulting in diminished nocifensive responses (Figure 2B; Table 1). These results show that CIRL curtails mechanical nociception by carrying out a cell-autonomous, dose-dependent function in C4da neurons.

Figure 2

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Video 1

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CIRL sensitizes proprioceptive ChO neurons by translating extracellular mechanical stimulation into a drop of intracellular cAMP. Lower cAMP levels, in turn, enhance the mechanically-evoked receptor potential of ChOs through a yet unresolved molecular mechanism (Scholz et al., 2017). Intriguingly, our behavioural data point towards CIRL exerting the opposite influence on nociceptive C4da neurons, whose sensitivity to mechanical stimulation is decreased by CIRL and increased in the absence of the aGPCR. A possible explanation for the antinociceptive action of CIRL is that the aGPCR also reduces cAMP in nociceptors, but that here the second messenger cascade acts on different molecular targets, i.e. specific ion channels, to produce an inverted effect. According to this model, low cAMP levels would dampen nociceptor activity. Next, we therefore asked whether increasing cAMP in C4da neurons (as may occur in dCirl^KO) promotes nocifensive behaviour. Because chronic changes of cAMP levels strongly alter neuronal development (Griffith and Budnik, 2006) we selected an optogenetic approach to trigger a rapid, nociceptor-specific increase of cAMP. The bacterial photoactivated adenylyl cyclase bPAC can be genetically expressed in selected Drosophila neurons to evoke cAMP production upon blue light stimulation (Figure 3A; Stierl et al., 2011; Scholz et al., 2017). Indeed, driving bPAC in C4da neurons (ppk-GAL4 >UAS-bPAC) led to increased nocifensive behaviour during light exposure, whereas control animals showed no light-induced effects (Figure 3B; Table 2). Notably, bPAC expression also produced some irregular behaviour in the absence of photostimulation (‘spontaneous bending’; Figure 3B), which is likely a result of the enzyme’s residual dark activity (Stierl et al., 2011). Nocifensive responses were further enhanced by bPAC in dCirl^KO larvae (dCirl^KO ppk-GAL4 >UAS-bPAC), in line with increased cAMP levels in mutant C4da neurons. Independent support for this conclusion was received by analysing larvae carrying mutant alleles of the phosphodiesterase (PDE) dunce (Davis and Kiger, 1981). Here, pronounced nocifensive behaviour accompanies chronically elevated cAMP concentrations (Figure 3C; Table 1).

Figure 3

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To further substantiate that CIRL influences nociception by acting on cAMP-dependent signalling, we inhibited the endogenous adenylyl cyclase activity by pharmacological means. Consistent with nociceptor sensitization by cAMP, dietary supplementation with the adenylyl cyclase inhibitors SQ22536 or DDA (2',3'-dideoxyadenosine) significantly decreased nocifensive behaviour of Drosophila larvae. Importantly, this treatment produced the same responses of control and dCirl^KO animals to von Frey filament stimulation (Figure 3D; Table 1). This result shows that CIRL acts in the same pathway as cAMP production by the adenylyl cyclase and supports the notion that the aGPCR exerts its antinociceptive effect by lowering cAMP levels through G_i/o -mediated inhibition of adenylyl cyclase activity.

Next, we used calcium imaging to directly test whether CIRL modulates the mechanically-evoked activity of nociceptors. To this end, we monitored calcium signals in C4da neurons labelled with GCaMP6m (Chen et al., 2013) during von Frey filament stimulation as previously reported (Hu et al., 2017; Figure 4—figure supplement 1). Consistent with the behavioural data describing a CIRL-mediated downregulation of nociceptor function, dCirl^RNAi significantly enhanced calcium responses to noxious mechanical stimulation (Figure 4A,B; Table 1). In principle, CIRL could influence the activity of C4da neurons by modulating cellular excitability or by modulating the mechanotransduction process, as is the case in touch-sensitive ChO neurons (Scholz et al., 2017). To differentiate between these possibilities, we again chose an optogenetic strategy and circumvented mechanotransduction by stimulating the nociceptors with light. Photostimulation of C4da neurons via the optimized Channelrhodopsin-2 (ChR2) variant ChR2^XXM (Nagel et al., 2003; Scholz et al., 2017) triggered nocifensive behaviour, consistent with previous work (Hwang et al., 2007). Notably, dCirl^KO larvae (dCirl^KO ppk-GAL4 >UAS-chop2^XXM) responded more strongly than controls (ppk-GAL4 >UAS-chop2^XXM) over a range of different blue light intensities (475 nm; Figure 4C; Table 3). This demonstrates that CIRL decreases the excitability of mechanical nociceptors, contrasting its role in touch-sensitive neurons where the aGPCR specifically enhances mechanotransduction (Scholz et al., 2017).

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We further asked whether signalling to different subcellular targets may correlate with different activation mechanisms of CIRL in these two types of mechanosensory neurons. Several studies have shown that aGPCR activation can occur by means of an intramolecular tethered agonist, termed Stachel (stalk) (Liebscher et al., 2014; Monk et al., 2015; Stoveken et al., 2015, for Stachel-independent signalling see Kishore et al., 2016; Salzman et al., 2017; Sando et al., 2019). This linker sequence of approximately 20 amino acids begins at the extracellular GPCR proteolysis site (GPS) and connects the GAIN (GPCR autoproteolysis inducing) domain to the 7-transmembrane unit (Figure 4D). In order to test for a role of the Stachel sequence in activating CIRL in mechanical nociceptors, we used two established mutants. Whereas the dCirl^T>A allele carries a mutation at the +1 position of the GPS within the Stachel sequence, the −2 mutation in the dCirl^H>A allele leaves the Stachel intact but reduces protein expression (Figure 4D; Scholz et al., 2017). Our analysis of nocifensive behaviour in these mutants reported normal responses for the T > A allele and a Cirl^KO phenocopy for the H > A allele (Figure 4E, Table 1). Thus, C4da neurons appear to be sensitive to reduced CIRL expression, which is consistent with very low protein levels in wild-type animals (close to the detection threshold; Figure 4—figure supplement 2). An intact tethered agonist, in turn, is dispensable for CIRL function in mechanical nociceptors, contrasting the situation in touch-sensitive ChO neurons, where mutating the Stachel sequence disrupts receptor function (Scholz et al., 2017). Taken together, these observations indicate that the activation mechanism of CIRL differs for the two mechanosensory submodalities.

Having established that CIRL downregulates nociceptor function under physiological conditions, we sought to investigate a pathological setting. The chemotherapeutic agent paclitaxel, employed to treat solid tumours such as ovarian or breast cancer, causes dose-limiting peripheral neuropathy in patients. Similarly, feeding Drosophila larvae paclitaxel-supplemented food induces axonal injury and degeneration of C4da neurons (Bhattacharya et al., 2012). Next, we therefore examined nocifensive behaviour in the context of this established neuropathy model. Consistent with chemotherapy-induced allodynia in humans, paclitaxel strongly enhanced nocifensive responses of control larvae (Figure 5A). We observed a comparable effect in dCirl^KO animals. Overexpressing Cirl, in turn, reverted the paclitaxel-induced sensitization of C4da neurons (Figure 5A; Table 1). Thus, CIRL tones down nociceptors in both physiological and neuropathic hyperexcitable states.

Figure 5

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Paclitaxel administration causes structural damage to C4da neurons (Bhattacharya et al., 2012). Following paclitaxel treatment (10 µM), we observed dendrite loss in the wild-type background and in nociceptors overexpressing Cirl (Figure 5B,C; Table 1). In fact, elevated Cirl expression itself reduced the dendritic complexity of C4da neurons. Thus, increasing CIRL protein copy number counteracts the neuropathic hyperexcitability of mechanical nociceptors independently of neuropathy-associated morphological defects. Consistent with the interpretation that modulation of nociceptor physiology by CIRL is not tightly coupled to morphological changes, dCirl^KO C4da neurons displayed only subtle structural alterations (Figure 5D).

Considering the evolutionary conservation of signalling pathways for nociception (Im and Galko, 2012), we next turned to a rodent model of traumatic neuropathic pain: unilateral chronic constriction injury (CCI) of the sciatic nerve (Reinhold et al., 2019). This model resembles paclitaxel-induced neuropathy in the development of thermal hypersensitivity and mechanical allodynia (Sisignano et al., 2016), i.e. a noxious reaction to innocuous stimuli like touch, reaching a maximum after one week (Figure 6A; Table 1). There are three CIRL proteins in mammals (CIRL1-3 also known as ADGRL1-3 or Lphn1-3) (Langenhan et al., 2016). According to RNA sequencing data from mouse DRG neurons, Cirl1 and Cirl3 are expressed in nociceptors (Thakur et al., 2014). We therefore investigated Cirl1 and Cirl3 expression in subpopulations of DRG neurons via in situ hybridization in the neuropathic context. Interestingly, Cirl1 mRNA probes described significantly reduced transcript levels in isolectin-B4 (IB4)-positive, non-peptidergic nociceptors one week after CCI (Figure 6B,D,E; Table 1). We observed a similar, though statistically insignificant trend in peptidergic nociceptors identified by calcitonin gene-related peptide (CGRP) staining and for Cirl3 probes (Figure 6B-E; Table 1). Notably, CCI appeared to neither affect Cirl1 nor Cirl3 gene expression in non-nociceptive, large myelinated neurons marked by neurofilament protein NF200. These correlative results are consistent with the Drosophila data linking low Cirl expression levels to nociceptor sensitization. It remains to be determined whether expression of Drosophila Cirl can be regulated physiologically to adapt or tune nociceptor sensitivity and whether activation of mammalian CIRL, in turn, can provide analgesia.

Figure 6

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The sensations of touch and mechanical pain represent distinct mechanosensory submodalities, which are separated at the initial sites of mechanotransduction. Despite their important roles in health and disease, an understanding of how these mechanistically different transduction processes are carried out at the molecular level is only just beginning to emerge (Delmas et al., 2011; Julius, 2013; Murthy et al., 2017; Szczot et al., 2017; Zhang et al., 2019). Similar to mammalian DRG neurons, Drosophila nociceptors are modulated by GPCRs (Hu et al., 2017; Kaneko et al., 2017; Herman et al., 2018) and can be negatively regulated by G_i/o signalling (Christianson et al., 2016; Honjo et al., 2016). In the present study, we provide evidence that CIRL, an evolutionarily conserved aGPCR, reduces nociceptor responses to mechanical insult in Drosophila larvae. This modulation operates in the opposite direction to the sensitization of touch sensitive neurons by CIRL (Figure 7; Scholz et al., 2015; Scholz et al., 2017). In both types of mechanosensors, these effects are connected to CIRL-dependent decreases of cAMP levels. The opposing cell physiological outcomes, in turn, likely arise from specific adjustments of different effector proteins through cAMP-signalling. Candidate effectors are mechanotransduction channels and ion channels, which are mechanically-insensitive but influence the rheobase, i.e. the threshold current of the sensory neuron (Boiko et al., 2017).

Figure 7

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The transient receptor potential (TRP) channel subunits NOMPC (no receptor potential, TRPN), NAN (nanchung, TRPV), and IAV (inactive, TRPV) govern mechanosensation by larval ChO neurons (Effertz et al., 2012; Lehnert et al., 2013; Zhang et al., 2013). The mechanically gated ion channel Piezo, the DEG/ENaC subunit Pickpocket, and the TRPN channel Painless, on the other hand, are required for mechanical nociception in Drosophila (Tracey et al., 2003; Zhong et al., 2010; Kim et al., 2012; Gorczyca et al., 2014; Guo et al., 2014; Mauthner et al., 2014). It is therefore conceivable that the receptor potential generated by these different mechanotransducers may be modulated in opposite directions, i.e. decreased in ChO neurons and increased in nociceptors, by cAMP/PKA (protein kinase A)-dependent channel phosphorylation. Matching our results in Drosophila, enhanced nociceptor activity in mammals has been linked to elevated cAMP levels. For example, mechanical hyperalgesia during inflammation involves cAMP-modulated HCN channels and sensitization of mammalian Piezo2 via PKA and protein kinase C (PKC)-based signalling (Emery et al., 2011; Dubin et al., 2012). Conversely, G_i/o-coupled receptors, such as opioid, somatostatin, and GABA_B receptors, counteract cAMP-dependent nociceptor sensitization (Yudin and Rohacs, 2018). In addition to this second messenger pathway, G_βγ subunits of G_i/o-coupled GPCRs can directly interact with ion channels. Thereby nociceptor signalling can be suppressed via activation of G protein regulated inwardly rectifying K⁺ channels (GIRK) or by inhibition of voltage-gated Ca²⁺ channels (Logothetis et al., 1987; Marker et al., 2005; Bourinet et al., 2014). Recent work has identified that CIRL2 and CIRL3 promote synapse formation in the mouse hippocampus (Sando et al., 2019). While Drosophila CIRL may also shape synaptic connectivity, our results indicate that CIRL modulates the mechanically-evoked activity of nociceptors independently of such an additional function.

The present findings show that CIRL decreases the activity of C4da neurons independently of mechanotransduction and that the aGPCR feeds into the same pathway as the adenylyl cyclase. Taken together, this strongly suggests that G_i/o coupling by CIRL regulates cAMP-dependent modulation of ion channels, which control nociceptor excitability. Work in cell culture has put forward a model in which Stachel-dependent and -independent aGPCR activation triggers different downstream signalling pathways (Kishore et al., 2016; Salzman et al., 2017). Here, we provide evidence in support of such a dual activation model in a physiological setting. The dispensability of an intact Stachel sequence in mechanical nociceptors and its necessity in touch-sensitive neurons argues for alternative activation modes of CIRL in these two types of mechanosensory neurons. This raises the intriguing possibility that such functional differentiation may be connected to specific downstream effects, e.g. Stachel-dependent, phasic modulation of mechanotransduction in ChO neurons versus Stachel-independent, tonic modulation of nociceptor excitability (Figure 7).

Many genes display altered expression in DRG neurons in neuropathy (Lopes et al., 2017). For example, receptors and ion channels involved in sensitization are upregulated, whereas endogenous antinociceptive mechanisms, including opioid receptors and their peptides, are downregulated in certain neuropathy models (Herradon et al., 2008; Hervera et al., 2011). Thus, neuropathy not only enhances pro-nociceptive mechanisms but also decreases endogenous antinociceptive pathways. Our analysis of rodent DRGs indicates that neuropathy-induced allodynia correlates with reduced Cirl1 expression in IB4-positive non-peptidergic nociceptors (Fang et al., 2006), a class of neurons, which have been linked to mechanical inflammatory hypersensitivity (Pinto et al., 2019). It is therefore tempting to speculate that CIRL operates via a conserved antinociceptive mechanism in both invertebrate and mammalian nociceptors to reduce cAMP concentrations. Future work will have to test this hypothesis by examining a direct causal relation between CIRL activation and nociceptor attenuation in the mammalian peripheral nervous system and to explore whether metabotropic mechanosensing by CIRL is a possible target for analgesic therapy. Limited options for treating chronic pain have contributed to the current opioid epidemic (Skolnick and Volkow, 2016). Opioids are powerful analgesics but have severe side effects and lead to addiction mainly through activation of receptors in the central nervous system. There is thus a strong incentive to develop novel peripherally acting pain therapeutics.

The specificity theory, put forward more than 100 years ago (Sherrington, 1906), defines nociceptors as a functionally distinct subtype of nerve endings, which are specifically tuned to detect harmful, high-intensity stimuli. The results reported in the present study are consistent with this validated concept and identify a physiological mechanism, which contributes to the functional specialization. On the one hand, CIRL helps set the high activation threshold of mechanical nociceptors, while on the other hand, CIRL lowers the activation threshold of touch sensitive neurons (Figure 7). This bidirectional adjustment, attributable to cell-specific effects of cAMP, moves both submodalities further apart and sharpens the contrast of mechanosensory signals carrying different information.

The presented data are summarized in Tables 1-3.

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Author details

1. Sven Dannhäuser

   1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
   2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

   Contribution

   Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

2. Thomas J Lux

   Center for Interdisciplinary Pain Medicine, Department of Anaesthesiology, University Hospital Würzburg, Würzburg, Germany

   Contribution

   Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1049-9872

3. Chun Hu

   Neuronal Patterning and Connectivity, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

   Contribution

   Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

4. Mareike Selcho

   1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
   2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

   Contribution

   Formal analysis, Supervision, Funding acquisition, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

5. Jeremy T-C Chen

   Center for Interdisciplinary Pain Medicine, Department of Anaesthesiology, University Hospital Würzburg, Würzburg, Germany

   Contribution

   Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

6. Nadine Ehmann

   1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
   2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

   Contribution

   Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

7. Divya Sachidanandan

   1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
   2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

   Contribution

   Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8219-8177

8. Sarah Stopp

   1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
   2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

   Contribution

   Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

9. Dennis Pauls

   1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
   2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

   Contribution

   Investigation, Writing - review and editing, Funding acquisition

   Competing interests

   No competing interests declared

10. Matthias Pawlak

    Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany

    Contribution

    Conceptualization, Formal analysis, Writing - review and editing

    Competing interests

    No competing interests declared

11. Tobias Langenhan

    Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany

    Contribution

    Conceptualization, Supervision, Funding acquisition, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-9061-3809

12. Peter Soba

    Neuronal Patterning and Connectivity, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing - review and editing

    Competing interests

    No competing interests declared

13. Heike L Rittner

    Center for Interdisciplinary Pain Medicine, Department of Anaesthesiology, University Hospital Würzburg, Würzburg, Germany

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing - review and editing

    For correspondence

    rittner_h@ukw.de

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4867-0188

14. Robert J Kittel

    1. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
    2. Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    rjkittel@me.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-9199-4826

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  citations for umbrella DOI https://doi.org/10.7554/eLife.56738