Function of the adhesion-GPCR CIRL in nociception and pain resolution

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Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in a vast range of physiological processes. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies, and cancer. Several aGPCRs have recently been linked to mechanosensitive functions suggesting that processing of mechanical stimuli may be a common feature of this receptor family, not only in classical mechanosensory structures. CIRL (ADGRL/Latrophilin, Lphn), one of the oldest members of the aGPCR family, modulates mechanosensory signal transduction bi-directionally in Drosophila. Whereas CIRL increases sensory responses to gentle touch and sound, the aGPCR decreases mechanical nociception in vivo by reducing intracellular cAMP concentrations. The present project will use optogenetics, electrophysiology and super-resolution light microscopy in Drosophila to elucidate the signaling mechanism of CIRL in nociceptors and to design neuropathy models to examine molecular pathways of pain resolution. To this end, a focused in vivo screen for nociception/pain resolution in bortezomib-induced polyneuropathy (BIPN) will include the aGPCR and candidate genes studied by other members of the CRU. In addition, we will investigate CIRL in the context of neuropathic pain resolution upon chronic constriction injury (CCI) and BPIN in rodents and in humans (work package 3). We propose that mammalian CIRL is involved in acute antinociception e.g. evoked by strong static or dynamic pressure. We further hypothesize that enhanced Cirl gene expression and protein function promote pain resolution by decreasing nociceptor cAMP levels via endogenous tonic activation independent of the full recovery of sensory function.