Toxins from natural venoms modulate pain sensitization by depolarization-independent mechanisms in sensory neurons
Anaesthesiology
Final Report Abstract
Chronic pain unresponsive to therapeutics is a severe clinical problem. Novel pain modulating mechanisms need to be identified for the development of novel analgesic compounds. Many venoms from natural sources such as scorpions, spiders, and snakes evoke pain, others inhibit pain. Together with our partner, Dr. Alexander Vassilevski at the Russian Academy of Science, Moscow, we were setting out to screen and characterize depolarization-independent pro-nociceptive as well as potentially analgesic toxins from natural venoms. Allowing higher throughput studies on primary sensory neurons, we used the high content screening microscopy approach, which we pioneer in the pain field. We screened 123 venoms in 5 separate screens. We identified the black widow spider toxin, latrotoxin (LTX), to activate directly pro-nociceptive Erk1/2 signaling in nociceptive neurons. This occurred not through pore building but by metabotropic signalling via latrophilin receptors. Indeed, latrotoxin-induced pain was Erk1/2 dependent in animal behavioural experiments. Two more candidate venoms were followed up but left unfinished due to the severe limitations by Covid-19 and the obligatory end of collaboration with Russian partners after the unlawful invasion of the Ukraine. In addition, we followed a candidate approach. Candidate toxins from remipede Xibalbanus tulumensis were identified to activate pronociceptive signaling in nociceptive neurons. Together with electrophysiological and computational biological data by our collaboration partners these data are currently under revision. Thereby we proof, that large scale screening of up to 60.000 toxins is possible on primary sensory neurons and that our signaling-activity readout identifies nociception relevant toxins. In addition, by identifying Latrophilin receptor to be able to exert pain sensitizing signaling, we provide first mechanistic evidence, that this class of GPCR-based mechanosensitive receptors may be involved in pain sensitization.
