Toxins from natural venoms modulate pain sensitization by depolarization-independent mechanisms in sensory neurons

• Applicant: Professor Dr. Tim Hucho
• Subject Area: Pharmacology ; Anaesthesiology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413120531

Current analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids often result in insufficient pain relief in more than 20% of patients. In addition, current therapeutics such as opioids are strongly limited by their side effects such as constipation, nausea, respiratory depression, and addiction1. Novel cellular and molecular pain mechanisms need to be defined urgently for the development of novel analgesic compounds.Venomous organisms evolved toxin mixtures of high molecular specificity and effectiveness. Many toxins evoke pain, and others inhibit pain. The power of toxins for the identification of cellular and molecular mechanisms as well as drug development is well established. Nevertheless, their use for target identification and as therapeutic compounds for pain relief is still an emerging field2. Currently, the most potent analgesic drugs such as NSAIDs and opioids modulate GPCR signaling and thereby the sensitivity and activity of nociceptive neurons. With our recent studies we succeeded to prove, that monitoring intracellular signaling with our innovative “High Content Screening (HCS)” microscopy approach is able to detect sensitization, desensitization, and depolarization inducing compounds. In our currently funded "venom/toxin Project" we have identified components for depolarization-induced sensitization signaling. We are now setting out to progress from our current research on depolarization-dependent sensitizing toxins, to identify depolarization-independent pro-nociceptive as well as analgesic compounds from natural venoms. For this, in Cologne (C) and Moscow (M) we will pursue the following objectives:1) Identification of novel depolarization-independent sensitizing/analgesic toxins from a variety of venomsa. Test venoms for cellular desensitizing/analgesic activity (C, M)b. Biochemical fractionation and cellular testing to isolate individual active toxins from the venoms (C, M)c. Structure determination of the active toxins (M)2) Analysis of the cellular and molecular mechanism of actiona. Production of recombinant analogs of the active peptides (M)b. Pharmacological characterization (dose-responses, kinetics) of the identified toxins (C, M)c. Subgroup specificity of nociceptive neurons affected by the active toxins (C)d. Analysis of the cellular mechanism (C)3) Analysis of therapeutic potentiala. Mechanistic and therapeutic corroboration of our cellular and molecular data in animal behavioral tests (C, M)

• DFG Programme: Research Grants
• International Connection: Russia
• Partner Organisation: Russian Foundation for Basic Research
• Cooperation Partner: Dr. Alexander Vassilevski