Tracking the fate of Tetrodotoxin bound sodium channels
Pain is a global clinical problem. Chronic pain caused by cancer, osteo/rheumatoid arthritis, operations, injuries and spinal problems affects millions of people worldwide. The current treatments for severe pain is unsatisfactory and include opioids, non-steroidal anti-inflammatory drugs, corticosteroids and tricyclic anti-depressants. Most of these drugs have limitations with regard to addiction, toxicity and thus there is a growing need for newer analgesic drugs that have greater efficacy, reduced toxicity and addiction. Chronic pain results from aberrant electrical signalling in the nervous system. Pain-sensing neurons in the peripheral nervous system express several isoforms of sodium channels. Sodium channel blockers currently in clinical use, though beneficial, are limited by their safety profiles. Tetrodotoxin (TTX), a naturally occurring toxin in puffer fish is currently being tested in clinical trials as analgesic by WEX Pharmaceuticals. TTX is non-opioid and is non-addictive. It is also 2000 times more potent than morphine. This project will address whether TTX affects sodium channel expression, trafficking and other targets in the pain pathway and thus will assist the industrial partner interpret their clinical findings by providing the molecular basis of mechanism of action of TTX.