Tetrodotoxin -- a Promising Drug to Relieve Cancer Pain

Tetrodotoxin (TTX) is a highly toxic alkaloid natural neurotoxin that selectively blocks sodium ion channels. As a poison, TTX has lethal effects when ingested in humans, with lethal doses ranging from 1.5 mg to 2.0 mg (9 & mu;g/L in plasma). However, when TTX is administered to patients at levels well below its median lethal dose (LD50), it can treat a variety of medical diseases, including heroin and cocaine withdrawal symptoms, spinal cord injury, traumatic brain injury, tumor, neuropathic pain, and visceral pain. Cancer pain is generally treated with opioids, but it has certain dependence and addiction. After decades of unremitting exploration, researchers have made gratifying progress in the application of TTX in the field of biomedicine, especially in the treatment of cancer-related pain. Here we first review voltage-gated sodium channels (VGSCs), which are transmembrane proteins composed of a large & alpha; subunit and one or more & beta; subunits. VGSCs play an important role in pain and are typically classified as TTX-sensitive or TTX-resistant channels. Furthermore, we focus on roles of three VGSC subtypes Nav1.7, Nav1.8 and Nav1.9, and present the current status of research progress in the field of cancer related pain. We also discuss the binding sites, tolerability, delivery and supply of TTX. Finally, we summarize the most relevant recent advances in the clinical development, efficacy and safety of TTX as a drug for relieving cancer pain, showing the promise of TTX in cancer pain relief. On this basis, the limitations of existing research are pointed out, and the research directions of TTX in relieving cancer pain and the development of targeted analgesic drugs in the future are prospected.