Sumedha B S, Bangalore University
What is chronic pain?
Chronic or persistent pain is the pain that continues for longer than 12 weeks despite medication or treatment. For most people, the pain reduces gradually following an injury or operation. In certain cases, the pain does not subside for a long time. Also, it might occur without any history of an injury. It may be caused by diseases such as chronic fatigue syndrome, endometriosis, fibromyalgia, inflammatory bowel disease, interstitial cystitis.
Chronic pain develops when nerves get damaged. The nerve damage makes pain very intense and long-lasting. So, treating the primary cause might not resolve chronic pain.
For treatment, opioid pain relievers like morphine (MS Contin), codeine, and hydrocodone, acetaminophen, or nonsteroidal drugs such as aspirin or ibuprofen are used. While these medications do work, they have their disadvantages. The development of highly effective, non-addictive, safer drugs is a major requirement.
How Tarantula toxin is the Answer?
Tarantulas can be unsightly and they give people the creeps because of their oversized, hairy bodies and legs. However, surprisingly their ‘hunter’ tarantula toxin might have the solution to treat chronic pain. The Chinese tarantula bite consists stinger-like toxin that enters into a molecular target in their prey’s neurons. The action of the toxin is instant as the tarantula toxin immobilizes its prey before it moves away. High-resolution cryo-electron microscopy was used to discover the mode of action. It was found that the stinger rapidly locks the voltage sensors on sodium channels. Voltage sensors are small pores on cell membranes that are responsible for creating electrical currents and signals in nerves and muscles. The ‘stinger’ lysine residue is plunged into a group of negative charges of the voltage sensors which locks it in place and prevents its function. The voltage sensors get trapped in their resting position. This mechanism can be applied to develop new approaches. By structurally designing drugs, chronic pain could be treated by blocking sensory nerve signals.
But, capturing the functional form of the tarantula toxin-ion channel complex, is not an easy task. So, the toxin’s blocking method is reconstructed in a small molecule. This has enabled molecular biologists and pharmacologists to design new drugs. Researchers engineered a chimeric model of the sodium channel. “Chimeras’’ were made. It was done by bringing structures of more than one species together. The toxin-binding region was taken from a specific human sodium channel. This was put into a model bacterial sodium channel.
A clear molecular view of the configuration of toxin from tarantula venom was obtained, it bound tightly to its receptor on the sodium channel. The human sodium channel used in the chimeric model is called the Nav1.7 channel. It plays a major role in the transmission of pain from the peripheral nervous system to the spinal cord and brain. This study revealed the molecular basis for trapping of the voltage sensor at the resting state by this toxin.
The structure obtained provides a molecular template for the further design of structure-based drugs. Future chronic pain medications could be designed such that they would block the Nav1.7 sodium channels. This will reduce unfortunate side effects of chronic-pain medications like drowsiness, slowed breathing and in the long term- liver damage, heart attack, stroke, etc.
Also read: Influence of Tau proteins on Parkinson’s disease
References:
- Wisedchaisri, G., Tonggu, L., Gamal El-Din, T. M., McCord, E., Zheng, N., & Catterall, W. A. (2021). Structural Basis for High-Affinity Trapping of the NaV1.7 Channel in Its Resting State by Tarantula Toxin. Molecular cell, 81(1), 38–48.e4. https://doi.org/10.1016/j.molcel.2020.10.039
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