Posted by Saeed Tarabichi, MSIV, Drexel University College of Medicine
Even before we learned how to use paper, mankind has delegated high priority towards learning to control one of the most instinctive of natural feelings: pain. As early as 5000 BC, there are clay tablets of the Sumerians regarding the cultivation of opium as a “joy plant.”
The point I’m trying to make is that people don’t like pain. A LOT. So much, that for as long as mankind has been in civilization these past 7000 years, we have constantly tried to eliminate it from our lives. Yet even after all these amazing technological advances we have made, it’s amazing to think that we have not yet solved the problem of unnecessary pain from our lives.
At this point, you might be thinking to yourself, “What are you talking about? What about all the powerful stuff we give people in the hospital like morphine, fentanyl, oxycontin? We even have things that can take the pain away from certain areas like lidocaine!” True, there are many options for pain that we can employ today, but these options are largely used to treat two of the three cardinal types of pain that humankind can experience: Somatic (the type of pain you get from cutting yourself) and Visceral pain (organ pain- think stomach ache). The third type of pain, neuropathic (damaged nerve pain), is one that we have not fully understood, and one that we have not fully learned how to deal with.
A recent research breakthrough might suggest otherwise. A group of researchers from France have found a very interesting new potential agent to help us treat this elusive neuropathic pain. This new agent was so interesting, that it intrigued the people over at Nature magazine to publish their article about it. So what is it that has all these people excited for the next potential cure to pain?
I bet you didn’t see where that was going (unless you already scrolled through this article, you cheater, you). That is a black mamba snake. The article published in Nature magazine is titled: Black mamba venom peptides target acid-sensing ion channels to abolish pain.
Black Mamba? Isn’t that the snake from Kill Bill 2?
Now you’re probably thinking to yourself, “Well isn’t that something?” Indeed, good reader, it is something. Something extremely dangerous, enough to “kill a man in 20 minutes,” can be used in a scientifically controlled environment for the good of mankind. If the promising stuff from this article holds true, we may have found our BOTOX equivalent for pain!
So now that I’ve beefed this article up enough, I think it’s time for me to get down to the nitty gritty details on what exactly the study was:
In order to understand the paper, there are a few concepts that need to be explained first. I’ll start with the physiological basis for how neuropathic pain works. There are these sensors within our peripheral and central nervous system embedded in the walls of these nerves called Acid Sensing Ion Channels (from here on known as ASIC). They are meant to sense the acidic changes outside of the neuron, which indicates local tissue damage has been done. Once these sensors are activated, they tell your body that there is pain in a particular area.
In the past, we have known there are specific types of agents that can be used to mess with these receptors. It was actually first noted that the Texas coral snake had a toxin that activated these receptors in order to cause pain. Amiloride, in high enough doses, has been shown to block this receptor as well. Now it has been shown that the snake venom from the black mamba contains a particular type of protein that interacts with this receptor in order to shut it off in a reversible fashion.
This protein is a 3 finger protein, that interacts perfectly with the ASIC receptor to shut it off in a reversible fashion.
The new class of protein that has been discovered from the black mamba snake venom has been cleverly named “mambalgins.” Try saying that 5 times in a row.
In both rats and humans, this research study has demonstrated that the use of this mamba venom blocks only the sensory ASIC receptors. They bind to the channel when it is in its “off” mode in order to decrease the sensitivity of the receptor to protons. The end result is that the receptor does not work when it’s supposed to, and signals can never begin to generate, stopping pain at the very source.
These complicated graphs show that when you increase the concentration of the mamba toxin, you decrease the total voltage seen in a specific neuron, indicating the neuron is no longer firing.
This graph compares the effect of the mamba toxin with morphine. They measure pain here within live mice by tail and paw flick latency. What this means, is the amount of time that elapses before there is a flick of the stated body part has been immersed in 46 degree C water.
What’s most amazing about this new finding is that “The central analgesic effect of mambalgin-1 shows reduced tolerance compared with morphine, no respiratory depression and involves the ASIC2a subunit.” On the graph below, you can see another comparision of the mamba toxin with morphine to the left. On the right, you can see the effect of each of the substances on respiratory effort.
Finally, they have shown that these ASIC receptors are also found in the distant extremities. They demonstrate that injection of the paw with the mamba toxin also effects paw latency indicating that not only are ASIC receptors located centrally, but are also implicated in nociception.
So what does this all mean? Have we finally found the cure to pain? I wouldn’t go so far as to say that. While the initial data from this study looks promising, there is still a very long way to go before we can apply this study into human treatment. We need to figure out the toxic effects it can exert on the human body. We need to find the optimal dosing and best way to deliver this drug to eliminate pain. We need additional studies to further investigate the potency of the toxin with regards to pain.
While much work remains to be accomplished, this article provides us with a promising starting point. In the not too distant future, we may see it applied towards people with chronic neuropathic pain in order to drastically improve their quality of life. There may be other uses in addition to pain for the black mamba toxin.
At the end of the day, I could see this new innovation used in intrathecal pumps to deliver very small doses of the toxin for people who have chronic neuropathic pain as a result of nerve injury, similar who how baclofen is used for spasticity. It will be interesting to see what other developments come from this protein.
To close this blog post out, I leave you with a video that will hopefully allow us to look at the most negative of situations and turn it around to something positive, just like these pioneering researchers did!