Creepy-Crawlies in Pain Research: From a Spider Venom to a Pain Reliever in Mice

Research on spider venoms could lead to a better understanding of pain and new treatments.

At the 2019 annual gathering of the Australian Pain Society, Glenn King described how research on spider venoms could lead to a better understanding of the pain system, and to ideas for new treatments. Image credit: jiaking1/123RF Stock Photo.

Editor’s note: The following is a summary of the John Bonica Named Lecture from the Australian Pain Society 39th Annual Scientific Meeting. John Bonica—considered to be the founding father of pain medicine—strove to provide an international and interdisciplinary forum to improve all aspects of pain, from research to treatment. This passion lead to the incorporation of the International Association for the Study of Pain (IASP) in May 1974. The Bonica Lecture has been a feature of the Australian Pain Society Annual Scientific Meeting since Bonica himself gave the first lecture himself in 1984. The 2019 Bonica Lecture was delivered by Professor Glenn King, a biochemist and structural biologist from the University of Queensland, at the recent meeting, which took place from April 7-10 on the Gold Coast, Queensland, Australia.

Animals can use venom to capture their prey, but spiders and other venomous creatures also use their venom to deter predators. Inflicting pain via a venom is a highly effective defense mechanism that teaches potential predators (and their offspring) to stay away. This is like accidentally touching a hot stove—you live to tell the tale, don’t do it again, and can warn others of the danger.

But do creepy-crawly creatures like spiders and the venoms they make have any relevance to the understanding of chronic pain in people? That was the focus of the Bonica Lecture at the 2019 Annual Scientific Meeting of the Australian Pain Society by Glenn King, a biochemist and structural biologist from the University of Queensland.

King made the argument that animal venoms could potentially be used both to learn more about pain perception in people and to serve as a source of safer and more effective pain relievers.

Understanding pain: A circuit board with missing components
King started by describing how the anatomy of the pain system is relatively well understood. Nerve cells in the skin and body called nociceptors (often referred to as pain-sensing neurons) first detect potentially harmful stimuli in the environment, such as high temperatures or dangerous chemicals. The nociceptors generate an electrical signal about this potential danger that is then relayed to the spinal cord.

The signal then reaches the brain, where it can result in an experience of pain. The brain itself can modulate the signal, sending information down to the rest of the body to amplify or dampen the signal.

But the cells and molecules involved in this process are far more complex in comparison to the anatomy. In fact, nociceptors contain a vast range of proteins known as receptors and ion channels that are essential for the electrical signaling between pain-sensing neurons.

“Trying to interpret all of this is like trying to figure out what is going on in a circuit board when you don’t know what all of the components are,” King explained. “Many of the ion channels and receptors involved in nociceptive processes have only been identified in the last 10 to 15 years, and there’s clearly more stuff that we don’t know about.”

King is interested in whether animal venoms can help pain researchers complete the circuit board by identifying more of the molecules involved in pain.

How venoms interact with the pain system
King and his team use an experimental model to show how venoms from animals activate the pain system. The group takes nerve cells from the spinal cord of mice, puts the cells in a petri dish, and then adds a fluorescent indicator, a tool that allows them to see when a nerve cell is active.

It turns out that venom from some animals such as the bullet ant, Paraponera clavate, can strongly activate all sensory neurons (nerve cells that are activated by sensory input from the environment, including cells involved in pain processing) within just three seconds. However, the venom from other animals like the Togo starburst tarantula, Heteroscodra maculate, activates most, but not all sensory neurons. These kinds of venom are of great interest to researchers like King.

“If you activate just a subset of the neurons it is much more likely you are activating a specific receptor or receptors, rather than activate every neuron,” King explained.

So King explores how venoms are involved in pain processing when they activate a smaller number of neurons and receptors. This makes it easier to identify the specific molecules within venoms that cause pain.

Through collaboration with David Julius, a researcher at the University of California, San Francisco, King and his team found that two related peptides (short chains of amino acids, the building blocks of proteins) from the venom of the Togo starburst tarantula were capable of activating pain-sensing neurons. These peptides are called Hm1a and Hm1b.

Interestingly, Hm1a was no longer able to activate the neurons when in the presence of tetrodotoxin. Tetrodotoxin—a highly potent toxin found in a range of animals, including fugu (Japanese puffer fish) and blue-ringed octopuses—works by blocking the activity of a group of ion channels on neurons called sodium channels.

Sodium channels play an important role in the electrical activity of sensory neurons, including pain-sensing neurons. The fact that tetrodotoxin interfered with Hm1a activity suggests that Hm1a also affects sodium channels.

You can’t judge a book by its cover
“We initially thought, that’s really boring—it’s just another sodium channel toxin,” King recalled of Hm1a.

That was because sodium channels were already very familiar to pain researchers. Three of these sodium channels, called Nav1.7, Nav1.8, and Nav1.9, are well known for their role in the pain system. Interestingly, many commonly used painkillers block sodium channels throughout the body, not just those in the pain system. This explains the side effects of many of those medications.

However, it turned out that Hm1a activated a different sodium channel, called Nav1.1. That channel had not previously been implicated in pain processing, so it looked like the researchers had something new and interesting in their hands.

King and his team then looked at what happened to nerve cells in the spinal cord of mice when Hm1a was injected there. They found that Hm1a made the mice much more sensitive to mechanical pokes with a thin filament (a common technique used in pain studies in animals). Hm1a had no effect on the sensitivity of the mice to heat or inflammation.

“This is really cool. These results suggest that the Nav1.1 channel is involved in the transduction of mechanical stimuli to the spinal cord,” said King. That is, the channel is involved in the process by which a mechanical stimulus, such as a poke to the paw, produces electrical activity in the nervous system, which is then relayed up the spinal cord and to the brain, potentially resulting in an experience of pain.

A mouse model of irritable bowel syndrome
King then collaborated with Stuart Brierley, a researcher at the South Australian Health and Medical Research Institute in Adelaide, Australia. Brierley had developed a mouse model of irritable bowel syndrome (IBS). The researchers asked whether Nav1.1 was involved in mechanical pain in the gut during IBS, which is a common feature of the condition.

Using Brierley’s model, the researchers saw an increase in the amount of Nav1.1 in nerve cells from the colon in the IBS animals. In fact, up to half of the nerve cells now contained the channel. The researchers then asked if they could find something that quieted the activity of Nav1.1 in order to decrease pain.

So King and his team returned to the animal venoms in search of an inhibitor of Nav1.1. By comparing tens of thousands of peptides from different animal venoms, they identified a protein called Hs1a from the venom of a spider, and it turned out to be good at quieting both the Nav1.1 and Nav1.7 channels.

Then, working with Irina Vetter, a fellow venoms researcher at the University of Queensland, Australia, the researchers then tested the effects of Hs1a by comparing it to other molecules that inhibited only Nav1.1, or only Nav1.7. This would give an idea of the relative importance of each of the channels.

It turned out that, compared to the other molecules, Hs1a was better at reducing mechanical pain in the IBS mouse model. This was because Hs1a inhibited the activity of both sodium channels, Nav1.1 and Nav1.7. In fact, Hs1a was as good as lidocaine, a commonly used anesthetic, in this regard. And, Hs1a relieved pain without affecting the motility (muscle contraction) of the colon. This is important because reduced colonic motility is a common side effect of lidocaine.

King believes that peptides such as Hs1a would work well if taken orally as a tablet. But further testing of Hs1a is needed before it could be considered for use in people.

It’s clear that venoms from spiders and other creatures have much to teach us about pain, both in animals and in people. And, as the work with Hs1a shows, they also point the way to potential novel treatments for pain. In the end, at least when it comes to pain research, spiders don’t have to be so scary after all.

Lincoln Tracy is a postdoctoral research fellow in the School of Public Health and Preventive Medicine at Monash University and a freelance writer from Melbourne, Australia. You can follow him on Twitter @lincolntracy.

This story is a plain language translation of a story that first appeared on the IASP Pain Research Forum here.