Studying Sleep and Pain in Mice: A Chat With Alban Latremoliere

Alban Latremoliere

Alban Latremoliere, PhD, is an assistant professor and pain researcher in the Neurosurgery Department at Johns Hopkins School of Medicine in Baltimore, where he studies changes in the nervous system that take place after injury, including the development of chronic pain. Latremoliere spoke by phone recently with Neil Andrews, executive editor of RELIEF, to discuss how he became a pain researcher, his recent study investigating how sleep deprivation affects pain sensitivity in mice and how the results may apply to people, what it’s like to start a new laboratory, and much more. Below is an edited transcript of the conversation.

How did you become a pain researcher—and is working in this field what you thought it would be?

I did my PhD in neuroscience back in Paris, beginning in 2003. At that time, the main reason I began working in pain research was because it encompasses the entire range of biology, from molecular pathways in the nervous system to the behavioral response of a whole organism, and I could work on both ends of this range. This is very exciting on an intellectual level, and I’m really happy that I’ve been able to achieve this.

I have discovered that pain is very complex, and that we know far less about it than I thought we would when I started my PhD work. But this makes pain research even more exciting. Just understanding what seems simple, like which nerve fibers or which proteins on nerve fibers are responsible for pain—we don’t have the answers yet. I also now understand how limited we are in treating people who have chronic pain, which is much more prevalent than I thought. This really motivates you to do good work—work that can make a difference and help a lot more people than I would have imagined at first.

Let’s talk about one of your recent projects, which looked at the effects of sleep on pain. How did you become interested in studying this topic?

It’s a matter of love [laughter], for two main reasons. First, it’s the love of science because sleep is such an enigma in neuroscience. I think that, deep down, every neuroscientist is intrigued by sleep—why do we sleep, what is sleep, precisely, and what happens when you don’t sleep enough? When you look at patients with chronic pain, poor sleep quality is one of the top complaints they have when they go to the doctor, but improving sleep is not really a treatment consideration at the moment and this is something we are investigating.

It’s also a matter of love because the person I’m working with on this project is Chloé Alexandre, who is my wife, and a sleep physiologist. We met during our PhD in France; she was studying sleep in mice, and I was studying pain in rats and mice. We thought, even then, that it would be really interesting to use our specific skills to see how those two areas interact, but this was not really feasible to do in France. Clifford Woolf, with whom I did my postdoctoral training over the last ten years at Boston Children’s Hospital, gave us the opportunity to start this project while I was in his lab. And so that’s how it all started.

The relationship between sleep and pain turned out to be a much more complicated question than what one could have imagined. Whether people with pain will have poor sleep depends on the type of pain they have, and in turn, sleep affects pain in different ways depending on the type of sleep disturbance.

How did you examine sleep in your study?

The way to record sleep in rodents is to use electroencephalogram (EEG) and electromyogram (EMG). These are the same techniques used to study sleep in humans. What we wanted to do in our study was make the animals sleep less and see if that affects their pain sensitivity.

But, to study sleep in rodents, most past studies used pretty dramatic protocols where a mouse or a rat is put on top of a little platform that is placed in water. When the animals fall into rapid eye movement (REM) sleep, the muscles become very weak, and so then the animals will fall into the water. Next they have to wake up and climb back on the platform and wait to fall asleep again. This is not very pleasant for the animals, and we thought it would be quite stressful as well.

In today’s modern society, however, people sleep less because they want to be entertained a little bit longer—before they go to bed, they will use their smartphone, watch TV, or play video games, and through that entertainment they restrict their amount of sleep. So we tried to entertain the mice to keep them awake. We recorded their sleep in real time while they were in their home cages, and every morning, the time when mice typically want to go to sleep, we would extend their activity time by providing them with new toys.

These were custom made toys that the mice could chew on. We would give the mice the opportunity to play with these toys, and when they got bored with them, we would quietly remove the toys and place new ones in the cage. We were able to keep the mice awake for up to 12 hours in a row with this approach.

How did the lack of sleep affect pain?

We found that sleep-deprived mice had increased pain sensitivity. Another interesting thing we saw was that pain relievers like ibuprofen didn’t really work to restore the mice’s pain sensitivity to normal; morphine was even less potent than it is in well-rested animals. This suggests that for morphine to work as well when there is sleep deprivation, you would need to increase the dose.

This has relevance to the current opioid crisis. There are many people who have been given opioids, but their sleep history is not something that a doctor typically would focus on or try to monitor. That could lead to serious adverse effects where patients who aren’t sleeping enough would need to increase their consumption of morphine for it to work as well. That’s when you increase the risk of side effects and even the risk of death.

What explains the increased pain sensitivity you saw in the mice?

We don’t yet know what makes the animals more sensitive to pain after sleep deprivation. But, while we found that pain relievers did not reduce pain sensitivity, we saw that two drugs that provoke wakefulness, modafinil and caffeine, were each capable of reversing the pain sensitivity. Those two drugs are very different, but we found that they might be working within the mesolimbic system, which is the brain’s reward system.

Increasingly, studies are showing that this reward system is involved not in the processing of pain itself, but with the reward associated with pain relief. This system also plays a strong role in addiction. That’s interesting because it’s been shown that when you’re not sleeping enough, you’re more likely to abuse drugs. The role of the mesolimbic system in pain resulting from sleep deprivation is a major project Chloé is setting up right now.

We also found through other experiments that the animals were sensitive only to things that can cause pain, and not other stimuli, such as noise in the environment, for example, or pleasant touch. This is exciting because it suggests that what we saw is a reflection of actual pain sensitivity, which is very hard to study in animals because they cannot speak to us and report their pain.

Typically in rodents we measure what we call ‘nociception.’ This is the detection and reflex avoidance reaction to a harmful or potentially harmful stimulus, while pain is the next stage of processing where the brain interprets this information and combines it with many other factors, such as attention, lack of sleep, anxiety, and memories, to generate a complex sensation. As a pain researcher, trying to measure and understand pain in rodents is one of my greatest quests!

You mentioned that caffeine reversed pain sensitivity in the mice. Does this finding speak to what patients with chronic pain should do with regard to their caffeine intake?

I’m very glad you asked this because when we published our study, some coverage of our work extrapolated the results to chronic pain. But we did our study in normal animals with no pain at baseline, which allowed us to show that sleep deprivation increased their pain sensitivity. But if you’re in a state where you have chronic pain, it’s a whole different biological system. What we want to do now is see if our results hold true during chronic pain, and whether caffeine or modafinil can relieve this abnormal pain sensitivity.

But I would say one thing for sure: We would not recommend that people with chronic pain take caffeine all day long or during the night to relieve their pain—if you’re not sleeping well, you would definitely not want to do that.

What we found is that the caffeine is going to promote alertness, and in that way improve pain. So taking caffeine during the day could be a strategy to help with pain if you have sleep deprivation (and that might be caused by chronic pain). But we also found that taking caffeine did not erase the effects of not sleeping enough.

So the best treatment we could advise is to get good quality sleep. You can drink coffee in the morning to help restore alertness, but the key thing is to try to go to bed a little earlier and avoid watching TV or looking at your cell phone too late into the night, and if necessary, take some treatments to promote sleep at night.

What other projects are you excited about?

I’m excited about lots of projects! In addition to continuing the work on sleep and pain, much of the work in the lab will look at changes in the nervous system that occur after peripheral nerve injury and cause pain. We want to understand why some people after nerve injury experience pain, including feeling pain from something that normally is not painful; this is called allodynia.

We’re also interested in a very challenging topic: how to assess spontaneous pain in animals. I’m quite convinced that mice, rats, and humans are truly going through similar experiences after nerve injury, but this has been difficult to investigate in animals. When you use animal models of pain, you create a nerve injury and then evoke pain with a mechanical or thermal stimulus and measure how they react to that. In this way we can see how much pain they show after the injury.

But in patients, evoked pain is not the main complaint they have. Instead, patients have spontaneous pain—they might be sitting quietly, and all of a sudden, have a burst of pain. Or, they can have a consistent burning sensation that never goes away no matter what they do. Spontaneous pain is extremely debilitating for patients.

Patients can express this with words, but animals can’t. But we think we have found, in our preliminary studies, some interesting new techniques to monitor spontaneous pain in rodents. This will help us not only to understand what causes spontaneous pain in the animals, but also potentially help bridge the gap between studying evoked pain in animals and what bothers people with pain the most—spontaneous pain.

Finally, we are also researching ways to promote sensory and motor recovery after nerve injury. Even though surgical techniques have improved, there is still a lot of room for improvement in terms of functional recovery. Using animal models of various nerve injuries, we will try to understand why sensory and motor recovery is affected and how to promote it.

The new lab that I have is at Johns Hopkins in the Neurosurgery Department, and I’m really thankful to Dr. Michael Caterina and Dr. Allan Belzberg, who are the directors of the Neurosurgery Pain Research Institute at Hopkins, and Dr. Henry Brem, the director of the Neurosurgery Department, for giving me and Chloé the opportunity to set up our dream labs here so we can pursue our projects!

When you’re not doing science, what are you doing? Any interesting hobbies?

We just had a baby about a year ago so that makes the answer to this question easy: when I’m not in the lab, my second job is being a new dad. It takes a lot of my time, but I’m very happy about it!

When I have some remaining time—that’s typically when my son is sleeping and before I need to fall asleep myself—I like to read on my Kindle. I’ve always been a fan of science fiction and horror literature and I’ve always been a huge fan of Stephen King. I also like science fiction movies and series; I like universes about utopian futures—Star Trek!—or dystopian futures—everything else really! I love being transported into new worlds with special effects through movies, series or video games.

If you could have a conversation with any scientist, living or dead, in the pain research field or outside of it, who would that person be and why?

I would love to chat with two people, both dead, at the same time: Charles Darwin and [the French naturalist] Jean-Baptiste Lamarck. Lamarck was very popular in France, but he got it wrong because he was thinking that the organism evolves on its own to adapt to the environment, rather than have the environment select the best animals to survive. While everyone has remembered Darwin being mostly right, there is more and more data showing that some of what Lamarck said is true to some extent.

I would love to see how they would discuss the topic of evolution with each other. While that is not really about pain per se, pain is one of the key systems that’s been here almost since the beginning of life, and it’s probably a driving force of evolution as well—the ability to detect potentially harmful stimuli is a critical system that helps the organism to survive, and therefore it’s critical for evolution. I’d like to chime into the discussion and ask both Darwin and Lamarck to discuss their point of view with regard to the pain system.

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