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David Roberson: NSAIDs, Opioids, Oxycodone, Heroin, Fentanyl & the Neuroscience of Pain | Transcript

Full episode transcript below. Beware of typos!

Nick Jikomes

David Roberson, thank you for joining me. Thank you. Can you start off by just telling everyone a little bit about who you are and what your background is?

David Roberson 4:38

Sure. My name is David Robertson. As you know, I am a neuroscientist and biotech entrepreneur. My general expertise and experience in the past a decade has been an analgesic pain drug development. They also have a really strong interest In addiction, and there's a lot of overlap, as you might expect between addiction and pain, especially in the drug development space, as well as trauma, which which interacts with both the pain and addiction spaces quite a lot. So that's kind of a, you know, sort of my, my academic and professional interests. My training is I'm a PhD trained neuroscience, I also have an MBA. And you and I kind of crossed paths

along both our journeys there. And yeah, that's, that's kind of the the 10,000 foot view.

Nick Jikomes 5:34

Yeah, so you're, you know, for people listening, David is a pain expert. That's one way of describing you. And I thought we would start out with a very, deceptively simple question, I think, which is, what is pain? Yeah. So

David Roberson 5:48

it's a good question, right. And it's one of these things that your academics have, for decades really kicked around. And it's complex, it's hard to describe it at the same time, we all get it, we all understand and know what it is, you know, the official definition from the International Association for the Study of pain is that pain is an unpleasant sensory and emotional experience associated with or resembling, that associated with actual or potential tissue damage. So, you know, it's, it's it's common complex, but at the same time, simple.

Nick Jikomes 6:37

Okay, so like, if something if you hear like a very loud sound, or something, or someone suddenly touches you on the back to scare you, there's no real damage done to your body, there was no real threat there, the stimulus might in another context be perceived as painful. But the sensory, the sensory side doesn't also come with that actual or potential tissue damage components, we don't tend to call something like that pain. But something where there is physical damage that might have happened, or that did happen, you would feel that pain for

David Roberson 7:06

well, and even to your example, there, you know, really loud noise, if persistent will cause hearing damage, right. And so it does seem like the things that do cause us sort of pain and and sort of trigger a reflexive withdrawal, whether it's to cover our ears or to, you know, pull away from a hot, hot surface. Those tend to be stimuli that are painful, or I'm sorry, that are causing damage, if they persist,

Nick Jikomes 7:36

I see. I see. And so how, how do we actually detect pain? So what does the the sensory neuroscience of this look like? When you touch a hot stove? Or you get pricked with a pin? What's actually going on? How do our neurons actually distinguish those stimuli from something innocuous?

David Roberson 7:53

Right? So, there are several categories of sensory receptors that are on you know, in the skin, for example. Among those are the trip channels such as trip v1, the trip in class receptors, as well as other sensory channels that together with trip channels or other sensory modalities can can be perceived as pain. There, there are several different types of pain receptors, right. So, one, the one that I think maybe most people might be familiar with, or at least have you seen on their radar in the past year is a tricky one. So trippy. One is an interesting channel. David Julius discovered this channel a few years ago, and in 2021 got the Nobel Prize for his his discovery along with art and Putin, who discovered some pizza channels which are responsible for tactile sensation. But the tricky one channels are both chemosensory so they detect chemicals, such as capsaicin, that makes chili pepper spicy, and they also detect heat. So they're, they're non selective QAT ion channel. So it's, uh, you know, they they're in the, the membrane of the sensory nerves and our skin. And when they're activated, they open up and they allow ions and that causes depolarization. And that sends a signal to the brain that is typically you know, perceived as pain.

Nick Jikomes 9:33

Interesting. So there's different types of neurons in the skin in the periphery. And there's a bunch of different types, some of them and they're all like tuned to different types of sensation based on these receptors or these channels that they have. And some of them focus mostly on mechanical you know, physical sensation, some of them are more chemically oriented or temperature oriented. And broadly speaking, all of those things are are the different lines that that different pain signals can Get into the brain from Exactly, exactly. And so what about, you know, people talk a lot about acute versus chronic pain. And I think we all intuitively understand those things. But can you unpack what the difference is there and how it connects to, you know, pain that's detected on the periphery on our body versus pain that's in the head, so to speak. Right, right. So that's,

David Roberson 10:21

that's a really good point. And, you know, generally speaking, chronic pain is a pain that is ongoing, and usually lasts longer than about six months. You know, there are varying definitions depending on different contexts and whatnot. But generally speaking, and acute pain is the pain that is caused by a stimulus, the stimulus can be present, such as you know, when you touch your hand on a hot stove, or it can be a downstream sequela, such as inflammation caused by a painful stimulus, that then continues activation or sensitization of those pain neurons. That that is generally what we think of at least what I think of as acute pain. Chronic Pain happens when those signals are actually should, let's turn it a turn on its head. Chronic Pain is when when that perception of pain persists beyond the time that we would expect it to, you know, for example, an injury may be healed, but you still have the pain and it physiologically, structurally, there's nothing visible or detectable wrong, but you still are perceiving pain or pain like phenomena such as allodynia, which is something normally that didn't used to be painful, but is now painful. So light touch that used to didn't bother you, you know, someone has, for example, neuropathic, chronic neuropathic pain that may be quite painful.

Nick Jikomes 11:56

Interesting. So So you, you mentioned a word that I think is really interesting sensitization. So I want to unpack that a little bit. Maybe a really good real world example will be just right now, I have a big bruise on my leg from kickboxing, and you know, if I if I lightly touch it, I get a little pain. Whereas if I do that anywhere else, my body, no big deal. How do we think about that? Is it literally that the area's inflamed, and so these pain sensors are being pushed against, and that's just making them more sensitive?

David Roberson 12:27

Right now, there, there's a lot of things that go on that can cause this sensitization. And broadly speaking, the pain sensitization happens either due to peripheral mechanisms, so things happening at or near the site of injury, for central mechanism, which is are things happening in the brain or spinal cord. So speaking about peripheral sensitization, which I think is the most easy to, to understand, in the case of your bruise, there are a lot of inflammatory mediators, you know, just crudely in the pain space, we refer to it as inflammatory soup, right, there's just, you know, a lot of different cellular release compounds and and different components there of the inflammation process that cause pain neurons to be sensitized. Meaning that they it reduces the threshold necessary to generate an action potential and send that signal to your brain. So that's peripheral sensitization that, the the flip side of that or I guess that the other end of the, the line is, is that in the brain, you have the perception of pain that occurs, and you can also have what's called Central sensitization. And central sensitization occurs when circuitry within the brain itself or the spinal cord become sensitized. And by sensitized I mean, it takes a lower stimulus to to generate a response than then previously, right. And so that sensitization can be mechanisms that are within the brain. Right.

Nick Jikomes 14:18

Interesting. So, so I think you you said it in an interesting way, it's very intuitive to think about peripheral pain. So if you've got a neuron, a little pain sensor in your skin, and it becomes more sensitive, now, if I push against the skin, they're obviously going to more easily feel something including a painful stimulus. But what you're also saying is that inside the brain, there are circuits that become desensitized so that you do genuinely actually feel things as more painful, even though it is literally coming from inside your head.

David Roberson 14:48

Exactly. It's it's quite interesting and it works in a way very similar to memory, right. So, you know, we can have a memory triggered have virtually anything any experience we've had. And, you know, we just just came through the holiday season, my family likes to put up a Christmas tree every year and this year we went and we cut down a tree, like an actual green tree at a Christmas tree farm and put it up. And immediately we put up this tree and a whole house smells like Christmas. And it took me back to my childhood I remembered that smelled and bring you know, and so you know, we can we have these memories that are stored and pain can also, you know, be stored as a memory. And, you know, those memories can be recalled those circuits can be reactivated, rather than from, you know, a stimulus coming from outside by Central Internal, you know, brain processes. And that's not to say that it's imagined or artificial pain or that it's, you know, sort of a shadow of the real pain, it can actually be as intense and intolerable as the original pain itself. But when you know, when pain, you know, when you have centrally triggered pain or pain that arises from Central sensitization, it is at least in part due to something going on in the brain.

Nick Jikomes 16:22

Interesting. So So we've got this distinction between peripheral and central pain, pain that's arising from inside your brain versus being detected on the surface of your body. And then we've got this distinction between acute short term pain versus chronic or persistent pain, can you start to talk a little bit about what what are some of the key brain areas or brain networks that one learns about if you want to learn about the central processing of pain? Yeah, now there,

David Roberson 16:48

there are a lot of different circuits that influence you know, central pain processing. And, and I think, broadly speaking, it's divided into this sensory component of pain and the emotional component of pain. And so the sensory areas are as you would expect, the sensory cortex, right, and you've got, you know, this sort of a monkey list that represents different parts of the body. And so you do have a sort of almost like a geographic map on your brain of the different parts of your, your body, and those areas are activated to correspond with the area in your body where you're feeling the pain, that's, that's the case, at least, it's thought to be a case, regardless of whether the signal is coming in from the periphery or, you know, arising from from Central mechanisms or sport, it could be both right, it could be that you have a stimulus coming from your body, that sub threshold normally, but because you have sensitization, it's now perceived as pain. But you also have emotional, so, you know, the, the, the emotional perception of pain involves, you know, all the different components of the amygdala, that are involved with, you know, fear and aversive emotional sensations. And then you also have even deeper, sort of your periaqueductal, gray and brainstem areas that are that are involved in pain and, and, you know, I like to think of pain as a very primitive sensation. Right. And, and it's, it's, you know, from an evolutionary standpoint, you know, the most arguably that one of the most essential sensory feedback mechanisms that an organism can have is to detect danger, right? Or detect something that could could cause injury, or or, you know, threat to your life is, is something that's pretty hard wired and, you know, involves some, some really primitive brain areas.

Nick Jikomes 18:57

Yeah, that makes a lot of sense. What, in terms of the, the evolutionary and ecological function of pain? One way to think about this is to ask the question of what happens when an animal you know, a human or a non human animal cannot detect pain, what is what does that look like? And what tends to happen to those

David Roberson 19:15

creatures? Sure, no, that's a really interesting question. And, you know, there have been several different genetic, genetically induced or genetic, you know, problems that people have, where they can have inherited lack of sensitivity to pain. Some of these have been, you know, pretty widely studied and, and typically, what you see in these folks is that they have repeated injuries. You know, they can, they can develop interestingly, they can develop normal, you know, really relational and cognitive functions, and they, you know, don't or don't necessarily have delayed you know, cognitive development But they will have repeated injuries, they often have repeated infections, you know that as as children that will be frequently injured and have, you know, broken bones and in things and they tend to take take more risks, right. And it used to be that you would see these, these people would be sort of discovered by the scientific community because they would be, you know, working in a sort of almost in an entertainment type role or job, you know, putting needles or knives into their body to, you know, to show people that they can, you know, tolerate pain and in, you know, almost like a busker. But but, you know, doing these these feats of superhuman pain tolerance, but yeah, so these folks do have, you know, when you don't have the ability to feel pain is problematic, right? And these folks tend to have a shortened lifespan and and end up with a lot of medical problems. Yeah,

Nick Jikomes 21:04

I had one conversation on the podcast with a scientist named Matt Hill who focuses a lot on the endocannabinoid system. And he told the story of a woman in the UK, I believe, and somehow she was discovered she has a very rare genetic mutation involving her endocannabinoid system. The end result of that mutation is that she had very high levels of this endocannabinoid called anandamide. And there were two sort of interesting phenotypes there, in my view. And I'm hoping you can connect something here for us because it sort of shows, I think, the link between physical pain as we normally think about it, and what you might just call emotional pain. And she was both, she's very immune to pain, basically, of all kinds. So she had a very high pain threshold, she was the type of person who could, you know, burn her hand on the stove easily, and not even not even notice it. But she was also very happy. She basically was immune to anxiety. And so she was just in this persistent good mood. And so I'm wondering if you could start to talk about the link there between what we would think of as perhaps being separate things this the physical sensation of physical pain, and anxiety and things like that?

David Roberson 22:14

Oh, that's a that's a great point. And an interesting topic for me personally, you know, I and I, like I think most most of us, you know, we think of physical pain and emotional pain being two different things, right, it's, but as I said, you know, physical pain does have a very strong emotional component to it. And there is sort of some philosophy around this as well that, you know, that that a lot of the mindfulness practice practitioners differentiate between pain and suffering, right, which suffering in their definition, you know, incorporates both a person's perception of this aversive stimulation or stimulus, but also a an intolerance of an emotional intolerance. Right. And so, you know, it's interesting, and I think it does tie into, and I hope we'll get to this in our conversation, it ties into, you know, how addiction and sort of seeking after an escape can be pharmacological or any other type of escape from pain is often sort of the flip side of the coin of someone who have people who have chronic pain states, right, they often have trouble with addiction. And it's, it's it, it's not surprising, because if you have persistent pain, either due to central sensitization or due to ongoing injury, it's, it's no wonder that people want to try to diminish that pain in some way. Right? And so the ways in and if it goes both ways, right, so you know, people who have physical pain, and and become addicted to, for example, opioid drugs, often also have psychological or emotional struggles or pain, right and emotional pain that that the drug the opioids also help with right and so that's one of the things that I think I didn't realize until I really got into this space was that opioids, while they're they're really fantastic analgesics, they work really well to reduce the perception of pain. They also reduce the emotional processing of pain and therefore, when someone carries a lot of trauma or you know psychological trauma that that is really difficult to manage and sit with the opioid drugs have a way of of dampening that right? And so it's thought that that's why the vast majority of people who are prescribed an opioid or try you can recreational and opioid will never become addicted no matter, you know, how often are they're exposed to it, we see this in animal models as well. But there are certain people that that will write in. And, you know, one hypothesis is that these, these people also have ongoing emotional pain that they're trying to process and deal with, and that the opioids help with that. Right.

Nick Jikomes 25:47

Interesting, I want to circle back to that when we talk about opioids in more detail. One of the things I want to clear up up front to help people give get a good foundation here is how we actually measure pain. And so let's start with humans, because, you know, many of us will have actually done this, and I'm still sort of blown away. You know, the maybe two or three times I've had to do this at at the doctor's office, where I say, I'm in pain of some kind. And I say, Well, how bad is it scale of one to 10? I remember being asked is the first time and I was like, you know, how do I even answer that? Don't you have some other way of assessing this? And they basically told me, No, you have to tell us on a scale of one to 10. And then they have some kind of rubric. So you know, something that's subjective? Yeah. Why is it that it's so hard to measure pain other than asking someone

David Roberson 26:35

now it's, it gets to exactly the what you said, and it is subjective, right. And the exact same stimulus if you take, you know, a thermal stimulus and apply it to the the forearm of someone and apply a certain heat, and energy through that, some people will find it more tolerable than others, and certain people find it quite painful. And so it is very subjective. And, you know, in humans, pain is primarily detected by asking people, how does this on a scale of one to 10, with 10, being the most, you know, most severe pain that you've experienced or could imagine, right? And so I remember the first time I personally realized, realize the impact of that question, and I was on a flight back from transatlantic transatlantic flight, and my parents had actually been a plane crash back here in the US, I was coming back with my pregnant wife, and, you know, trying to come back to check on my folks. And fortunately, they survived and ended up recovering. But at the time, I didn't know that. And I had developed a kidney stone, like, four hours into a 13 hour flight. And there was a urologist on board. I didn't know what it was, I'd had a kidney stone before, but there's a urologist on board who asked me, like, you know, how severe is this pain? Yeah. And I was like, this is like, a nine or a 10. I've never ever, I didn't know I could hurt this back. Right. And so however, had you asked me, you know, the day before, if I had, you know, broken, you know, my finger or something that would be quite painful, but not not kidney stone painful, right? I would maybe call that an eight and nine or 10. Right. And so it's so subjective. And, and I do feel like, you know, my wife has given birth to all of her children. Obviously, I didn't do it. But, you know, and I think a lot of women have this experience where, you know, they experienced childbirth and realize that, oh, you know, this is like, the worst pain imaginable. Right. And so it's, yeah, it's but it's very subjective. It's very relative, and, and that, but that's really the best we've got.

Nick Jikomes 29:01

Is there any reason to think that the, the brain itself is sort of relativizing pain measures, meaning, like, you know, if you go through something new, like a kidney stone or childbirth, it's excruciating, that your brain sort of recalibrates of the other things you've you've you've experienced before such that subsequent episodes those things are perceived as less painful

David Roberson 29:22

I don't know it's a little outside my little niche of of pain but but that seems reasonable. Right? Certainly that's my experience right when it but but at the same time, right, so my relative pain perception changes when I've experienced something more painful than anything previous but it doesn't make you know, what used to be my my nine what is now a seven any less painful, right? It just means that i There's a whole nother level of pain that I'm taking have proceeded.

Nick Jikomes 30:01

So yeah, yeah. And then, you know, if we measure pain in humans by asking them how painful it is simply because it is so inherently subjective. This brings up another question, which I think is fascinating, which is, you know, we developed so many of our drugs and our tools for treating things like pain and other things and animal models. Yes, we do this for pain. But obviously, you can't ask a monkey or a mouse or something, how much pain are you in? So how do we actually assess pain in our models in the context of drug development?

David Roberson 30:31

That's, that's a really great question. So, you know, the standard ways that this is this is done is that these these methods have been around for 5060 plus years. But you know, that the model organisms that we typically use for many areas of drug development, in particular for development of neurological drugs, right, so including analgesics, which are pain drugs, there are two to try to model the disease that we're trying to treat in roads. So the way we model or, or test pain in rats and mice is to apply a stimulus that is, you know, hot, for example, like a heat stimulus is one example. So thermal stimulus that's hot enough that it's perceived as painful by humans, presumably perceived as as painful by an animal, but not so hot that it just immediately causes severe pain, right? And, and so you apply a stimulus, such as a heat stimulus to the paw of a rodent, and you wait, and you see how long does it take before they perceive the stimulus and pull away voluntarily? Right. So, you know, in rats and mice, you can apply a to roughly 50 degrees Celsius stimulus, which is like the, like the belt, like the outside coffee cup, right with hot coffee in it. And so you apply the that stimulus and, you know, if you ever touch a hot, you know, warm coffee cup, you can hold it for a few seconds, and it's warm, it's not painful, and then it gets painful, pretty quickly, and it can get so painful that you have set it down, right? And this is what we see in rooms, right? So you apply the heat stimulus, typically, with an infrared beam of light to the underside of a paw of an animal that's in a cage that has a wire floor. And you can you sit there literally with a stopwatch in hand, and you say, how long does it take for this animal to pull their paw away, and then typically, you know, somewhere between five and 15 seconds, and, and then you give them a pain drug. And you see if that moves the needle in the direction toward extending the time that they can tolerate the pain before they pull away. And the flip side of that is if you have, you know, arthritis or any other sort of disease that can be modeled in in rodents, that tends to make them more sensitive to this thermal stimulus. So that's generally how pain is modeled in rodents. And these are called reflexive with withdrawal assays, we can do the same thing with a mechanical stimulus. So we can poke the animal with a certain force on the bottom of the pond, see, how much force does it take before they pull their paw away from sort of monofilament like, almost like a little piece of fishing wire to poke them, and eventually, they'll pull away. And this is the best we've got generally, I mean, there are some other ways they're they're placed preference assays and some more complicated things that are quite time there, that there takes a lot of animals and takes a lot of time to do those assays. And frankly, they're not that much better, if any than these reflexive withdrawal acids. And so, but there are a number of problems. Chiefly, I think, in my opinion, the worst, the biggest problem is that we are not necessarily even detecting perception of pain in rodents with this right. So it's possible and and, in many cases probable that when you apply a heat stimulus to the bottom of the POV of a rodent, that it's pulling its power away as a reflex, right? And that reflex just like when you know, the doctor taps your knee and your need your foot jerks. That reflex is not due to a perception or voluntary withdrawal, right. It's it's more of a reflex, right? It happens independent of our perception and and intention. And so that's important because when we take pain drugs when humans take pain, drugs, the intent of those pains Drugs is to reduce the perception of pain, right? And so for that reason, and likely others as well, but pain, drugs and pain, drug development has been an extremely difficult venture. And unlike most drugs, Washington State, unlike most drugs,

do not. Let me actually, let me just back up and say this a different way. So

when when you take a drug, and you develop it in animals, and then you go into human trials, in many fields, you might have 70 80% of the response rate in humans that you have, I'm sorry. I'm totally like, talking circles around myself here. All right. Let me just start with pain when you develop a pain drug, and tested in in rodents. And then you go into humans with that pain drug nine times out of 10, it fails, either due to lack of efficacy in humans, or side effects that were not predictable, right. But in in pain drugs, that left lack of efficacy, lack of effective, predictive potential of the efficacy of the drug is is particularly problematic.

Nick Jikomes 36:25

So many drugs that seem like they're gonna be good for pain in a road model just don't end up being good for humans Exactly.

David Roberson 36:31

Know Exactly. And, and, and it's a real problem. And, you know, the other. The other piece of this is that these assays are extremely difficult to do they, there's a lot of variability, you know, when you have a scientist like myself sitting there, you know, applying a stimulus to an animal waiting for it to pull its paw away, and you're timing it with a stopwatch, there's a lot of variability in what I might call, you know, a six second delay before this, you know, animal removed, his paw might be, you know, eight seconds or four seconds for someone else, or they might not even call it notes offensive withdrawal, right? They make, which is the term that we use for something that's pain related withdrawal, right? Sometimes, you know, the animal might just start walking away, right? Is it painful or not? And so what we know that there's a lot of nuance around? Well, it's a, it's a nose offensive or pain related withdrawal, if the animal pulls its paw away and flicks it, but not if it just lifts its paws and starts walking. But but as you might imagine, that's very subjective. Right, right. Yeah. So because of that, it's important that when you do pain studies, both in academic setting or in a, you know, drug development industry setting that the same investigator measure all the animals that are in a particular study, right, so you want the same person making all the measurements across all the time points in all the different groups, which is a real bottleneck, and it makes you know, pain, drug development, very costly. And it's a really inefficient way to do things and and not least of which is a really it's not very fun to do that. The studies, right, I spent, I don't know how many hours doing doing these types of studies at night, because pain, you know, rodents are also nocturnal, right? So the more active the night in the dark cycle, and, you know, in so I tried to come up with so many different ways to improve on this, you know, do using night vision goggles, and, you know, doing it in the dark to see if it would get more consistent results. And maybe the animals would be less likely to fall asleep if it was dark. And but yeah, it's very problematic.

Nick Jikomes 38:54

So, are there any new tools and development that take advantage of any, you know, emerging technologies to address this type of problem? Yeah, no.

David Roberson 39:03

Absolutely. And this is actually half of my PhD project. So did my PhD with Clifford wolf at Harvard Medical School and Boston Children's Hospital. And half of you know, half of my PhD project was developing new new approaches, right to try to come up with better ways and I tried a lot of different things. You know, videotaping mice from different angles and different ways to train animals for place preference, but ultimately, the thing that sort of really stuck in and it has worked the best and actually it's been something I've I've spent a good part of my career on is developing ways to use total internal reflection within a glass sheet, which is to basically use this phenomenon to create a light signal, that gives you a readout of how much pressure an animal is putting or rodent is putting on the floor beneath their feet. And with this light signal, and, you know, for example, different types of machine vision, machine learning algorithms, you can come up with a really more a much more sensitive and objective way to measure pain and roads.

Nick Jikomes 40:29

Interesting. So literally, you can use like, you can use tech to tell quantitatively how much pressure and an animal's putting on its paw. So if you imagine like an animal that's walking with a limp, they're gonna change the pressure, and you'll be able to measure that directly.

David Roberson 40:46

Right. And, you know, another really important piece that I'd like to put it put in at this point is that your rodents are actually prey animals, right? So you're intrinsically fearful of predators. And we are in the case of laboratory mice, we are their predator, right and, and, and there is a phenomenon called Pink fear evoked algae. So what happens is that when investigators present you see reduced pain or the outcomes outputs are reduced, the thresholds are increased, right, so it takes a higher stimulus to get the withdrawal. And and where you really start to see nuance around this is that it's it's rodents show higher pain levels, when female investigators are doing the assay than when male investigators are doing this. And Jeff mogul at McGill did some really interesting work on this 10 or 15 years ago, where he showed that if you do these standard reflexive withdrawal assays in mice and rats, and you have a female investigator doing the work, you get, you know, this one threshold level, if you have a male investigator, the animals appear to have less pain, right, so their pain threshold is higher, and the they they seem to be experiencing less pain, or at least their withdrawal threshold is is reflective of that. But you can get male like, you can get the same response as as you get with a male investigator, simply by putting the t shirt that a man has worn overnight, and his pheromones have gotten on to the shirt, you put that in the room with the animal, suddenly it has the same response as if there was a man in the room. Why?

Nick Jikomes 42:44

So the basic idea here is, you know, if men are generally bigger and that much scarier than female humans to the mouse, the mouse, what you're saying is basically the mice are probably more scared of the male investigators, therefore, their adrenaline might literally be jacked up higher, and so they can tolerate more pain.

David Roberson 43:03

Yep, exactly. Right. And, and so that, you know, there's just so many problems with having a person present doing these assays. And so this this technology that Clifford and I came up with Allison, she'd mentioned, you know, CO CO adventures on this are Bob data, and Alex will show who were quite helpful, you know, when we were trying to ideate and really think about how to go about this. But ultimately, we came up with a way to put a mouse in a box, the glass floor of that box has sensors within it, right? That it's got that allow as the mouse walks around, each of their footprints creates a light signal that scene from below. And you can very clearly see if the animal has a limb, right? And whereas normally, you know, if you look, if you take one of these videos, I'll show you I've actually got some examples I can show you, but if you take up a mouse in a box that's, you know, say injured, right, say, say it has arthritis, it's really hard to detect from watching the mouse walk, it's really hard to see if it has a limp, or if it's actually favoring one pine pa over the other. It's you just can't see it from above. Right. And, you know, the hypothesis there is that in my mice being prey animals have evolved to hide signs of injury from the viewpoint of the predator,

Nick Jikomes 44:33

right? Yeah, but eventually gonna want to pick off the limp. Yeah,

David Roberson 44:37

exactly, exactly. So it really makes a lot of sense. And frankly, even you know, even if natural selection won't do that, the types of selection that we do in the lab, absolutely well, right, because any animal we we've bred mice in the lab for, you know, 50 100 years, the strains that we have have been selected over time. If an animal shows any sign of injury, we don't breed it. Right. So we're we're actively selecting for animals that do not show signs of injury or disease. Because when we take them outside of the breeding pool, it doesn't mean that we we removed all the mice with a limp. Right? Say we're taking out a mouse that has a lead riders injury, we're only taking out the ones that show up, right? So right, even we have actively done what nature has been doing for millions of years. So all that to say, you know, we, the idea was you if you put a mouse in a box and leave the room and look at it from below, you know, a viewpoint that predator has never seen, we should see some interesting things. And that's absolutely what we what we find

Nick Jikomes 45:43

interesting. Yeah, can we actually see some of that?

David Roberson 45:46

Sure, just let me pull this up. So for those

Nick Jikomes 45:49

just listening, we're going to look at some video data now. And we'll describe it verbally, so people can follow on the audio only version, but you will be able to actually see this on the YouTube version.

David Roberson 46:01

Sure. So this, what I'm showing first is just some snapshots, and still images of different types of mouse behavior viewed from above versus from below. And the point of this is just to show that even if you're talking about, you know, anthropomorphic Lee defined behavior, such as paw biting, or licking, or scratching, right grooming, that if you look from above, it's really hard to tell and differentiate between these behaviors. So if you look here, over the left hand column, pop biting, versus licking paw licking, or you can see that like looking from above, they look like they're doing basically the same thing. But when you look from below, you can see so much more detail, right? You can see exactly where the mouth, the animal's mouth is and where the paws are. And, and so, you know, this was the first hint that I got that, okay, I'm on to something, right. So I made some devices to look from above and from the sides of the animals. And it wasn't until I put a camera underneath, I was like, Okay, now this is the viewpoint that we want. So the next thing we did was to see this to move forward. So this now showing a schematic for those of you listening is this, it's a side view of what this technology looks like. Right, so you're on the top, you have a mouse that's inside of a box, the floor of the box is made of glass, and beneath that glass, you have a camera. In this case, we're using near infrared light to illuminate the animal and to eliminate the pause. Near Infrared light is invisible to mammals, so humans and mice cannot see near infrared light. So it it gives them the perception that the illusion that they're in the dark, right, so the animals apparently in the dark, and they're nocturnal, so they feel safe, there's no humans in the room, so they also feel more safe. And and we have two different light sources. The first light source is over here on the left, where it says near infrared trans illumination. And this is simply an LED light shining from below the animal through the glass to illuminate their body from below. And then we have a separate set of lights that are shining into the long edge of the glass. So these these lights are totally internally reflected. It's a phenomenon called frustrated total internal reflection and every time a beam of light hits that glass air interface, it creates an evanescent wave and that evidence deficit evanescent LightWave diminishes exponentially as it moves further from the glass and what that what that does that creates a pressure sensitive signal. So as the animal presses their paw down on the glass, the you know sort of ridges in their their skin come more and more in contact with the glass and you see that that signal between the PA and the glass becomes brighter than more pressure is put pushed down. And you know, in this case we because that signal is you know, on the one hand you want to see the whole body which is why we have this transillumination signal, but that transillumination signal can interfere with detection of exactly the precise time when the paw hits the glass. So I'm not sure how clear this will be to the your listeners that they're not watching the YouTube video but you know if you imagine your have a flashlight looking through a piece of glass and on top of that glass a mouse is walking around, well, if every time the mouse puts his paw down, the, the pop creates a little light signal, and you're also shining light from below, those two signals are going to kind of cancel each other out and you're going to be able to in your, you're not going to have as clear distinction as you would if you didn't have the flashlight on. And so there are a couple of ways that we've used to mitigate this issue and correct for it. And one is to use simply two different wavelengths of near infrared light with a and use two cameras, right with a bandpass filter on each one. So that you're you have the wavelength of light, you're illuminating the animal is different than the wavelength of light that you're eliminating the pause. And we've done this is to

Nick Jikomes 50:53

alternate the illuminations on different video frames. So one video frame, you look at the pause and the next video frame, you look at the body work equally well. But But I guess the punchline here is a you've removed humans from the environment, you're doing this in the dark in a situation where the animals sort of maximally comfortable and able to go go about its business and fearfully. And two, you've used cameras and infrared light in a clever way such that every time that a mouse steps on its paw, you can literally see how much pressure that's being put on.

David Roberson 51:25

Yeah, exactly, exactly. And I've got some videos here that really our videos worth 1000 words. So on the left is the Pol image on the right is the mouse. And then I'm bringing them together here and kind of overlaying them so that you can see what that looks like. And this is just showing a mouse sort of just is scratching kind of walking around a little bit. But we've, with the signal from the pause, We've color coded it so that it's like a heat map. And that way you can sort of intuitively see what the mouse is, you know, how much pressure is is is is both within each pot. And what the difference in the pressures between the two paws.

Nick Jikomes 52:13

Yeah, no, I mean, it makes perfect sense. Like I'm looking at this mouse, I can tell just by looking at it from below that it's it's standing back on its hind paws and not on its front paws. But in the heatmap makes it clear what the computer is gonna see, which is the pressure is on those hind paws, and it's not on those front paws so much. Right,

David Roberson 52:28

exactly. And so I've got a couple more videos here. This next video is showing sort of the workflow. So, you know, it's not enough to simply, you know, show them the mouse, walking around and detecting limp, which, which I'll show you in a moment, we really wanted to be able to automate this and let machine learning algorithms tell us, you know, what's going on. And so in the workflow there is that we basically, you know, used, you know, these machine learning, or machine vision algorithms, rather to identify the four paws and the tail and the snout of the animal, and then on each video frame to orient the animal, so that's always facing the same direction. And this, this makes it much easier for subsequent analysis of each video frame, because you always know that the left paws are going to be on the left side of the image and the right paws are going to be on the right and it's not going to change when the animal turns around goes the other direction. And then the next the next video here is showing, you know, the unaligned frames. And this is where we've used the algorithm to look at each of the paws. And the yellow here is identifying the left hind paw of the animal. And the blue is identifying the right hind paw of the animal. And we can also use the same algorithms to identify each of the other paws. And want to point out here we're using a lot of the Office of off the shelf machine learning algorithms. Deep lab cut is a toolkit that we find really helpful to work on this and we actually have a paper that's under review right now. So I don't want to preempt where it's going to be published. But we do expect to publish this in the next couple of months and and all of these

Nick Jikomes 54:35

algorithms and the source code there will be made publicly available. So interesting. Yeah. So now you've got a way to it's really an objective way to measure pain in a more naturalistic setting.

David Roberson 54:48

Yes, and you know, what we find is that we can in doing this, not only do we see that it's really clear when an animal is In pain versus when they're not in pain, and particularly if the if the pain is, you know, in one of the hind limbs. But we also see that we can, we can reverse that pain with a pain drug at a much lower dose than necessary to reverse reflexive withdrawal. And so it's a much more sensitive assay. And it you know, it's backward, it backwards translates all all existing analgesics worked really well. And it's our hope that it will also be quite predictive of future analgesics, and that we'll be better able to predict. And the last thing I'll mention that I think is is I'm really excited about is that it whereas typically, we have to use somewhere between 10 and 12 animals, typically per group, to get statistical significance in a pain assay. With this approach, and and the, you know, machine learning analysis of these data, we can do the same thing with three or four animals. So we're cutting, you know, the number of animals needed to be used pretty dramatically. And additionally, we can actually do high throughput screening of behavioral phenotypes of pain and analgesia in mice

Nick Jikomes 56:17

very efficiently. I would love to, I would love to start talking about some of the different kinds of pain drugs that are out there and how they're actually interfacing with the nervous system. So if we go off of the screenshare, I think a good place to start perhaps Oh, no. Do you have a video that's good for this? Well, yeah, actually, let

David Roberson 56:39

me let me show one last video here of the pain. Yeah, this goes with what I was just saying. So this is a mouse pain model on the left, and you can see that his left hind paw is not as bright as the right is the one he's scratching there with and and then when he the same mouse after we give him an analgesic, and you see that those hind paws are now equal, right? So on the left, you know, he's really favoring one pot over the other and on the right, he's no longer doing that. I'll stop the share here.

Nick Jikomes 57:11

And we can move on. Yeah, that makes perfect sense. So the animals got a pot problem favoring one pot over the other, and then you give the pain med and basically, that goes away. He doesn't notice right now. Exactly. Interesting. So there's a bunch of different types of pain drugs. This is I mean, unlike other areas, this is, you know, a place where most people listening will have direct experience with at least some of these. And we've all heard of probably most of them. Right? Right. But I wanted to start with maybe just sort of an everyday type of pain drugs, go to the store and buy. And that's NSAIDs non steroidal anti inflammatory drugs. So can you give us you know, starting with the very basics, what are the NSAIDs that people have heard of? And then can you get into like, what they actually do to alleviate pain?

David Roberson 57:57

Right, right. So your NSAIDs, as you said, the non steroidal anti inflammatory drugs and they relieve pain by reducing inflammation, and yeah, they work quite well for a lot of different types of pain, you know, muscle musculoskeletal pain and strains and, you know, post operative pain or even certain types of headaches, arthritis, colds and flu, you know, pain related to that generally respond quite well to to NSAIDs. You know, here in the United States, Ibuprofen is quite widely used in Europe. The diclofenac is really commonly used over the counter INSEAD, and they work actually quite well for acute inflammatory pain.

Nick Jikomes 58:50

Interesting, and then, do you know, what the mechanism is there? Or is it like a, like a brain receptor they bind to or is it something else?

David Roberson 58:58

Yeah, there's, you know, there are two different types of NSAIDs. You know, some of them are non selective, but others are Cox two selective and you know, the Cox two is an enzyme involved with inhibiting pain but also involved with thrombosis and other things. And so, you know, largely your, your inner interrupting or intervening in the function of an enzyme.

Nick Jikomes 59:34

I see. So there's an enzyme in the body that's naturally involved in producing stuff related to the inflammatory response and the NSAIDs get in the way of that. Right. Right. Interesting. So how does that differ from, you know, so we've all probably taken these types of drugs at some point, ibuprofen or whatever. How does that differ from something that's more potent like an opioid?

David Roberson 59:55

Sure. So opioids work on a different system, right? opioids work on opioid receptors which are present throughout the body. And they're present in the peripheral nerves, as well as in the spinal cord, and in the brain. And opioid receptors are. The activity of opioids as analgesics is, is probably best demonstrated in the spinal cord where you have inhibitory circuits and and you know, when you activate opioid receptors, it actually inhibits that pain signal from being sent up into the brain. And so they work really well for, for blocking pain because they actually can block those pain signals and block the transmission of the pain signals in the spinal cord. And they also work in the brain in some of the same circuitry that's involved in processing of pain both in the somatosensory perceptive areas as well as the emotional area, areas of perception the brain.

Nick Jikomes 1:01:06

And is that tied to why they're not only diminishing the perception of physical pain, but there's also a euphoria? That's tight? Yeah, an opioid? Yeah, I

David Roberson 1:01:18

mean, it's, um, I don't know, I think that those things are separable. But there are certainly a lot of overlapping circuits. And the, you know, the new opioid receptor, which is the one that's predominantly activated by conventional opioid drugs, is responsible both for the pain relief and for activating the circuitry, the reward circuitry of the brain.

Nick Jikomes 1:01:48

I see. So activating that receptor has analgesic effects, right effects, and it also has this sort of emotional feel good pleasure effect. Yes, exactly. And so what's, um, I mean, I suppose that's tied to the addictive properties of these drugs.

David Roberson 1:02:04

Yes, yes, certainly. Right. There, you know, opioids are addictive. For a number of reasons. Right. And, you know, there, one, certainly, is that they they do activate these reward centers, they cause euphoria, right. But another thing that makes them quite difficult to make some quite challenging as a therapeutic, right, and contributes to really the opioid crisis, is that two factors. So one is that you pretty quickly when you start taking opioid develop a tolerance, right? So the first dose of opioid that you take for, you know, if you've got pain, you may or may produce, you know, 80 or 100%, even of pain relief analgesia. But if you continue to take that drug, within a day or two, you'll start having to take more and more of the opioid to get the same pain relief, right. So there's this escalating dose that happens simply to maintain the same level of pain relief, you have to keep taking more and more and more. The other thing that happens is that when you stop taking an opioid, if you've taken it for, you know, a matter of days or weeks and you stop taking it, then you'll have withdrawal symptoms. So not only do you have to take more and more to maintain the same level of pain relief, but when you stop taking it, you've just feel like you just feel you have like a flu like symptoms, and you just feel terrible. And your pain is even worse than if you hadn't started taking the drug to begin with. So it's it's really problematic. And opioids for that reason are, you know, the, the best practice is really to only use them for acute pain. Although, you know, there are there are patients who do take them for chronic pain and sort of seem to have a ceiling effect to that tolerance. But, you know, it's these, you know, factors of being both euphoric in when taken at high levels, and, you know, requiring increased doses and then causing withdrawal when you stop taking it are the reasons that, you know, we have the opioid crisis.

Nick Jikomes 1:04:26

What about, you know, what, what about the differences between different types of opioids? So, for example, Oxycodone is a famous prescription opioid I believe, but then, you know, what about something like that versus say heroin, like, what, what's the or are they more or less the same drug or are they quite distinct? Well, they're

David Roberson 1:04:44

the more or less the same drug, right? So heroin and morphine are actually effectively the same, right? So you know, and the way they act on the new opioid receptors are exactly the same. Right. So it's it's, um, you know, the opioids, whether you're talking about a drug of abuse, you know, heroin, or you're talking about a purely prescription drugs, such as oxycodone, which certainly can be abused. Their mechanism is still by acting on this new opioid receptor. And they activate that mule receptor. It's present throughout the body. It's present in the reward circuitry of the brain, as well as in these pain relieving circuits in the spinal cord in and elsewhere.

Nick Jikomes 1:05:34

I see. So for opioids broadly speaking, in terms of the mechanism, the first thing people should think about is new opioid receptor.

David Roberson 1:05:42

Yep. That's the the one that you know, the three canonical opioid receptors, but the new opioid receptor is the one that is activated by, you know, all of the opioid analgesics on the market. Mm hmm.

Nick Jikomes 1:05:58

What about? You know, this is another one that basically everyone has heard about at this point. But in my lifetime, you know, I went from having no idea what this was to this thing, coming to the forefront of everyone's mind and, and US culture right now, which is fentanyl, which is, I believe, one of the if not the most potent opioid drug that's out there. So why was this developed? What makes it so potent? And why is it? Why is it doing what it's doing right now? Yeah, no,

David Roberson 1:06:26

so fentanyl is an extremely potent mute and mute opioid antagonist, right? So it activates the new opioid receptor at extremely low concentrations, right. So the reason it's so potent is that it requires such a small amount of it to put, you know, to activate the new opioid receptor just did just hardly takes any, it was developed as a prescription intravenous use analgesics for surgery. And it's still used in that context. And it works quite well. I think the reason that it's, you know, in the vernacular, all of us now, and everyone's heard of fentanyl is that, because it requires such small quantities. And because, you know, opioid addiction is such a problem, particularly in North America, you're the illicit drug providers, and the folks in the labs around the world that are making illicit opioids have found that it's much easier to you know, make a little tiny bit of fentanyl and ship it wherever it needs to go around the world to the to the end user, and then diluted in something that's not fentanyl, and sell it as heroin, right. So whereas, you know, a certain quantity of heroin might might be, you know, fit in a thimble the same potency quantity of fentanyl might fit on the head of a pin.

Nick Jikomes 1:08:04

Right? Well, so so that there's an economic drive there, it actually reminds me of the illicit cannabis market where, you know, the, the economics were such that people wanted to get as much potency into as much matter as possible because it made it easier to transport this without getting caught.

David Roberson 1:08:22

Right. Right. And, yeah, and it's, it's really problematic. And, you know, personally, I think that, you know, we've made it worse with war on drugs and the way we've criminalized people who suffer from addiction and rather than treating it like a disease and a medical problem that could be solved with medical tools and and we've treated as as a criminal act, which it just exacerbates the problem.

Nick Jikomes 1:08:55

Why is it so deadly? Is it because it's potent as

David Roberson 1:08:58

well. So the reason all opioids can be deadly is that they act in this pre Batboat singer complex in the brainstem, where they inhibit, that cause respiratory depression, so they slow our breathing. Right. So typically, what happens and this is the problem with fentanyl is you know, someone who is addicted to opioids, oftentimes, you know, they may have gotten prescribed by their doctor for legitimate pain, and, you know, begin taking more and more of it also as prescribed, but then find it really difficult to get off or find that the reward that they get from it, whether whether it's the euphoria or simply the the relief from some some emotional or psychological pain that they're experiencing, is is is enough that they then get addicted to it right. And as they continue to take it, it it works less than, you know, the efficacy diminishes, and they they build a tolerance to it. However, you don't tolerized to the respiratory depression, right? So you even see in the clinic, right? So there, there are patients that, that even under the supervision of a physician, you'll start to see respiratory depression as they give them higher and higher doses. So it's not necessarily something that is, you know, someone just decided they wanted to get really, really high and take a ton of it and they overdose. No, no, I think most often, what happens is that people know exactly how much opioid they need to to get their fix, whether that whether they're looking for a high or they're simply trying to keep the pain at bay, you know, they know how much they need. They think they're, they're getting a certain formulation, you know, they think they're getting heroin, or they think they're getting morphine or oxycodone. But instead, they're getting something that's that's laced with fentanyl, and, you know, may not be mixed in well, so that one, you know, one, you know, dose of this powder has a lot more fentanyl in it than than another dose of the same mixture. And eventually, if you keep elevating the dose, you get to a point where it makes you unconscious, and then you stop breathing. And I see. Right, so

Nick Jikomes 1:11:28

so so eventually, if you take enough of an opioid, and it doesn't actually matter which opioid it just turns out that fentanyl is the most potent, so you don't need that much. It just slows down your breathing. And at some point, it stops your breathing. Yes. Right. And you basically just go to sleep, I guess.

David Roberson 1:11:41

Yeah, yeah. No, it's, um, it's, it's tragic. And, and really sad at so many levels. But, and, and it's, um, yeah, it's, it's a big problem, you know, with with COVID. Obviously, you know, we're not hearing about it nearly as much as we did, you know, a few years ago, but actually, during COVID, the number of deaths has really soared. And just this this year, and 20, I should say it's 2022. Now, but in 2021, we just passed 100,000 deaths per year due to opioid overdoses in the US.

Nick Jikomes 1:12:19

So I think that's actually more than COVID, or am I wrong about that?

David Roberson 1:12:22

Um, so the cumulative COVID deaths in the US, I think, are now up in the hundreds of 1000s. Right. But, you know, I can say that, that the opioid deaths, there are more deaths per year in the US from opioid overdose than cardiovascular disease cancer combined.

Nick Jikomes 1:12:42

So it's near its near to the top of of the number of cars mortality. Yes. Wow. Yeah. Um, another area that I want to ask you about is cabinet because I know there's some overlap here. Yeah. Yeah. A lot of people talk about cannabis for chronic pain. And I know there's some interesting synergistic effects that can apparently happen between opioids and cannabinoids such that perhaps, you know, you could take something with THC in it say, and that would allow you to get the same level of pain relief using a lower dose of your opioid Do you know anything about what's going on there?

David Roberson 1:13:17

Yeah, you know, I actually don't, I should probably, as you know, in, in, in science, a lot of times you get sort of siloed into your little narrow niche, and, and the, I know a bit about it, but I don't feel enough to to really give too much detail other than there certainly is a an additive effect writing and in there's a real synergy between not only cannabinoids, but a lot of the different analgesics and you know, the cannabinoids, you know, I like to think of as sort of, you know, they, they change the sort of the, the synaptic signaling between neurons, right? And, and so they kind of act as a way of fine tuning a lot of different processes, including pain, right? So it's really not not terribly surprising that, you know, when you take a cannabinoid in addition to a lot any of the other analgesics that people find it beneficial.

Nick Jikomes 1:14:32

What about I mean, I imagine that there's a lot of effort to develop novel pain drugs, and I know that you've been involved in this in different ways. So I mean, high level like how does this work, generally speaking, and is it possible say two? Is it possible to make a novel pain drug that say derived from an opioid such that it preserves the pain management component, but gets rid of things like the addictive potential or The respiratory depression aspect Yeah,

David Roberson 1:15:02

no, yeah, there's a lot of folks doing interesting work in this space. Myself and and a couple guys that at Harvard that I was in the lab with started a company Blue therapeutics, five or six years ago doing this work and and that company is still ongoing and doing some interesting work. You're one of the ways before I get into to BLU, you know, typically, the way that people have gone about trying to develop non addictive or less addictive opioids is different ways of formulating them, right. So you can imagine that if you make an extended release formulation, right, or something that, you know, within extended release case, you might be able to just take one pill, and you have sort of a slower steady state, and so you don't get the peak in the serum levels that could sort of trigger that euphoria. You know, in theory that that works, but in practice, you know, people can just take, if they want to get high from an extended release opioid, they can just take a couple of them, and then they're high for a long time. Right. And so that that's actually what happened with Purdue pharmaceuticals and the Oxycontin, right, which is an extended release oxycodone. So, you know, that was the first attempt, a lot of the first attempts were extended release formulations, which really ended up causing more problems, then then they helped I think, in a lot of a lot of cases. Other ways, other folks have used biased agonism. So, you know, the mute opioid receptors or G coupled protein receptors GPCRs. And you can, when you activate a GPCR, there downstream signaling cascades that that are respond to their activation, and you can design molecules that favor one downstream signaling cascade over another, and, and see some differences in in the clinical profile of those. And there are some, some companies doing that. Other Other groups have tried to come up with peripherally restricted opioids. So these are drugs that don't enter the brain or the spinal cord, but act off only in the periphery, I've only ended the body right on the opioid receptors in the skin and the muscles and whatnot. And those have also shown some limited Promise, promise, but, you know, in clinical trials haven't worked that well, in my opinion, it's not terribly surprising, because, you know, chronic pain, which is is what is sort of the the big bad wolf of the pain space, that's the most difficult to treat, and and where there's the greatest need chronic pain is largely due to central sensitization. And so, you know, if the central sensitization is driving the chronic pain and your pain drivers, peripherally restricted, it's probably not going to work all that well for chronic pain, right. And so it's going to have a limited use case. But you know, one approach that I think is just the most interesting to me, and like I said, I gave several years of my life to this is using receptor receptor interactions as a, a way to target subsets of receptors. So this could be done in any using ear to target any receptors in the brain or really anywhere in the body, but in the pain in opioid space. Guy named Phil Porter Gacy, who's a medicinal chemist at University of Minnesota, together with RJ Corolla, who has a PhD neuroscientist, who does PhD with with with Phil, they came up with some molecules that activate opioid receptors only when they're interacting with each other, right. And so for example, I mentioned earlier there are three different types of opioid receptors Mew, Kappa and Delta. They're they are present in different parts of the brain. Some areas they are present together other areas, only one or the other will be available at present. And so RJ and Phil came up with a way to design molecules that activate these receptors only when they interact. So the one the one that blue therapeutics pursued and still is developing toward the clinic is a drug that acts on mew kappa interactions. So if you have a mew opioid receptor, which is present in the areas for the reward circuitry, the pain relief circuitry as well as you know Some of these areas that underlie tolerance and withdrawal. And you and then you also activate a kappa receptor, which is present in the pain relief circuitry, not present in the reward circuitry, but it is also present in some areas that caused dysphoria and some unwanted effects. But if you if you can activate only the interaction of those two receptors, and only when they come together, you can you can target certain tissues that have only the that expressed both of those receptors.

Nick Jikomes 1:20:38

Yeah, it makes sense. So instead of the drug coming in, and sort of hitting every possible receptor that it touches, you've now created a drug that, in effect, it's only hitting a quite a small subset, I would imagine of all of the individual opioid receptors,

David Roberson 1:20:53

right. And in this case, it's hitting the mew kappa interaction that occurs predominantly in the spinal cord circuitry that is responsible for pain relief. And so, yeah,

Nick Jikomes 1:21:07

so So the hope here, and I mentioned this, what they're testing is, you can preserve much are all of the pain management side of things that you get with opioids while at least lowering the addictive potential or the overdose potential. Exactly. Right.

David Roberson 1:21:21

Right. And and they work quite well, right. So blue therapeutics has a compound called Blue 181. That is similar in potency to fentanyl. But it does not have respiratory depression, it does not have tolerance. There's no place preference in rodents. And it really, I mean, it looks by all the preclinical measures like sort of the holy grail of pain relief, right? In that it, it has this, this profile were extremely potent, really strong pain relief, no tolerance, no withdrawal. And it's, it's, you know, it's like I said, it's currently being developed, and I was full full disclosure part of that company, until about a year ago, when I stepped away to, to, to pursue these additional technologies in the space to with blackbox bio, where we're developing these assays for screening of additional pain drugs, as well as psychedelics and some other compounds.

Nick Jikomes 1:22:29

Interesting. So, so it sounds like where we're at in the pain world is there's actually people have developed drugs today, that preclinically, meaning in rodents, are as potent or compared li potent to something like fentanyl, they work for pain as measured in rodents, they don't have the respiratory depression side effect, and they don't appear to be addictive or nearly as addictive. And so I guess it's I suppose it's just a matter of time before we know whether that holds for humans.

David Roberson 1:22:56

Yeah, I think so. You know, it's there's a lot going on behind the scenes that, you know, that I can't get into on a public podcast. But yeah, it looks really promising. And you and I do hope that, that we do get to see these drugs tested in human trials.

Nick Jikomes 1:23:15

So So you mentioned that you are continuing work with this machine vision technology for doing automated behavior detection that I looked at previously. And you're doing things related to the psychedelic space, which I know you're really interested in. So what what can you tell us about that stuff?

David Roberson 1:23:33

Yeah, so blackbox bio is the name of the company that is developing this mouse touchpad technology that I showed the videos of earlier. And you know, what, what really came about there is that we realized pretty quickly, that while this is super helpful in the pain space, and we want to develop a product, and we have we actually have a product, this is sort of my full time gig right now. And we're selling these to different labs and drug development companies, we realize that it's not limited to just the pain space, but we can sort of automate detection, a lot of different behaviors that are important for a lot of different types of therapeutic areas. Right. And, you know, I've I've long had an interest in psychedelics. And, and really, you've interviewed a lot of people on your show, and I'm sure a lot of listeners are very familiar with the promise in the psychedelic space, and they've shown a lot of promise in for treating addiction and PTSD and anxiety, depression. And all of these disorders have common circuitry and similarities and a lot of them Different levels with chronic pain, right. So a lot of people with chronic pain have a traumatic trigger, they have, you know, different your fear base and and emotionally, they have different emotional triggers that can cause the chronic pain similar to how, you know, people with PTSD can have emotional work or, you know, situational triggers that can cause panic attacks and all these sorts of things. And so the thought here is that we can use these some of these same tools that we can use to detect pain readouts, and rodents that we can use some of these same tools to differentiate between some of the different phenotypes behaviorally and experientially of broadly speaking psychedelics, I'm using that term loosely, to include in theologians and dissociatives, which I think we can likely differentiate using this blackbox detection technology.

Nick Jikomes 1:26:04

I see. So So one potential application here is. So again, this comes back to the problem of we like to in general and research, people like to do work in animal models first, and then pursue promising avenues that come from that in humans. So just like you can't ask a mouse, if it's in pain, and you have to come up with clever ways to assess the pain. You also can't ask a mouse if it's tripping on acid, you have to come up with some other way of doing that. Right. Do you want to mention how that works today? And how you got into that?

David Roberson 1:26:36

Yeah, so you know, right now, you know, there's the psychedelic space is an interesting space, because there's been a lot of anecdotal and really well developed experiential literature on on how people have experienced and used plant based psychedelics, not not just in modern times, but for quite a long time. And, you know, there are our benefits. And I'm certain a lot of uses for the naturally occurring psychedelics. But I think there are also a lot of potential use cases that could be developed using synthetics that are derived from the same compounds, and we can fine tune them to different indications and use cases and maybe find ways to fit them better into our current healthcare system. The difficulty there is that or I should say a difficulty is that when you develop a any new drug, that that's a new molecule that does not exist in nature, before you can test it in humans, you do have to test it in animals, both for efficacy and safety. Safety is something else that we're doing with the blackbox technology. But on the efficacy side, you know, psychedelics, there's really just one readout behaviorally that is used to detect sort of the hallucinatory type properties of a psychedelic, and that is the head twitch in mice. And this is a rapid rotational movement, that mice exhibit it from all of the classical psychedelics, but it's a very infrequent behavior. And it's very difficult to detect. And so you end up having to literally have people watching videos of mice for hours on in and writing down, you know, a handful of head twitches that happen here and there. And the problem with this is that while it is quite sensitive to psychedelics, it's infrequent enough that it means that a lot of animals have to be used, it's expensive to do, and it takes a lot of time. So the first thing that we can do with the blackbox technology is that we can automate this, right? So instead of people having to watch this, we can automate it and just right out of the gate, you know, detect these these head twitches automatically. But beyond that, I'm convinced that we're going to see quite a few behavioral differences using some unsupervised machine learning approaches, where we will be able to differentiate not only between Is this a psychedelic or creating hallucination like effects or not, but even to sort of, to really tease out is this a compound that has entheogenic or in pathogenic type properties is an NGO lytic right. So a few of your previous guests have talked about you know, the the psychedelics tend to act on the serotonin h2 a receptor, which produces hallucinations, but also a lot of the potentially a lot of the therapeutic beneficial aspects of psychedelics, but you also have the HT two B receptor and so the HC two a in addition to these causes fear Right, which is why if you take a really high dose of of LSD people report, you know that they can have some really fearful experiences. Whereas the HTTP receptor, which is activated by compounds like MDMA, six APB some other compounds can actually be anxiety lytic. And so we've got some readouts, I'm happy to actually show you a little video clip of how we can read out in real time using different measures that I showed you earlier, the present state of anxiety in a row are using Yeah. So if you want, I'll show I'll show you another little video.

Of this. So let me go to this next slide. So anxiety rats, so if you look at the on the left, here, we've got a rat, this is the same rat. So for those of you listening, there's a video of a rat walking around in a chamber and his paws are illuminated, using this touchpad technologies blackbox technology. If you look at the contact points of the rat, it looks like he's standing on the pads of his feet, instead of sort of the outline of the footprint, you see these points of light that are, you know, sort of round Points of Light, like at the balls of his feet, right. And so that's what all the rats and mice for showing this suddenly show that it works in both rats and mice, but see the same thing in mice. And that's, that's what all the rats look like after they've just been handled. But if you leave the rat in the room, and you leave the room, you you see an entirely different footprint. So this is the same rat 10 minutes later. So I've left the room, just left the lab rat to hang out there, and they get flat footed. And if you think about it, sort of intuitively, it makes sense. It's almost like the, you know, it's I think it's a vigilance readout, right. So, you know, if a rat is scared and and sort of wanting to be ready to run, you have to kind of on their tiptoes just like a human sprinter would get on their toes to start a race, right. And when they're calm down, they get flat footed. And so we have this anxiety related footprint. And and that's dramatically different from the calm or the, you know, zeolitic footprint. And we see this, it's not just, you know, after human handling, you can even if you go to the door of the room where these animals are housed, and just jiggle the doorbell, it'll immediately go from this flat footed appearance too, you know, on the tip toes again.

Nick Jikomes 1:32:46

I mean, this, this makes a lot of sense. And I guess, you know, the idea here overall, is using these objective readouts, you can not only do behavioral assessments faster and more cheaply, you can actually just detect things that you wouldn't have been able to detect before and this isn't limited to pain. It's it's anything, right?

David Roberson 1:33:06

No, exactly. And just to mention, similar thing that you know, because I, you know, really have this interest in the psychedelic space. So this is actually a video of, it's actually a cropped video that I showed earlier. And this is just showing a flinch and lick response. So I'll play it again. So if you watch what this mouse does, so his, let me see here, I gotta think it's his left hind paw is is injured, he has an inflammation model so his left hand polishes little less bright, is is presumably in pain and he kind of flinches it and then licks it, right. And so I'll stop the video here right at the point. So right here, yep, yep, he flinches. He like shakes it and then right after he shakes it, he licks it, and this is a very common sequence, right? And and so if you apply a heat stimulus to the foot of a mouse, they do the same thing. They flinch it and then they lick it. But but with dissociative drugs like ketamine and other other compounds, they will flinch. But so you see that they they have this pain, phenotype behavioral phenotype, but they don't lick it. They don't attend to it. Right. It's like, they're aware that it hurts but it's like not bothersome, maybe, you know, anthropomorphizing here, but point being that this is another another behavior that we can automate, right? So, if you can imagine when you start stacking these these behaviors on top of one another, it makes it quite easy to to tell for novel compound is this, you know, if you're a drug, psychedelics development company, which has a lot of activity in this space, and you've got, you know, 20 new compounds and Do you think they're likely from some of the cell based assays and other approaches to be have psychedelic like properties? But is it more like MDMA? Is it more, you know, like an LSD or psilocybin? Or? Or is it even potentially a dissociative compound, right. And so we can behavioral behaviorally really distinguished between all of those. And that's, that's sort of the next thing that we're doing there at Black Box commercially, is that we are in the process right now of setting up a contract research organization in the Dallas Fort Worth area to do high throughput screenings for third party. So we're not doing any of our own drug development work. We're simply setting this up as an assay to provide service to the psychedelic drug development space for anyone that's developing compounds and really wanting to tease out what kind of compounds do they have prior to entering into humans

Nick Jikomes 1:36:02

I see. So it sounds to me like there's two, two things going on that will synergize in terms of what you're doing with this right? One, you could just have someone, let's just say you had a research lab, whether it was academic or private, you're interested in screening compounds to see if they might be hallucinogenic. Today, the way that people do that, is they have a researcher spend probably hours and hours looking for this head Twitch response and video. So you guys can just automatically detect that so that they can do that type of screening faster. Right. The second thing that sounds like you're doing is, you could you know, if you gave different groups of animals, different drugs, by videotaping them, and using machine visions in the way that you've shown us, you could create a kind of behavioral fingerprint for each drug. Right? In other words, you know, animals, when they get MDMA, they tend to do these types of behaviors, but not these ones. Those LSD, there might be some overlap, but it's different. Even something like psilocybin versus LSD might have small differences between them. And then you could take a completely novel drug, say, and just compare it to all those known drugs with known effects and rodents, and then subjective effects in humans. And in theory, that should be able to give you quite a bit of predictive power for what a novel drug will actually feel like.

David Roberson 1:37:15

Yeah, we hope so. And I think that will be the case. And I'm excited to figure it out. I mean, that's also one of the beauties of science, right, is that you come in with these hypotheses and some data suggesting that it should work a certain way. And then you give it a go and see how it does.

Nick Jikomes 1:37:33

Interesting. Um, last area I want to ask you about David is, you know, since your expertise is in pain, and that's what we mostly talked about, is there any indication you have any, anything you might speculate on in terms of whether or not any of the psychedelics or dissociatives or other drugs like that have any potential related to pain that, you know, the one thing that comes to mind here for me to get you thinking on this is, you know, I know a lot of these drugs actually have sometimes very potent anti inflammatory effects that might be so potent that that you can use sub psychedelic doses to achieve them. So what are your thoughts in that direction?

David Roberson 1:38:11

Boy, that that we could do a whole whole nother podcast on on this topic, but I think that there's a lot of promise. And I have Yeah, the there there is a lot of promise and and I think that you know, it's interesting the psychedelics because they have been scheduled as and for those not from the US are not familiar with the the FDA slash DEA process for controlling substances in the US that is similar in other countries. But, you know, the psychedelics have basically been put really arbitrarily into a category of saying they have no clinical benefit. Without, you know, despite the the evidence has been around for decades, showing that they do have clinical benefit. But the the downstream impact of this has been that it's been virtually impossible for academic groups in particular to study these compounds that at length and to look at, you know, what are the the anti inflammatory properties of these compounds? And can we harness that to develop a therapeutic? So certainly, you know, all the way from, you know, the various psilocybin strains of mushrooms to peyote and other compounds. There are a wide range of anti inflammatory compounds and molecules, right terpenes triterpenoids, that are that are present in these compounds I'm particularly interested in in the cacti and some of the masculine related compounds as well as triterpenoids that are in the cacti and how they may have analgesic property. And but but also I think that there's really a lot of interesting overlap and and potential synergy between the ways that psychedelics are being used with psychedelic assisted psychotherapy for anxiety, depression, and whatnot that could be that could translate to, to using the same approaches for treating chronic pain. So we know that a lot of chronic pain is kept alive, I shouldn't say we know there's, there's a lot of evidence to support the hypothesis that that in many cases, chronic pain is kept alive and kept chronic by a fear of the pain itself, right. And I've experienced this right where, you know, you, you have a bruise on your leg, right from from kickboxing, and, you know, you're not thinking about it, but you, you know, almost run into something, or you have something that triggers a fear of that pain. And as soon as you have that fear, suddenly you're aware of the pain again, right. And so, you know, for people that have traumatic experiences that are tied to to their chronic pain, my folks have mentioned earlier in the podcast that they were in a plane crash, and my mom still today has, has a lot of chronic pain. And it is it's like clockwork, when when she has sort of some emotionally challenging experience or, or when when things related to her plane crash come up, her chronic pain is back and it's it's in debilitating, it can even put her in the hospital, right. And so you haven't seen this firsthand with her. And also just kind of understanding, you know, how central sensitization works. It makes sense to me that the psychedelics do hold a lot of promise for chronic pain and, and it's a space that I hope to move into.

Nick Jikomes 1:42:03

Yeah, I mean, what you're saying is evocative of more or less what seems to be going on with something like MDMA for PTSD, at least conceptually, you know, it's it's sort of somehow dampening the strength of the association that someone has with some past traumatic event. And that's, you know, that's more or less, I think, what what you're referring to here?

David Roberson 1:42:23

Yes, No, exactly, exactly. It's really an exciting time. And I think there's a lot to be hopeful for, for chronic pain patients. And, you know, a lot of activity investment development is needed, as well as a lot of advocacy, I think for, you know, both both for continued funding for developing these therapies, as well as continued access for the plant based compounds that that people would like access to, prior to the, you know, release of these marketed FDA approved compounds.

Nick Jikomes 1:43:01

I think that's a pretty good spot to end it. David, thank you for your time. And you've shared with us and I look forward to following what is on the horizon for some of the stuff that you're working on, Nick, and I really appreciate

David Roberson 1:43:12

your time as well.

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