About the guest: Gregory Scherrer, PharmD, PhD is a neuroscientist whose lab at the University of North Carolina studies the neural basis of pain, including its sensory, emotional, and cognitive components.
Episode summary: Nick and Dr. Scherrer discuss: the neural basis of pain sensation & pain perception; opioids & the opioid system; cognitive modulation of painful experiences; neural basis of placebo effects; endogenous opioid system; and more.
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M&M #52: Pain Drugs, NSAIDs, Opioids, Oxycodone, Heroin, Fentanyl & the Neuroscience of Pain | David Roberson
M&M #159: Neuroscience of Social Behavior, Pain, Empathy, Emotion, Brain Mechanisms of MDMA | Monique Smith
*This content is never meant to serve as medical advice.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Gregory Scherrer 2:26
So I'm Greg Scheer. I'm a professor at the University of North Carolina. In terms of background, I started in France, in east part of France, at the University of Strasbourg. I started with a PharmD. I did a PhD. So my background at time was in opioid receptor biology. My supervisor during my PhD was Bridget Keefer. And Bridget is known as the person who first cloned the genes that encode opioid receptors and then showed that one of these receptors, which is known as the mu ped receptor, is the one that's responsible both for the analgesic properties of opioids, why we use them in the clinic, but also the side effects, including addiction and so after this background. So when you sort of start with opioids, you can go different places. You can go more towards addiction or towards better understanding pain and opioid and angesia, and that's what I decided to do. So moved to the US 2006 and I did two postdocs. My first postdoc was with Alan basbaum at UCSF on neurobiology of pain. And after three years, I had background at that time, it was really pharmacology and molecular biology. So I'd never taken a formal neuroscience class at that time, so I wanted to really become more neurophysiology. So I went to Columbia, spent a couple years with Emmy McDermott, where I learned spinal cord electrophysiology, and then started my first lab at Stanford in 2012 and recently I moved my lab to UNC.
Nick Jikomes 4:03
You're a pharmacologist who sort of became a neuroscientist, and that happened sort of via the study of pain and reward systems in the brain. Exactly. So I want to talk about opioids a little bit. Most people know what they are, at least on one level, obviously, these have been widely used medications. They are given as pain relievers, but of course, they can also be highly addictive, and it sounds like those two things are intimately related. So can you tell us a little bit more about the opioid system? You mentioned that there's this mu opioid receptor that's responsible for both the analgesia, the pain relief, and the addictive properties of opioids. Are there other opioid receptors? Are these two things, sort of, are they two sides of the same coin? Or can you separate the addictive and the pain relieving parts of this great
Gregory Scherrer 4:51
question? So, you know, the first studies that really demonstrated that there were sites in the brain, they were binding opioids, such as, more. Infantile in oxycolon, all these things sort of work the same way. Suggested that there are specific proteins that neurons express that combine these drugs. And so it's really the fight the discovery of the genes that sort of clarified what the endogenous opioid system is. So our body expresses a number of receptors and number of peptides that are part of what we call the endogenous opioid system. So this is a system people don't always fully realize this, but essentially, what these very dangerous drugs do is to hijack our endogenous opioid system. But normally in our body, even when things function perfectly well, our cells can release some endogenous opioids that are known as endorphins or enkephines, that produce effects that are useful for us, that are not dangerous. And they do that by acting on these receptors that are known as opioid receptors, and they come in several flavors, three main receptors that are known as mu, delta and kappa opioid receptors. And so at the time when people and so this, you know, this has been a long problem, right? People often ask me, How come we still have to deal with opioid addiction? This has been known for so long. What? What's the what is, why is it so difficult? And so at this time, so you have different receptors that can potentially bind opioids such as morphine. And so there was the possibility that one of the receptors was responsible for the positive effects, the analgesia that we we still need in the clinic, and maybe one of the other types was the bad one. Right? Yeah, right. So then, if that was true, then what you need to do is to have chemists doing, you know, their work to generate novel compounds that are what we call more selective, that will preferentially activate the nice receptors, and you know, not those that are causing the side effects, unfortunately. So the work that Bridget Keefer, my PhD manager, did demonstrate that that's not the case. It's actually the same receptor, which is known as the mu opioid receptor, that is responsible both for the pain relieving properties of opioids, but also essentially all the side effects. So the the rewarding properties that cause the transition to addiction, the respiratory depression. So one of the reasons why opioids are so dangerous is that normally they are addictive. So many drugs are or habits are potentially addictive. But opioids have this particular property, that they they have receptors in the brainstem, in the respiratory centers. And so most people who die by opioid overdose die by respiratory failure, because opioids directly inhibit respiration, and since, since they're also like sedative, people can fall asleep and essentially stop breathing in their in their sleep. So that's quite different. If you think about cocaine, for example, or psychostimulants, you know, they get too excited, so and they're they don't have this effect on the respiratory system, so you can still die from overdose, but it's much less common than than with opioids, I
Nick Jikomes 8:07
see. So, so they're sedative and they can depress the respiratory system, so the fact that that's very dangerous, yeah, you those two things simultaneously, you just fall asleep, right? Exactly.
Gregory Scherrer 8:17
And so, so, what Bridget did at the time they had she had just cloned the genes that encode the different opioid receptors, and so she made, well, you know, knockout mice, so mice that are completely normal, except that they don't express one of the opioid receptors. So you can think about this as three different strains of mice that lack either mu, delta or kappa opioid receptors. And it turns out that if you give an opioid, whether it's morphine, Oxycontin, fentanyl, to the mu opioid receptor knockout mouse, this mouse is essentially immune. Nothing happens. You don't have pain relief, but you don't have addiction, you don't have respiratory depression, you don't have constipation, nausea, vomiting, all the side effects of opioids are gone. So that's a much bigger problem, right? Because instead of having to work with chemists to make better molecules, now you have the same receptor that generates both the positive and negative effects. So are what? How are you going to tease that apart? And so this paper on this mu, P receptor, no cut mouse, was published in 96 and we still don't have a solution. So you can see that that's really the core of the problems, like the same receptor is both good and bad, and compared to other drugs of abuse, the drug that's abused is an FDA approved drug that's absolutely essential in medicine. No hospital could function without opioids because they are
Nick Jikomes 9:39
so effective at that pain, and we don't have
Gregory Scherrer 9:42
alternative, right? So if you want to treat moderate to severe pain, there are several other things you can treat, but at some point, most patients will will need opioids that may or may not work. It depends, but it's it's still the best option for severe pain. And
Nick Jikomes 9:57
so, you know, we could ask two questions, which might. Really biologically be one question. Why are opioids so good at generating pain relief and so addictive? Are they? Are these mu opioid receptors responsible for both the pain relieving effects and the side effects? Are they in, like, really important specific parts of the brain? Are they all over, like, what parts of the brain make it so, so potent as a pain agent and an addictive agent, right?
Gregory Scherrer 10:26
So, so, for the pain part, what's really interesting is that this receptor, European receptor, is essentially present all along the pain circuitry, in the primary affensory neurons that detect painful stimuli in the periphery, in the spinal cord, neuron that process, that receive and process the information, and in the brain center that create the percept of pain. So if you wanted to start a new project and find a way to treat pain, you would probably pick a receptor that is present at all these spots. And it turns out that that's where this receptor is, and it's a receptor that, in terms of molecular signaling is inhibitory, so it's going to reduce the ability of pain sensing neurons to communicate this information to the downstream neuron in the circuit in a way. So several things they in terms of neurotransmission, opioid receptors are coupled to different effectors in the cell, in a neuron, and so several things happen when an opioid binds to its receptor. First, these opioid receptors will inhibit calcium channels. So these are ion channels that are very important for neurotransmitter release at a synaptic terminal, when neurons fire action potential, there's going to be an increase in intracellular calcium, and this signal will cause the fusion of synaptic vesicles with the plasma membrane. And so then the neurotransmitters that are inside the synaptic vesicles will be released onto the next cell to sort of activate or inhibit it. And so what opioid receptors do when they're activated is that they're gonna diminish the ability of this, these calcium channels, to let calcium in. So in the presence of an opioid, you have less calcium flowing in the synaptic terminal, less transmitter release, so this neuron is less able to communicate pain information to the next neuron in the circuit. So that's one effect, and the other effect is through another kind of ion channels, potassium channels, and that's regulating the excitability of the cell. So in that case, opioid receptors, when they bind fentanyl, can open potassium channels, so more potassium flows out. And since this is a positive charge, and neurons already have more charges that are positive outside the cell compared to inside. You do what we call a hyperpolarization of the membrane. So now it's going to become more difficult for this pain sensing neurons to get excited in the first place. So you really have these two effects on the neuron. First, they are less less easy to excite. And then, even if they're excited, they cannot recommunicate This information very well. So you can imagine that if you do that multiple times along the pain circuit, it's going to be quite effective to reduce pain.
Nick Jikomes 13:11
Yeah. So the odds, the odds of any signal getting through, are quite low, because you have this inhibitory effect. You've got it at the places in the periphery where pain is first detected. You've got it in sort of the middle relay stations of the spinal cord that connect the periphery to the brain, and then you've got it additionally all the way up in the brain, so there's very little room for something to get through.
Gregory Scherrer 13:30
So for opioids, you know, even though the receptors are also present in sensory neurons, there's good evidence that most of the analgesia probably comes from action in the brain and spinal cord
Nick Jikomes 13:43
I see, and I want to give people a little bit more of a sense for how pain information is detected and relayed in the absence of a drug. So, you know, let's just say, you know, if, if a needle or something or a pin pokes me in the arm, obviously I feel that pain. I know where it is. I can localize it to the part of my arm where I got the pin prick. Can you kind of walk us through on a very, very basic, high level, like, how is that detected and relayed up to the brain? Right?
Gregory Scherrer 14:08
So, you know, when you have this discussion, you have to think about the percept that your brain creates, so that what you just talked about is more what we call the sensory, discriminative aspect of pain, and so you're able to distinguish all these stimuli. For example, you can know if it's you know if you just you were cooking, you put your hand on the hot stove, you get distracted. You can tell it's painful, but it's also burning heat that's different from if you drop something very heavy on your foot, right? You can tell. And so you can tell, because we have different kinds of sensory neurons that innervate skin, muscles, bones, viscera, etc, that are called nociceptors. So these are the sensory neurons that are specialized in the detection of stimuli that are intense enough that they can damage our body. Okay, but these come in many flavors, so some are specialized. The detection of the pinprick. So they have transducers that respond to this type of mechanical stimulation. Others are specialized in detection of thermal stimuli, noxious heat or noxious cold. And so we often think about the system for pain, at least in a periphery, as a label line system. So like a freeway with different lanes, where cables detect a particular type of stimulus because they have the sensors that do that, and then they sort of transfer this information to the spinal cord and to the brain, because based on where the stimulus is on your body and what kind of stimulus it is, you can react differently, right? So each is not exactly pain. It's also unpleasant. But for example, when you're present of presence of a painful stimulus, you have this withdrawal reflex. And then you know, if you again burn your hand on the hot stove, you have your withdrawal reflex. Then you probably go to the sink, turn on the cold water. Doesn't get better. You go to the doctor, all these things, if it's a paretogen, so a molecule that causes each you don't withdraw your first reach and you scratch right. So this shows you that the ability to detect detect different types of noxious stimuli, or Pareto Gen, or, you know, light touch, is because we have these different types of sensory neurons that can help the brain decode what has just happened on your on our body. And so it sounds
Nick Jikomes 16:27
like, so there's many types of sensory neurons. There's many types of pain sensing neurons. So they're sort of, they're virtually at two levels, and it sounds like so on the one hand, we can detect painful stimuli as distinct from non painful stimuli. But then, even among the pain sensing neurons, there's different types, so we can distinguish between a burn versus, you know, something that would cause a bruise or that's putting a lot of pressure on the body. And it sounds like an important component of the pain sensing neurons is intensity, like the stimulus has to be intense enough to trigger them. There's probably other sensory neurons that that don't respond to pain but to respond to innocuous touch and things like this, and they probably have different thresholds of of firing for in terms of the intensity, all right?
Gregory Scherrer 17:13
So, yeah, intensity coding is an interesting question. You know this happens to Yeah, both cellular and molecular mechanisms, we have types of sensory neurons that are called low threshold mechanoreceptors. These are the ones that typically, typically detect light touch, and these cannot detect stimuli that are too intense, so they in the normal condition. We can talk about what is called tactile, aerodynamic when touch becomes painful. That's, quite interesting mechanism. But normally these cells are unable to fire when the stimulus is too intense, not receptors. It's the opposite. If you don't reach a certain intensity that can damage the body, they don't respond. So there's that. And then you have within a certain cell also intensity coding, whereby some cells fire more when the stimulus is more intense. So you have these two main ways to sort of code intensity, at least in a periphery.
Nick Jikomes 18:12
And then you know when a painful stimulus is detected, whether it's a high pressure stimulus or very hot stimulus or something like that. What happens next? Where does it go from the sensory periphery? Does it? Does it have? Does it have to go through the spinal cord and particular pathways in there before going up to the
Gregory Scherrer 18:30
brain? Yes, it does. And you know, this is well known. If you have a spinal cord injury, of course, you you know, you lose the ability to to move, but you also lose sensation. So things that are painful are like a noxious stimulus on your arm or on your leg. If it's a spinal cord injury, high level, cervical level, you lose also the sensation. Yeah. So you know this the system is the sensory neurons are unusual, so most neurons in the brain, in the spinal cord have two three main parts, but one part are called dendrites, right? This is where the information comes in. Our neurons listen to other neurons that are located upstream in the circuit, and then they communicate this information using their axon. Sensory neurons for pain are not like this. They're called pseudo unipolar neurons, and they don't have dendrites, so they don't listen to other neurons. They don't care. The only thing they care about is what happens in the organ that they innervate, whether it's a visceral organ, skin, bone, muscle, and so they're called Soto unipolar because they have one axon that leaves the cell body. So cell bodies are in ganglia that are very close to the spinal cord. They're called either dorsal root ganglia for most of the body and trigeminal ganglia for the face. So the ganglia are located very close to spinal cord, and then they have one axon that bifurcates, sending one branch that is very long to anywhere nearby. Body. So you can have, for example, a sensory neuron that is in a ganglion at the lumbar level, and that innervates the tip of your toe. So this sensory neuron axon is very long, and that's where pain information is detected in the periphery. Then through action potential firing, pain information is transferred back to the cell body. But in fact, this axon sends a second collateral, another branch, to the spinal cord, rarely to the brain, but there are some neurons that do that. And so then this information gets to the spinal cord, where many types of neurons will process this information, and specific class of spinal cord neurons known as projection neurons of the anterolateral tract with relay this information to the brain. And at this point, the information is emotionally inert. There is no emotion or percept yet, but something has happened the periphery, and the brain is going to be aware of this. And
Nick Jikomes 20:54
there's almost, you know, it's interesting to think about the difference between the detection of pain and the creation in the brain of the conscious perception of being in pain. And sometimes you can almost experience the difference there, in the sense that you know, if you, if you pay very close attention to your experience, when you, you know, put your hand on the stove or something, the painful experience often comes with a lag, right? It comes after you sort of detect that something's hot, and withdraw your hand, there's almost like a split second that goes by before the pain actually starts. Does that have to do with the fact that it just takes time for the peripheral signals in your skin to get all the way up to the brain? Right?
Gregory Scherrer 21:31
Well, it Yes, to some extent. But in that case, in your example, you also have learned that the stove is hot and so you see it. So there's there are lots of things that happen here. Maybe we'll talk about the cognitive aspect of pain if we discuss the placebo analgesia aspect. But yes, mostly this difference between the visual reflex and the percept is due to the fact that when sensory neurons that have detected a painful event in the periphery get to the spinal cord almost immediately, through one synapse, they activate motor neurons for a withdrawal reflex, such that you can preserve your body even before the percept is generated. So
Nick Jikomes 22:13
the withdrawal reflex, the signal in the nervous system that gets you the safety or gets you away from harm, it doesn't actually need to go all the way up to the brain. No, he
Gregory Scherrer 22:22
does not. Yeah. In fact, you know, there are many studies that have been shown where you if you use preparations, where the communication between the spinal cord and the brain has been inhibited, somehow you still have the withdrawal reflex when you have a noxious stimulus, and that's important, right? Because you want to remove exposure to the noxious stimulus as soon as possible, and then there's enough time to think about what just happened and make a decision about what's the next move. But first of all, you have to get out of the way. Yeah. So
Nick Jikomes 22:56
is, are things segregated in the spinal cord. So for example, obviously, if someone has a complete transaction of their spinal cord, it's completely cut. Nothing can go up or down. You can't move certain parts of your body depending on where the lesion is, and you also can't feel those parts of the body. What if you were to say damage? Part of the spinal cord is one part of it for signals going out to the muscles to move your body, and another part for the inputs coming into sense things, or are things all sort of a mishmash in
Gregory Scherrer 23:25
theory? Yes, but these things are pretty close. They're close enough then, you know, normally with an injury that would happen, for example, with a trauma car accident, you would probably have both, both types of problems. So the the way the system is organized is that the sensory neurons that project to the spinal cord are relatively close from the axons that come down from motor cortex to to produce movement. So in you know when in our research, right when it's not an accident, but in our research, we can use tricks such as optogenetics, chemogenetics, to manipulate specifically neurons that are either part of the sensory or the motor system, and we can tease these things apart, but with a natural injury, these things are pretty close. So I
Nick Jikomes 24:21
see, so in principle, yeah, the sensory and the motor side, they're functionally and they're anatomically distinct. You could, you know, if damage is just right, you can damage one, but not the other. But in practice, you know, based on just the raw size of things, if you get a spinal cord injury, you're probably going to take out the sensory and the composite spinal
Gregory Scherrer 24:39
cord is, you know, pretty small. So, and usually the, you know, when there's an injury of this kind, if it's a severe trauma, yeah, sparkle, take a hit, and you can still have selective deficits. But anatomically, these things are pretty close. It's not like, you know, the front part of the brain and the back part of the brain Exactly.
Nick Jikomes 24:56
Interesting. So, okay, so. The painful stimulus is detected in the periphery, on the surface of the skin. Say, sensory neurons are doing that. These sensory neurons are different from a lot of other neurons. So instead of listening mostly to other neurons, these these neurons are listening to the external world By, you know, penetrating a given tissue and so, so they're different in that sense, they send their information to the spinal cord and then up to the it gets up to the brain eventually. What we don't need to be fully comprehensive here, but what are some of the major brain regions, the major players in the brain that are involved in processing pain, right?
Gregory Scherrer 25:33
So you said, you know, external world, but also inside our body, right? So viscera, for example. So we have different sensory neurons that some are project to the skin. So obviously, in that case, it's for the external world mostly. But most sensory neurons are going to innervate our own tissues, where they can also detect diseases, problems. If
Nick Jikomes 25:56
I have a, you know, my ups, if I have an upset stomach and there's some kind of information in there, or maybe I've got a bleed internally, there's actually sensory neurons detecting that in a similar fashion to the ones in my skin. So,
Gregory Scherrer 26:07
you know, the stomach. You could also argue that external world, right? Because you just got some food, like you ate something very spicy, yeah, your sensory neurons are not gonna be very happy about about that, about that choice of meal, but that's still the external world. But for example, and this is relevant, you know, for a number of disease, including cancer. So organs were, you know, that are densely innervated are more likely, for example, to detect the growth of a tumor than other organs that that are less well innervated in terms of sensory neuron density. So you know, you might know that, for example, for certain types of cancer, like pancreatic cancer, one of the issue is that sophone diagnosed late, because it's not painful early,
Nick Jikomes 26:52
ah, because it's not innervated very much, or
Gregory Scherrer 26:55
because, you know, the changes in the organ are not sufficient for these sensory neurons to be, to be engaged I see. So, you know, the the pain system, in a way, is, is its efficacy is different based on the organs and the type of stimuli
Nick Jikomes 27:12
I see, I see. So pancreatic cancer is diagnosed late, typically, because people just never have a painful stimulus early on, never
Gregory Scherrer 27:19
or it's at a stage where, you know, the tumor can be quite large, yeah? So that has to do with the skin is the opposite, right? So when you have pain that comes from internal organs, often it's like dull, not very well localized, right? Well, yeah, on the skin it's extremely precise. That's because the type of sensory neurons that innervate different organs have different receptive fields that are, you know, smaller or larger. And so our brain has get some information that is more or less precise, depending on the body parts and the properties of the sensory neurons.
Nick Jikomes 27:56
So these sensory neurons can be bringing information that originates in the outside world, like, you know, something touching my skin, they can also be bringing sensory information that originates inside, somewhere in my viscera. That stuff is being relayed up to the brain via the spinal cord. And what are some of the major nodes in the brain that then take over,
Gregory Scherrer 28:15
right? So, you know, you can think about pain as a multi dimensional experience, where there are three main components, sensory, emotional, cognitive. So for sensory, that's, you know, where is the stimulus on my body? What is it like? Is it, you know, heat? Is it mechanical stimulation? And so that goes through the sensory part of the thalamus and then the somatosensory cortex. And here, there's, you know, a map of our body where these stimuli are represented. And our our brain can decode where the, you know, the noxious event has occurred inside your body, in that area, on the skin, on the end, on the foot, etc. And so that information is important, because the first thing you're going to do after the withdrawal reflex is where, what's going on. So you have to know where. You know where, where the painful event has been, has been, to put your end under the cold water, put a band aid, Deal, deal with it. So that's the sensory, discriminative aspect of pain. And then you have the emotional aspect of pain, so that you know that's the aspect of pain that's essential for survival. The only reason we care about pain and we deal with it, we go to the doctor, we do what's necessary is because there's this aversive signal that is generated during perception. So we have to dislike pain to consider, okay, this is an important thing that I don't want to experience very long, so I'm going to do whatever it takes to make pain go away. And that's happening in different areas of the brain. It's not overlapping with these other areas that are important for sensing pain, also the thalamus, but other nuclei. Eye that are located less laterally but more on the midline, and then other cortical areas or subcortical areas, such as the amygdala, singular cortex, insular cortex. So there's really like these two main pathways that that detect pain sensation or generate pain sensation and then generate the emotional, affective component of pain that's necessary for survival. So people who have mutations, for example, in some sodium channels where they they can sense pain, they can generate the negative aspect of pain, so the unpleasantness. They usually don't live long because they have injuries in their body, and they don't deal with them because they're not bothersome. You
Nick Jikomes 30:46
break your leg and you keep trying to walk on it, yeah,
Gregory Scherrer 30:49
I still want to go, you know, watch a movie or whatever. It's okay. The the unpleasantness of pain that that is, uh, crucial, and that is the, you know, the problem that when pain persists and becomes a disease. This is really where it's really problematic for patients. It's not to know the representation of the painful stimulus in terms of where it is. It's really this aversion that's generated and that prevents them from doing things that they like.
Nick Jikomes 31:17
Yeah, so it sounds like the painful information that's getting to the brain. So these sensory, these nociceptive neurons have detected that pain. Is there some in some form or another, somewhere in the body, that information gets up to the brain. The brain then has to, like, solve a number of problems. The one is, as you mentioned, where is the pain coming from? And so that's where the somatosensory cortex comes in, and the brain sort of maps using its map of the body, up in the somatosensory cortex, where the brain actually is on the body. There's also the emotional component, you know, the pain needs to be perceived as aversive in order for the whole organism to learn, sort of to dislike it and avoid it. In the future, where are some of the brain regions that are responsible for that aversiveness?
Gregory Scherrer 32:01
So one important side is the amygdala, so that's a region that's important for emotions in general, positive emotions, negative emotions, so things we like, things we dislike. And so there are a number of studies that show that for this particular pathway where neurons that are in the spinal cord project this pain information to a small structure that is the parable nucleus, then then relay this information to the amygdala. And so there are case reports that show that if you have a lesion in this pathway or in the amygdala, the sensory discriminative aspect of pain can be conserved, so people can still detect stimuli, but they are no longer bothersome. And so we've we've shown in rodents too, that if you artificially inhibit cells in the amygdala, you can disassociate these two aspects of pain experience, the sensory aspect and the emotional aspect. So the
Nick Jikomes 32:55
amygdala really does seem to be belong involved in the emotional aspect. Here
Gregory Scherrer 33:01
it is, and
Nick Jikomes 33:02
then, of course, layered on top of that, there's this sort of cognitive or higher level processing that can happen. So to sort of connect this to everyday life, there's actually many examples that we probably all experience where something is painful or at least uncomfortable and it's naturally experienced that way, but nonetheless, we do it, or even keep doing it, or even learn to enjoy it. So you know, maybe I decide I want to go to the gym tomorrow and start working out. I start lifting weights. My muscles burn during the experience. My muscles ache the next day. These aren't pleasant experiences. I don't like them, but actually I can make myself keep doing this anyway, and maybe over time, I actually come to enjoy the sensation, in some sense. So how does the cognitive layer start to fit in here?
Gregory Scherrer 33:45
Yeah, yeah. These are, these are great examples. So, so you know, in in systems that are less developed, for example, some invertebrates, the priority of the pain system remains to avoid noxious stimuli that can, you know, damage your body or kill you. And so in these systems, usually noxious stimuli equals escape. But then as animals evolve and become more intelligent, we all know sometimes we have bigger plans. There are things we need to get done, and so we need to have the ability to calculate if it's more important to prioritize avoiding pain and not do the other things that we had planned, or if the pain is not too severe, too serious, we can decide to ignore pain. So, you know, you're a tennis player, you've been practicing your entire life. You're finally in the final of the US Open. You have a light sprained ankle, you know, in the first set you're gonna your cortex is going to tell your amygdala, okay, keep quiet, because I know what this is. I've had all the sprained ankles. I've been working towards this goal for a long time. I can deal with it. I'm going to decide to continue, you know, playing tennis. And so it's, it's crucial. To to achieve long term goals that can be very important goals for survival as well, to be able to make this calculation based on our previous history, if we expect this pain to be something transient that's not, you know, severe, or if it's something that's really important that hasn't been encountered before, where we're sort of like, okay, this, this seems really bad. I've never felt that before. Probably should go to the doctor. So, yeah, this cognitive aspect is, like, the dimension that's very important becomes prevalent, I would argue, in humans.
Nick Jikomes 35:31
And you know, obviously that's very important, especially for organisms like ourselves that can engage in long term planning. You know, we can prioritize how much we want to avoid some temporary pain right now in order to achieve some larger goal that will that will pay off later. Another thing I want to think about here get people thinking about is so we talked about, we've talked about these different components of pain. There's the sensory side, there's the emotional side, the actual experience that is unpleasant, and there's the cognitive dimension here the thing that can tie into, you know, goals and planning and, you know, higher order stuff like that. There's also, there's also, maybe another distinction we could make between different types of pain experiences. So people might make a distinction between physical pain and emotional pain. So they're both going to result in an emotional pain experience that's unpleasant and aversive. But one of them, you know, if I smash my finger with a hammer, there's a clear physical cause that's related to tissue damage, but if, say, a family member dies, or a pet dies, there's no tissue damage, there no potential tissue damage to my body. And yet we talk about it as being a very painful stimulus. Is that a valid distinction to make? And do those types of emotional experiences tap into the same pain circuitry? Centrally, it's,
Gregory Scherrer 36:49
it's a very valid, you know, it's an important question. So, you know, if you're a researcher in a pain field, the the second, the second case where there's no physical damage is not really pain, right? We use this term pain like, you know, I, I, you know, I bet on this team, and, you know, I lost. This is painful. But no, it's not painful. Nociceptors have not been activated. You know, the signal that's been generated in the brain is not really pain. It's something that we we perceive as an unpleasant experience, but, you know, there's no actual or potential tissue damage, which is really the definition of pain. So pain as a definition is like unpleasant experience with sensory and emotional components, but it has to be associated with either Frank, actual tissue damage, or the potential for such damage. So, but there's, there's overlap, right in the brain regions that are active when you wear when we have an unpleasant experience, whether it is actual physical pain or something that is, as you said, emotionally painful, the singery cortex, number of other regions are activated. So there are areas in the brain, in the periphery that are a little bit more pain specific. We call them nociceptive neurons. And there are other areas in the brain where neurons do all sorts of things so they can get engaged during pain that's unpleasant, but all the things that are unpleasant or pleasurable. Now,
Nick Jikomes 38:21
so far, we've sort of talked about the natural way to think about information flow, which is sensory detection in the periphery, relayed through the spinal cord up to the brain. Further processing happens. Can things move in the opposite direction? And I want to ask you that in the context of something like psychosomatic pain. So can I form beliefs in my cerebral cortex that actually feed all the way back down to my nociceptors in the periphery to create a pain percept in the periphery that's entirely internal in origin?
Gregory Scherrer 38:54
That would be less common, because that would mean that you have, you know, your your brain has created a pain percept that is very specific and associated with a particular body part that would have, like simulated, it can happen, but that we have simulated exactly activation of a discrete set of sensory neurons that only innervate, you know, the dorsal surface of the arm, and that this, This is, you know, perceived as painful the top down organization of the pain system is more as a modulation system whereby, you know, I can give you the example of the fight or flight response, where you know, a firefighter goes in a house on fire, you know, saves A baby, super happy. No pain reports to the hospital, very severe burn pain that should be excruciating. So what has happened in that case is that there are neurons in the brain that have activated this descending pain modulation circuit so that, you know, starts in a Cortex, but goes through regions such as the peri architecture. Gray and then rostral, ventral median medulla that then projects to the spinal cord. So we have brain neurons that can regulate how much nociceptive information is going to transmit from sensory neurons or spinal cord neurons back up to the brain. So the pain system really has an ascending component and a descending component, and many connections and interactions between these two systems when you have, for example, phantom limb pain, or types of pain like this, when the sensory neurons are not actually activated by
Nick Jikomes 40:38
a noxious stimulus, yeah, like, I guess in the case of phantom limb, they're not even there anymore. That's right, they're
Gregory Scherrer 40:43
not even there, but there's a part of the pain circuit that's still there. So for example, part of the nerve that can still be there, or the corresponding spinal cord nerves postsynaptically. And so when there's activity in the nerve or in these spinal cord nerves for our brain, it's as if it was actually coming from the terminals that are in the skin or in the organ. So the brain cannot sort of erase this percept that the arm or the, you know, the leg, is still there. And so in that case, you can have types of pain that are perceived when there's aberrant activity in the nervous system. And the brain just doesn't have a way to figure out that this is not an actual noxious stimulus, but it's just activity in the circuit, yeah,
Nick Jikomes 41:25
yeah. From from the somatosensory cortex, this perspective, the same part of the body map gets activated, yeah.
Gregory Scherrer 41:31
And so it could, this could happen many places in the spinal cord or brain, right? If you have upper activity for your somatosensory cortex or other parts of the cortex, it's going to look the same. And
Nick Jikomes 41:43
you know, we've mentioned opio exogenous opioids so far. They're very effective and very addictive. Because of this, their ability to inhibit neurons via the mu opioid receptor, and part of the reason for that is this receptor sounds sort of at all stages of this pain circuitry, from from the sensory periphery all the way up into the brain. I want to ask you a little bit more about endogenous opioids, things like endorphins and enkephalins that you briefly touched on, what are some of the normal natural situations in which the brain releases these endogenous opioids?
Gregory Scherrer 42:16
All right, that's a great question. Can I just tell you one more thing about the I think you had a question that beginning that was about, you know, pain relief versus addiction. And so I said, you know, opioid receptors are inhibitory, and so this is why they reduce pain. So if you think about that molecular logic, you might think, Oh, they should reduce addiction too, because they're in, you know, addiction there, and therefore they inhibit addiction neuron they shouldn't be addictive. So just to clarify now this works. There's another area of the brain that's called the ventral tegmental area that has dopamine neurons. So dopamine is one of the, you know, transmitters that make us feel good when it's released. What happens in that case is that opioid receptors are not in the dopamine cells. They're in between, theory, neurons that control dopamine cells. So this is actually disinhibiting the dopamine Exactly. So when opioids are on board, they're going to turn off the inhibition of the dopaminergic neurons. And so this is why, mostly in the pain system, opioid receptors are inhibitory, but are in the pain cells, not in the cells that inhibit the pain cells. But for the reward system, unfortunately, they are not on the cells that are rewarding themselves, but on cells that control the rewarding
Nick Jikomes 43:24
I see. So if you go to the doctor and you get an opioid pain medication because you actually have a physical injury, the pain will go away or be diminished because you're inhibiting the neurons that actually generate the pain signal, but it will feel good. You'll feel euphoric and so forth, because you're actually disinhibiting or activating exactly the reward neurons, right?
Gregory Scherrer 43:48
And to pick up on your question with, you know, endogenous opioids, what's interesting is that we are not addicted to our endogenous opioid peptides, right? So what's the difference? And so, you know, these peptides are labile. They're released by the cells. But they, you know, they sort of float around a little bit, and then they're degraded. In contrast, and you know, they're peptides, so they can, they cannot really cross membranes. Well, right? They bind the opioid receptor. They don't go inside the cell. In contrast, something like morphine is, you know, going to be in your body for hours. And so there are several things that happen, right? They they can activate opioid receptors, where, at the cellular level the peptides cannot go. For example, there's data now showing that there are intracellular receptors that, you know, traffic in cells that can be activated by exogenous opioids. And peptides normally do that, don't do that, and they're around for hours. So instead of being like, you know, a fine signal that sort of fine tune neurotransmission, which is what peptides do, these drugs massively activate opioid receptors for hours. So they have very different consequences in terms of how neurons function, yeah. So
Nick Jikomes 44:59
the endogenous. Opioids are spatio temporally precise. They're sort of used where and when they're needed. Whereas, you know, if you take, you know, if you take an opioid pill, it's going into systemic circulation. It's sort of hitting all the receptors everywhere at once. It's sticking around longer. It sounds like there's an analogy there with with cannabinoids, right? Endogenous cannabinoids are, you know, they don't last very long. They're used on a synapse to synapse basis, so they're very localized spatially. But if you take an exogenous opioid like or exogenous cannabinoid like THC, it's sort of hitting all of the receptors at once, everywhere, very
Gregory Scherrer 45:32
similar and very similar for, you know, most drugs that act on these categories of receptors, like the opioid receptors, are called G protein coupled receptors. That's what they're useful to treat disease, because, you know, you can get it once or twice a day and for a laborative, long, long time through signaling of that particular receptor you can, you know, resolve your High Blood Pressure problem or whatever problems you might have.
Nick Jikomes 45:56
Yeah, so, so going back to this notion that, right, we've got multiple sort of layers to pain. There's the sensory side, where you first detect the pain, there's the emotional side, the actual subjective experience of pain, the aversiveness or unpleasantness of it, and then there's these cognitive modulations of that experience. One of the things that you've studied recently, and work done some interesting work, out the circuitry behind this has to do with the placebo effect, which is pretty well known, especially as it relates to pain. But nonetheless, I want to start out very basic here. So what is the placebo effect as it relates to pain?
Gregory Scherrer 46:33
Right? So placebo effect is something that we know very well in the pain field for several reasons, but one of them is that we just talked about opioids quite a bit. One of the reasons why opioids are still used clinically is that we don't have good alternatives. One of the reasons why what has happened is that many drugs have anti clinical trials, and a number of them have failed, not because they didn't have some level of pain relief, but because they didn't beat the placebo group. So when you do a clinical trial to get FDA approval, you have to demonstrate that your treatment is useful, that it's better than the reference treatment, but you also need a control. And so in the pain field, it's known that people who are in the placebo arm often have a very strong response, so they have a level of analgesia that is high, that makes it hard for the new drug to demonstrate efficacy beyond the placebo effect. And so it's a it's a reduce reduction in pain perception that results from the expectation that pain is going to be reduced or go away in the absence of any actual treatment,
Nick Jikomes 47:44
and do we understand what the physiological basis for that effect is? So, for example, when people believe that the sugar pill is going to relieve their pain, do they have a release of endogenous opioids or something like that,
Gregory Scherrer 47:59
right? So there's been many, many studies on what is placebo and how it works. Much of it has been done through human imaging studies. That's in part because we'll get to that. But placebo is not easy to model in mice, because it's through verbal suggestion, where your doctor is going to tell you, I'm going to make this prescription, it's going to be great for you. It works in everybody. And then you have this placebo effect. It's hard to model this in the mouse, but so yeah, what happens in that case is that you you're forming this expectation. And sorry, going back to your question, that was,
Nick Jikomes 48:39
oh yeah. Just like, so the placebo effect. So I'm told by a doctor that this pill will make me better. It's a sugar pill. I don't know that, but I believe it's gonna make me better, and then I actually experience pain relief. So it's a real effect. Is that due to endogenous opioids or something
Gregory Scherrer 48:55
like that, right? Yeah. So, so these are, you know, a few things we know. So through the human imaging studies, we know the parts of the brain that are activated during the placebo effect. And the other thing we know from studies by John Levin and Howard fields in the 80s is that if you give Naloxone to people, you're going to reduce the magnitude of the placebo effect. So opioid blocker, yeah, an opioid receptor antagonist. So the same molecule that's given in Dr to save people's life when they when they overdose. So this blocks all opioid receptors. And so the fact that you have a reduction, sometimes elimination, of the placebo effect in the presence of naloxone tells you that it is indeed a release of endogenous opioid peptides. That is, you know, the the molecular mechanism by which the placebo analgesia is caused. So somewhere in our brain, when we have an expectation that pain is going to get better, some neurons can release endogenous opioids, and that elevates pain threshold. Pain is more, you know, acceptable, or seems to be less intense. So
Nick Jikomes 49:56
the opioid system is involved in the placebo effect. If you you. If you block, if you use an opioid receptor blocker, can you prevent the placebo effect from happening? Yeah, that's
Gregory Scherrer 50:06
what that's what happens, yeah. So indeed, in these studies, sometimes, you know there are other mediators that that are involved, but usually, in most studies, there's a strong reduction in the placebo pain relief when opioid receptors and
Nick Jikomes 50:23
so it sounds like in human beings, we can kind of figure out with imaging what parts of the brain are involved in the placebo effect. We can figure out that the opioid system is involved, that you could block it with an opioid blocker, say, but we can't really get in and understand the circuitry and find detail. To do that, we'd have to do invasive experiments in animals. And as you mentioned a few moments ago, it's really hard to study the placebo effect in mice, because how do you build that expectation into them? But nonetheless, you guys seem to have come up with a way of doing this.
Gregory Scherrer 50:51
Yeah. So one thing mice are pretty good at is associative learning, and so what we did was to design an assay where we have two chambers that are next to each other with a small door in between. And so if you put a mouse in that environment, the mouse can free move between the two chambers. And so what we have is that in that assay are also distinct visual cues in the two chambers. So black and white lines that are either horizontal or vertical, and mice are very good at distinguishing these two things. And so then we are going to condition the mice. So it's a condition based possible analgesia model. The way we're going to do this is that we have the ability in this test to change the temperature of the floor. Okay, so we start that. It's a seven day test, where we start by three days of arbitration, where the floor is is at three such as degrees, which is very comfortable. Mice like it. And so they are naturally like us, driven to explore. So they're going to spend their time moving around, transitioning between the two chambers and getting familiar with the environment. And we do that for three days, and then on the on the fourth day. So from day four to six, we are going to treat them. We are going the first chamber where we place them. At the beginning of the assay, we're going to set the temperature of the floor at a noxious temperature, 48 Celsius degrees. So when we put mice on that floor, they now know the environment they will explore to try to escape heat pain, and they will learn that if they move to the other chamber that is still at such 30 such as degrees, pain will go away. So they will experience pain relief by transitioning from the first chamber to the second chamber.
Nick Jikomes 52:38
I see, so you're teaching the mice. You've got two chambers. They look a certain way, they smell a certain way. One of they start out at the same temperature, but then after a few days, you you make one of the chambers too hot to handle for the mice. They don't like it. And they learn okay if I go into this one bad, too hot, and if I go in this one comfortable. So you just train them to discriminate these two locations based on temperature. And
Gregory Scherrer 52:59
we started test by putting them on the hot side, so they have no choice. They have to find a solution to their pain problem. And so they the treatment that they find is to go in the other chamber. And
Nick Jikomes 53:09
so you can then directly measure and quantify how much they're expecting the other side to be hot, how much they don't like it, by how much time they spend in the other chamber, exactly.
Gregory Scherrer 53:17
And so they're, they're really good at this after just, you know, one day, or certainly after three days, you see that they spend almost all their time in the chamber that's not hot, and their latency to transition from the hot chamber to the to the chamber that's that is at 30, such as degrees, is getting shorter and shorter. So they relearn the task well. And so here we think we have after six days recreated the expectation of pain relief. So then the other component that we need to test that is that, is there actually pain relief? Do they experience less pain? And so for that, on day seven, we're going to trick them one more time. Now we going to set both floors at 48 such as degrees. So they've just learned that where they start, they just have to move to the other side and experience pain relief. In that case, they go on the other side, it's still hot and it's the exact same stimulus intensity, so they should perceive the same pain on both sides. However, when we measure pain with our assays, so we look at leaking of the pause and movements that suggest that mice are perceiving pain and want to make pain stop, rearing, jumping to escape. What we see is that mice still show much less pain behaviors on the side that is associated for them with pain relief, even though it's the exact same same
Nick Jikomes 54:36
stimulus, intensity, same temperature, but they're showing less avoidance behaviors, or less vigorous avoidance behaviors, presumably because they have this association that's that's baked in. Yeah,
Gregory Scherrer 54:48
exactly. And going back to the opioid part, if we give them Naloxone on day seven before testing them, we lose this analgesic effect that's related to the. The expectation of pain relief,
Nick Jikomes 55:01
I see. So you've created a true expectation, then you can actually, you can actually block the effect. You can give an opioid antagonist. And now when they go to the second side that used to be comfortable, it's now also not just like the first side. They respond with pain related behaviors, avoidance behaviors, that are just like the other side,
Gregory Scherrer 55:19
right? So we have two groups of mice, so the mice we just talked about and their siblings that go through the same seven day protocol, but they don't have the day four to six when they were conditioned. And so we compare pain behaviors of mice that have been conditioned to expect pain relief on the right side of the of the assay to those that have been going through the same session, but without the conditioning. And if we compare behaviors for avoiding pain perception in these two groups of mice, we see a strong reduction in those that have been conditioned, even though they are physically exposed to the exact same noxious stimulus.
Nick Jikomes 55:58
So so you can train mice to do all of this stuff. They learn very quickly to avoid the painful side, engage in certain behaviors after they experience a painful stimulus if they go to that side, and there seems to be this opioid system dependent expectation effect, akin to the placebo effect involved. How do you actually then look inside the brain at what neurons are doing while all of this is going on, all right? So
Gregory Scherrer 56:24
that was the first phase, right? It's always for us, sometimes the most difficult part is, how can we model the human phenomenon? So at that point, we felt like we had a good model to study, to study the system. And then, you know, reading the human literature, we found that there was evidence that one part of the brain, particularly the singular cortex, was active during the placebo energy zero task. So we use a number of techniques, but one of them is to use miniature endoscopes that can collect fluorescent signals inside the brain. It's called a mini scope. It's been invented by Mark Schneider, Stanford, so you literally, you
Nick Jikomes 57:02
literally mean, like a miniature microscope that is right hooked up to the animal's head. Yeah.
Gregory Scherrer 57:07
So it's tiny. It's about three grams. And so you can mount this on the mouse head like a hat. And the mouse, because it slide, mice, you know, behave normally. They function completely normally. And so what you can do with this is that you can then use viruses to express in certain neurons that you want to study a calcium indicator. And so when neurons fire action potential, the intracellular concentration of calcium is going to rise, and that's going to change the fluorescent signal that you can then record at the single cell level with this microendoscope that we call a mini scope, I see
Nick Jikomes 57:41
so you can engineer mice such that specific neurons in the brain, in the amygdala, in the cortex, somewhere, you know, basically wherever you want. You can make those neurons literally light up if they are sending out nerve impulses or action potentials. And then, because you've got this endoscope, this miniature microscope, hooked up to the animal's brain, you can actually record when those neurons light up. And so then you can put such animals into the chambers, like you just described a few moments ago, and you can watch to see what kind of activities neurons display as the animals are doing this, uh, pain, pain related learning,
Gregory Scherrer 58:19
exactly. So there, you know, there are other ways to record activity of neurons, but sometimes you have to anesthetize the animals. Or there are, you know, other aspects of the methodology that do not really permit the type of things that we want to do, which is in molecularly defined types of neurons in a freely behaving animal what happens when they perform the task? Yeah, yeah.
Nick Jikomes 58:44
So a strength of this way of recording is that you might not get signals that are as precise or temporally precise as, say, an electrode if you're measuring with electrodes, but you have the advantage that you can record from molecularly defined groups of neurons in particular parts of the brain, and the animals can walk around and behave just as they do in normal conditions, exactly. And
Gregory Scherrer 59:06
so when we use that technique in our placebo analgesia task, what we found is that as mice are learning the task, that they moving from chamber on the left to chamber on the right from heat to like comfort just before they cross and they get on the other side, these cells in the singular cortex light up, but not all cells. We found that it's a particular subset of cells in the singular cortex that light up. And what's really surprising in that study is that it projects to an area of the brain that's not known as being one of the major center for pain modulation region in the Ponce, that's the pontine nucleus.
Nick Jikomes 59:47
And so you know before, before going further with these results in terms of what you guys found, so the the cingulate cortex, what do we know about it? What? What is it sort of known for doing? Before you even went into the study, it's.
Gregory Scherrer 59:59
It's a very important region for pain perception, and particularly for the affective and cognitive aspects of pain perception. To the extent to which there's actually it's still happening a little bit, but it used to be a major procedure whereby you could treat intractable pain through surgery by doing something that we call a single otomy, where you will lesion the axons of these single cortex neurons that leave the cortex. And that's a way by which you can remove some of the emotional unpleasantness of pain. Wow,
Nick Jikomes 1:00:33
when, under what context would that happen? It
Gregory Scherrer 1:00:37
seems a little Barbar but you know, pain is so is so difficult to to live with that for some patients, it's been maybe a little less, but it's a surgery can still be performed where you can reduce the affect that is associated with pain experience, which, again, is really what's problematic for patients with, you know, severe chronic pain
Nick Jikomes 1:00:58
well. So if you have, if you have severe enough chronic pain, and it's not you can't help it through drugs or other means. It's almost like epilepsy, like there's severe forms of epilepsy, which, you know, you just can't treat them other ways. So they end up going in and just slicing part of the brain. And that's what actually helps, yeah.
Gregory Scherrer 1:01:12
So that's, you know, cutting out the the axons of these cells and preventing them from communicating. This, you know, affective signal, effective signal, yep.
Nick Jikomes 1:01:23
So, so the animals are experiencing pain if they walk into one side of the chamber, there's an emotional component to that. Obviously they're learning, right? So there's they have to think, I guess, and do this. So there's a cognitive component for those reasons, I imagine, because you already knew the cingulate cortex was implicated in these types of things. That's probably why you pointed your microscope there. But then the surprising thing happens that you mentioned briefly a moment ago, where the neurons that were lighting up the most were projecting to a region called the pons, which you probably didn't expect to see. No,
Gregory Scherrer 1:01:54
we did not. So the simplest way by which we could explain that cognition and for example, a positive expectation about about pain, that pain is going to be relieved, would work is, for example, a single cortex that we know is reciprocally connected with the amygdala would send a signal to the amygdala to decrease activity in the amygdala to reduce the aversiveness of pain. There are a number of other regions that we were expecting, you know, medial Thalamus, some parts of the striatum, but that's not at all what we found. So this main projection to the pontine nucleus was really intriguing, because the only output of the pontine nucleus is the cerebellum, and the cerebellum in, you know, pain neurobiology has always been a little mysterious. It's not easy to study. It's much more studied in in the movement field, where we know it's essential for motor coordination and motor learning. In the pain field, it's often seen as activated in human imaging studies. But there's this issue that, of course, when you're presented with the noxious stimulus you withdraw from, it always involves movement, right? Yeah, and so perhaps this signal in cerebellum that is seen during these experimental studies of pain is due to movement, or even just to the intent to move. What we find in our study is that the part of the cerebellum to which the pontine nucleus that receives this expectation signal from the scenery cortex projecting cerebellum is not the motor areas that are particle areas of the cerebrum that are more related to cognition, and this is where this signal is going. And
Nick Jikomes 1:03:36
so, so you know, classically, you know, in textbooks and things as you mentioned, the cerebellum is associated with movement and motor coordination and motor learning. So historically, it's really been thought of as a motor region, not as a cognitive region. But, you know, based on this work and based on some other work that that's been coming out, it seems like the the cerebellum reputation is changing, and it is, in fact, involved in various cognitive operations. Very much.
Gregory Scherrer 1:04:02
Yeah, so like you said, it's been studied in the context of movement and partly modern learning. Now there's evidence that the cebum learns many other things, right? So there are other publications that show, for example, that some types of neurons in the cebum, known as granular cells, can encode the rewarding aspect of a stimulus, such as in a study, when mice leak sucrose, which they like, there are some cells in cerebellum that are turned on. So it looks like the cerebellum is important to learn about pain and some other things. And, you know, do many more things beyond motor control. So we're quite excited now in understanding what the cerebellum does with that information, and now it's about to to reduce pain. And so we've started some some studies that are not part of the of the paper that just came out, where we find that, in fact, the cerebrum is very well placed to control pain, because in terms of outputs, you have. Several nuclei that are well connected to important places of the pain circuitry, notably the descending pain control circuit, the periaqueductal Gray, but also projections back to Thalamus, to single cortex. There are even proteina cells that project to the parable area. So this is this first region in the brain that gets information from the spinal cord before sending it to the amygdala. So when we look at the connectivity of the cerebellum, it actually makes a lot of sense that it can modulate pain. And there's this also intriguing association between movement and pain. If you think about when you sprain your ankle or you have low back pain, you change your posture. So that's, in a way, also about expectation, anticipation. You're gonna start positioning your movement in a certain way that will reduce the experience of pain by limiting, you know, activation of sensory neurons that that you know that cause pain. So it makes a lot of sense that the cerebellum is actually an important part of the pain secretary. And so we we want to push for this notion that maybe textbooks that show these ascending circuits that you know, involve Thalamus, amygdala and then different cortical areas, often the cerebellum is not on these cartoons, and perhaps it should be.
Nick Jikomes 1:06:19
And so what are the implications of this work for humans in terms of how we administer and think about placebo effects,
Gregory Scherrer 1:06:27
right there? There are several applications. One first is that's not an application. I mean, it's already an application. In fact, it's cognitive behavioral therapy. So you have three ways to treat pain, drugs, neurostimulation or behavioral therapy. So there's something called cognitive behavioral therapy, where patients can, you know, learn to live with their pain, be more optimistic about the future, and that's sort of retraining their brain to think differently about their painful condition. And we think that perhaps the circuit that's activated is, you know, has to do with single cortex and cerebral in that case, so perhaps it's already in use. What we would like to explore is if we can use these two other techniques, drugs or neurostimulation, to artificially recruit these circuits in the absence of conditioning or placebo, just to relieve pain. And so what we show in the study is that, well, first of all, if we turn off this pathway during the placebo energy task, mice do not no longer have the pain relief. But more importantly, in mice that are naive and have not been conditioned, if you artificially turn on this circuit, this elevates pain threshold, so less pain perception in mice. So if this is true in humans as well, you can try to engage this circuit, either by using transcriptomics, for example, to figure out what's in these cells that we could target to activate this pathway, or use neurostimulation, either in an invasive way, or transcriptional magnetic stimulation to generate activity in this circuit, and relief pain.
Nick Jikomes 1:08:05
Interesting. And so, like, how do we how do you think about too? Like, you know, you mentioned earlier, you know, the gold standard for whether drugs get approved is, do they do better than placebo in human clinical trials? Sometimes they don't, sometimes they do, oftentimes they don't, but when a drug doesn't do better than placebo, but at the same time, we know the placebo effect is real, and it's quite strong, and we know we're starting to undercover uncover the circuit basis of it. I don't know. Is it possible that there are drugs that are sort of working at a similar magnitude as placebo effect, but they are nonetheless going through a different mechanism, and so they're not actually just, you know, they're actually doing something, you know what? I'm
Gregory Scherrer 1:08:48
sorry, yeah, yeah, that's a great question. And you know, one of my take home messages when I when I give these talks, is that perhaps we have to reconsider what's really important to have a new pain medication approved, because the people who are in the placebo group do get pain relief. So if like you say, there's an synergy between the placebo effect that happens and the actual mechanism of action of the drug that makes it useful for people, maybe this is an important consideration and not just a statistical comparison to the placebo group, because the placebo is, we know now there's a neural circuit that does it. There are molecules that are that are released, endogenous opioids and opioids, we know exogenous opioids, are very potent analgesics, right? So it's, it's placing on the field a very high bar that the most potent drug that we have, an equivalent our endospeptides are being released, and that's the thing that you try to beat with the new drug. Yeah? The
Nick Jikomes 1:09:52
bar is that you have to do better than one of the most potent endogenous drugs, for lack of a better term that's inside of us already, yeah.
Gregory Scherrer 1:09:59
Or, you know, pay. Modulation system that is there since, you know, millions of years in terms of evolution, this is what we use when we do yoga or marathon, and, you know, we have decent pain control. So it's a pretty high bar to beat, and the placebo effects are strong,
Nick Jikomes 1:10:16
yeah. And so there's also a question here of variability. I don't know too much about this, but my understanding is there's variability in the placebo effect, meaning some people are very prone to strong placebo effects, and other people much less so in the human literature, is that the case, or in your mice and the experiments that you described a few moments ago, is there variability from mouse to mouse? And the strength of the expectation
Gregory Scherrer 1:10:38
there is, yes, absolutely like in humans, and that's, you know, this cognitive aspect of pain is also what explains pain. Subjectivity, based on our experience, based on the context of where, you know, the noxious event occurs, we are going to have a different perception of of pain. And that's something that we really, you know, interest in studying. It's not easy in terms of methods, because you would, for example, you want to compare two groups of subjects or two groups of mice, and put these mice or humans in the two different groups that are possible responders and possible non responders when you start the study, but you don't know yet, right? So in our mice, you know, we can do the miniscope implants to look at their activity patterns, but we don't know which are the ones that are going to display a very strong effect and those that will not. But we can now, when we have more subjects, we can start doing these correlation analysis and ask if we go even in the details of the molecular content of these cells, what is different in that mouse that had a very strong placebo response in terms of the amount of underdog opioids released the molecules that are present in these cells, compared to the mouse in which the pessimistic mouse you know, that didn't Have a placebo effect. So you really want to understand here what are, yeah, what are the molecular, cellular substrates that explain pain subjectivity, or why we perceive pain differently depending on the context? Yeah. And
Nick Jikomes 1:12:14
what's kind of interesting to think about, too, is like, if, if I think about a clinical trial design, and I think about the participants in that trial. You know, being a participant in a clinical trial, it's sort of inherently maximizing the odds of a strong placebo effect. Because, you know, I have to go to a hospital. Doctors are talking to me. It's a very formal, very fancy setup, and so you sort of naturally are going to build up virtually everyone's expectations. But then you run into this problem of you might actually sort of mask genuine effects of therapies that simply aren't stronger than the placebo effect, but are nonetheless doing something
Gregory Scherrer 1:12:47
exactly, and that's my point. So if you, if you take another viewpoint, which is the, you know, the patient's viewpoint, where I just want to be better, right? I want to have less pain, those who have been in the control group and got the placebo, lived a better life at the time they were doing the Tryon right, because their pain was was reduced. So maybe this is what is important. And if the if, obviously, we would want the drug, you know, molecular mechanism of action to add something to this. But, but again, it's a pretty high bar, maybe to try to beat endogenous opioids. So far, it doesn't work very well.
Nick Jikomes 1:13:22
And so what kinds of studies are you guys doing now or doing next that are related to this work?
Gregory Scherrer 1:13:28
So related to this work, we want to understand how it works, so how this pathway is able to reduce pain. So we're looking at the cerebellum, how the cerebellum is connected to the rest of the brain. This is the placebo effect. We're also quite interested in the opposite, which is known as the nocebo effect, where some subjects can develop something that's called as pain catastrophizing, where pain is perceived as worse than it should be based on the injury or the disease or the actual, you know, stimulus. And so we we have some Prem. So we were just talking about subjectivity, and, you know, inter neural differences. We have previous studies where, if we start, for example, with 10 mice, and we will briefly expose to the hot floor every day, right, so that they get used to it, but they they don't like it, right? So at some point, you put them on there, and, you know, at some point it's enough, they jump and they escape. And you do that every day. And so every day, the latency for the jump response is, you know, lowered. After a few days, you just get it, you put them on it, they're like, Okay, I don't want to be there. I just jump. And then after a few days of conditioning like this, we are going to put them back in the exact same context, on the same plate, but the plate is no longer turned on, so it's at, you know, comfortable temperature. And you have a certain proportion of mice, between one and three mice, depending on on the, you know, on the experiments, that will still jump, even though there's no reason to jump. So they have a very they're very pessimistic. You. Yeah, and very negative expectation about this based on the context, while it's not that bad on that day. And so what's different in the brain of that mouse compared to the the other mice that that that have made the right decision? Because in the wild, this mouse, by making the wrong move, can also be eaten right when you're in pain, you have to hide, you have to protect yourself. So this decision making is really important, as we discussed at the beginning. And so that, you know, these are the two things, placebo, Nocebo, how we make decisions. This is a part of pain that's at least in terms of basic science. And you know, cellular, molecular mechanism is a little bit understudied compared to all the work that's been done in the peripheral nervous system. So that's one area that's really interesting for us, and we generally, we're interested in phenomena in humans that are causing strong pain relief and that we think we can study. So another example of projects we have that's related is distraction. Don't know if you have kids, but anybody who has kid, your kid has to go to the dentist. You're gonna give them the you know, your your phone or the iPad or whatever. And dental pain no longer exists, right? So destruction is a very important way to to generate analgesia. Same thing. Can we model this in mice? What are the circuits that produce analgesia from destruction? And along the lines of, you know what we do with placebo when we find the cells then, is there a way artificially to take advantage of that circuitry that exists in our body to find another way to treat pain? Well,
Nick Jikomes 1:16:41
this has been fascinating. Gregory, very interesting stuff. Is there anything you want to reiterate that we discussed, or any sort of final thoughts you want to leave people with that has to do with pain and pain perception and how we experience pain,
Gregory Scherrer 1:16:55
maybe pain treatment, because I think that's, you know, with the opioid epidemic and many, many people being in pain, this is really a priority. Maybe this notion that ideally we want to have as many new painkillers as possible, so some that work in the periphery. But I think it's really important to study these other aspects of pain, the emotional aspect of pain, the other cognitive, the cognitive aspect of pain, so that we have different treatment options and ideally, things that we can combine. If you think about other fields of medicine, infectious disease, HIV, metabolic disease, diabetes, cardiovascular disease, high blood pressure, cancer, many patients get clinical benefits for having prescribed multiple drugs that act on different aspects of the disease. So I think one thing that we could try to do more in the pain field is to have drugs that we can combine that act on sensory system, on emotional system, on cognitive system, to over reduce the experience of pain, and that, I think could be really useful for patients. Excellent.
Nick Jikomes 1:17:57
Well, yeah, again, this was fascinating, and I thank you for for your time.
Gregory Scherrer 1:18:01
Thanks so much. Nick.
Neural Basis of Pain, Placebo Effects, Opioid Pain Relief & Addiction | Gregory Scherrer | #177