How Does Touch Lead To Pain Or Pleasure?

25:44The beauty of working in rodents is that many of the genes and molecules, the neuronal pathways I've talked about, are highly conserved, right? The wiring and the neuroanatomy of the pain system is very much shared between rodents and humans, okay? We really do operate under the space that some of the things we discover can have direct application. I'll just mention an exciting example is some papers in the early 2000s and humans showed that there was a family of patients who can't feel any pain whatsoever. And there have been these rare cases throughout history of people who just don't feel any pain.

26:17It's actually like not a good thing because many of these patients don't live long lives. They actually injure themselves, You know, pain is from an evolutionary perspective, good for our bodies. Good information. It's good information. And especially during development, you learn like to not touch that hot stove, right? To not do things that could hurt you. Anyway, there was a family of people in Pakistan who didn't feel any pain. So you could do genetic studies and kind of trace the pain insensitivity. And the scientists went over there and did really heroic work where they sequenced their DNA and they found they all had mutations in a single gene.

26:53It's called NAV 1.7. It's a voltage-gated sodium channel, okay? This channel, this protein, seems to be very specific to pain neurons in the periphery. So if people don't have a functional version of this protein, they won't feel pain. And then conversely, there's another class of patients that have the exact opposite. It's called like Burning Man Syndrome, where they just have spontaneous pain, mainly in their extremities throughout life. It turns out the mutation is in the same protein. This one protein, you don't have it, no pain, too much of it, lots of pain. Same thing happens in rodents and many other mammals we've studied.

27:32This voltage-gated sodium channel is very important for the activity of the neuron, propagating an action potential, and specifically in pain neurons. And in fact, there are new drugs that have been improved that actually block this particular receptor and seems to improve pain for many patients. There's another version of this protein called NAV1.8 that seems to have similar functions. So maybe some of the therapies in the future will kind of do a double block of both of these proteins. And this work, a lot of it is going on in rodents. Here's one example of a lot of like back and forth and crosstalk between animal studies and actually direct translation.

28:12One of the things we're very excited about doing in my lab, I mentioned these behavioral tools and what our behavioral tools we can delineate in rodents, the sensory component of pain versus more emotional components of pain. And so there does appear to be an emotional network in the brain, areas like the amygdala, the interior cingulate cortex, insular cortex, and some other areas that seem to confer the emotional component of pain. How that works, you know, we and others are hard at work. But the point I want to make back to your question about translation, it would be very nice if we could have therapies of the future that don't target the pain at the level of the peripheral nervous system, at the level of sensation, but alter it at the level of perception and maybe alter the negative emotional state of pain because maybe you don't want a world where you can't feel any pain.

29:04As we mentioned, it does serve some purpose, right? But if we can remove the hurting component, but keep the sensory and tact that maybe this is how we want to tackle pain. But we have to know how that works at a deep level to be able to kind of target that. But I can envision a future where that's possible. It's so interesting. I don't even want to know how they discovered that this family felt no pain. I don't even want to know what happened to them that brought that to the scientific community. You know, in some countries, there are a number of street performers, actually, who do things, you know, they'll walk on hot coals or like do things.

29:37And, you know, One of the kids in that family, he would do tricks. He would climb the second floor building and jump off and just pop right up and everyone would cheer and so these sorts of things. The ability psychologically to overcome pain or to mitigate pain is so fascinating to me because, of course, we act like psychological is disconnected from the body. But what we really mean is what the neurons are doing in the brain. And I think that there is this kind of culture of magical thinking that we can transcend pain, but there might be a sense in which that's literally physiologically possible.

30:12That is very true. And what you're talking about, too, is one of the reasons I got into pain and pain research. There's a really nice book called The Challenge of Pain written by Malzak and Wall, two really pioneering scientists in our field who came up with one of the most important theories in the history of pain, the gate theory of pain. But anyway, in this book, they lay out like as you're getting to all these cases where people should be experiencing lots of pain, but they don't. You know, some people who you can hypnotize them and their pain goes away. And there are too many anecdotes like this to think that it's not a real phenomenon, a related phenomenon that we do know a little bit more about.

30:50And people are starting to model this in rodents, which I think is really cool, is the placebo effect, which is very strong for pain. actually. If they have a strong expectation and belief that this thing will alter my pain, it can actually work. And conversely, if you tell someone, I'm going to give you this treatment and it hasn't worked for anybody, everyone says it's crappy, but you're out of options and I just want to try it anyway, they'll come back and say, doc, you're right. It didn't work. And it could be the same medicine, right? So this expectation and belief of pain relief is very strong.

31:21We now know So it definitely taps into our endogenous opioid system, our endogenous system to kind of control pain. It taps into these things. If you block like opioid receptor signaling, you can block many of these effects. It's not magic, but it's acting on defined neural circuits in the brain. And there are many labs that are hard at work, Greg Corder and Matt Banghard and Greg Scherer, amongst others, to try to map how this is working. Amazing. I did see that you had talked about the pain addiction connection. particularly with opioids. Correct. And what you're saying is there's a biological substrate reason why there's a connection between pain and addiction.

32:02Yes, that's very true. We have an endogenous opioid system that can be activated by many things. And we have these opioid receptors all throughout our body. I mean, the discovery of the opioid receptors back in the late 1970s in rodents, they could stimulate this one area in the brain, the parietal ductal gray, and you could get really strong pain relief, the rat tail would be on the hot plate and you stimulate this area in the brain, then they don't respond. And they found that this area is flooded with opioid receptors. And this response was dependent upon activation of the endogenous opioid system.

32:37Opioids can be powerful relievers of pain and the receptors are everywhere. This is why they also have so many unwanted side effects because they act on the pain system, but they act in the periphery, they act in the bladder and the gut and the DRG neurons, the spinal cord. They're loaded everywhere. So they come with so many unwanted side effects beyond just pain relief. Wow. So many surprising and very immediate things to think about there. I think anyone listening to this can relate. I didn't really appreciate that the opioids, of course, I knew there were pain relievers, I guess. I knew that was the story.

33:15People were originally going to seek pain relief, but I thought it was an external consequence. You know, I didn't think it was targeting the same biology. That was really surprising to me that, and that we have this endogenous natural mechanism that can do the same thing, which is why it suggests we can overcome pain psychologically to some extent, you know. I guess it also just shines a light. There's a lot we don't understand about how our own minds work and bodies work. I believe it. Watch any magic trick and you'll see that. But no, I mean, in something as corporeal as pain, I mean, right, that's not an illusion.

33:52And yet maybe some aspects of it are an illusion. It's confusing. Yeah. I don't know that it's an illusion. I mean, things are triggered. There are signals, right? But you can flood the receptors with other chemicals. I mean, that's really what it sounded like to me. And it has an interesting evolutionary role, right, pain, in terms of survival. It's important that we don't go running if our foot's broken. And it is very disadvantageous to survival to have no pain receptors. And they know that there are certain people who don't feel pain. So just appreciate when your back hurts at the sink, Steve.

34:29Yes, I see. I should be grateful for my pain receptors. Yes, exactly. Well, after the break, we're going to leave pain behind and we're going to talk about something a little more pleasant, and that is the wonderful naked mole rat.

34:54Welcome back to The Joy of Why. We're speaking with neuroscientist Ishmael Abdusabour, who studies the brain and our sense of touch. I do want to turn to your important work in Antithesis to Pain, which is about gentle touch and social touch and pleasing touch. So I'm both curious what drew you in this other direction and, of course, how the receptors involved in gentle touch or stroking touch are different from pain receptors and why this is so important in the social fabric of possibly both animals and humans. Great question. You know, as I was ending my postdoctoral studies at UPenn and opening my lab about eight years ago, I started to think about, OK, who will want to come work in my research lab?

35:43And if I only have projects studying paint, maybe that could be off-putting. Could be some people who prefer to study, you know, social touch, repetitive, something good. And that was the case. Yeah. I want to pay homage to a colleague of mine, David Anderson at Caltech. He published this paper that I read as a postdoc, and it was just so fascinating and exciting because what they had discovered was that there was a population of neurons that seemed to be activated by stroking touch on a mouse's skin, consistent with these being pleasurable social touch detectors. In that paper, they didn't look in the brain and they hadn't linked it to any behavior.

36:18So I thought this was right for someone with my background in genetics and molecular manipulations, really careful analysis of behavior, and also linking that with brain imaging. So the thing that differs between these neurons and this pathway in pain is that it's a different molecular population. These neurons happen to express, at least in the mouse, this gene called MRGPRB4. It's a tongue twister. They do express piezo channels, this other mechanosensor. I'll tell you that's important. So they're definitely mechanosensory neurons. What makes them special is their constellation of genes they express that's different than some of the other classes that mediate other types of somatosensation.

36:58Their wiring, where they innervate the hairy skin, areas that are normally touched, the neurons that they're connected to in the spinal core and from spinal core to the brain. Basically, the whole pathway from skin to brain is going to be different than a pathway for hot or cold or pain. So the whole circuit, the anatomy, the wiring is totally different. Wow. So highly specialized again. Highly specialized again. For example, if you stimulate like a pain pathway to animals, like quickly, they give you signs that this is painful and they don't like it, they avoid it. But with this pathway, they give us signs that they actually like it.

37:37They want to spend time in environments where this pathway is stimulated. And if we look at, for example, dopamine release in the brain's reward center, we can see that stimulating this pathway in the skin leads to like this dopamine release. Or if we genetically ablated these neurons, we see social touch behaviors are greatly kind of diminished. Now, some of our ongoing studies where we're really excited because this gets to your question again about like why it's important and translational impact in humans. You know, we think this pathway is also important for the ability of touch to relieve stress and anxiety and depression.

38:11When you're down or going through some negative emotion, Just think about a hug from a loved one, a parent, a friend. It can really calm you down and make you feel better. We appreciate this phenomenon, but how it works at a molecular, cellular, neuronal level is almost completely unknown. The skin-to-brain pathway for social touch that we've been discovering and elucidating, we think could be important for that. And we have really strong evidence. It's unpublished, but hopefully, you know, maybe later in this year, we'll submit this paper showing that activating this pathway can relieve negative states, which is really exciting.

38:44and we do think has direct therapeutic potential. Maybe we can even think about treating diseases of the brain, chronic stress, not in the brain, but by targeting neurons in the skin. Wow, fascinating. Now, there's this research that you've done where you have genetically altered mice to become sensitive to blue light so that instead of physically stroking them, you can illuminate them with this blue light and they have the experience of being gently touched. So I have many aspects to this question. One is what a crazy thing to do. That's not a question. And the other is, are we going to genetically alter human beings so that they can do blue light therapy as part of this attempt to heal certain disorders of the mind?

39:31Yeah, it would be nice if we get there one day. So this technology is called optogenetics. And I think it is one of the most important technologies in all of neuroscience. And hopefully there's a Nobel Prize on its way for some of our colleagues. But anyway, this shows that the beauty of like evolutionary biology and looking across diverse species, there's this protein and algae that allows the algae to propel through these muddy ponds to blue light. It's an ion channel, a non-selective cation channel, which just basically means there's a part of the protein that when blue light hits it, the channel opens, it allows positive ions to flood into the cell that expresses this protein.

40:08This is like perfect for neurons. neurons are electrically excitable cells that fire to a positive ionic current flowing into the neuron. So if you can put this special protein on the surface of your neuron through some sort of viral genetic engineering, you can confer ability to directly activate these neurons in this way. So part of this project that we did some genetic engineering, crossing mice together to put this blue light sensitive protein only in these neurons, and we can just shine light directly to the skin, as you mentioned, to confer behavior. Now, to do this in humans, one would have to get to a point where you could do like gene engineering to add this protein to cell types of interest.

40:49People are doing this now to treat, this is not our work, but to treat like forms of retinal degeneration and blindness actually is really incredible. So maybe there is a pathway for using this technology to treat people. You were discussing similarities in how certain neural networks are working for mice and for human beings and some of these complex systems. But you famously work with naked mole rats. And who doesn't love a great naked mole rat colony? Of course. Please, for those who are not in the know of the extraordinary naked mole rat, can you describe them a little bit for us and why their colonies are so unusual in the rodent kingdom?

41:28Yeah, they are amongst the most fascinating animals I've ever encountered. Some days we're just like, what are we studying? Some days we literally just sit there and just there. Watch them? Yes, yes, yes, because their biology is so fascinating. But some of the things that really excite us about them. So for one, they don't feel many forms of pain for reasons that are not fully clear. They seem to be immune or recalcitrant, unable to get cancer. They're long-lived for rodents. So they live about 30 to 40 years. Wow, that's a long-lived rodent. Yeah, yeah. Most mice and rats, they only live one to two years.

42:01And they don't really have traditional no signs of aging. So when they die, they just die. You can't look at them and age them. They don't seem to have any like cognitive or physical decline. They just die. And they're highly social. And this is the thing that we really keyed in on my lab to date. In the last three plus years or so, we've been working with them. They're actually the most social animals in the entire mammalian kingdom. So one colony can contain dozens or hundreds of animals all living together in a really tight-knit colony. And they're driven by this really single dominant queen who's the matriarch that kind of guides the whole society.

42:38And all the other animals are essentially workers and drones and are reproductively suppressed in the presence of the queen. She's the only one who mates with one or two like breeding males in a colony. And she continues to give birth her entire life. So no menopause or signs of slowing down. And so as she has a litter, they never leave. The colony just gets bigger and bigger and bigger. OK, they've decided that it's best for their survival of their colony to do everything together. OK, they chiefly come from East Africa, Kenya, Ethiopia. They live completely underground as well. And the leading hypothesis is that, you know, maybe in this dry, arid desert climate where food and resources are not plentiful, there was easier to have a communal form of living such that some animals are foraging and hoping to stumble upon a tuber like a sweet potato.

43:31And if they do, like the whole colony is alerted and they all can feed off that together. It's insect-like. It's very insect-like or bee-like, but they're mammals, which is very interesting. So, you know, we want to know, like, how does this pain and sensitivity work? How does, you know, in this highly social life, like how is it set up? How is it maintained? How do they even recognize one another, especially because they're essentially blind? And they're hairless. So there's a lot of skin-to-skin contact. There's a lot of skin-to-skin contact. They crawl right over each other. They're always touching.

44:03Even if you make the colony really big and you go to look at them, they're always like on top of each other. They just are always touching, you know. And from our early studies and observations, it appears that, not saying other senses are not important, but touch is certainly outsized. You know, most of their sensory cortex seems to be dedicated to touch. So they've lost the visual parts of their sensory cortex because they're blind. But the somatosensory cortex, the touch cortex has like encroached upon it. So we think they're like touch specialists and they might be able to do things with touch that other seeing animals do with vision.

44:37Like communicate and recognize one another and know who it is that they're interacting with. Wow, fascinating. And so is there a sense in which we're trying to understand human social interactions through touch by studying the naked mole rat? or are these just two disparate fields of study? I hope they're not disparate fields of study. One could even make the case that their long-term stable relationships are more akin to human societies than a mouse, which is the predominant model system used to study these things, right? We have long-term stable relationships. You know people for 10 or 20 years, or you see a friend from college or whatever, you remember them.

45:14And these sorts of dynamic relationships that we see in their colonies, we don't see like in other animals. So I think there are like principles that we hope are very similar and could teach us about societies. You know, I think one very exciting idea is that if we can learn like the principles, the genes, the molecules, the neural circuits, the neural networks that they use to like cooperate with one another and you share resources, like maybe some of that can be used to like inform human societies and how we can better cooperate given limited resources, for example. In human societies, touch is a sensitive issue.

45:55Yes, no, it's very true. Pardon the pun, but there's an important role, obviously, that social touch plays, both aversion and appeal. Are you thinking about this in human society, or is that kind of a meta level that you dream about maybe when you're walking down the street, but isn't really part of your actual research? No, we do think about that. That question we're actually trying to address on the mouse side of the lab, not in the naked mole rats. maybe in the naked mole rats one day, but right now we are working on this. It's really fascinating, as you mentioned, right? If you're in the comfort of your home and a loved one strokes you on the back or arm, it may feel good.

46:34But if you're on the one train or something and someone touches you like that, right? You want to recoil and it's not going to feel good, but it could be the same touch to the skin. So then how does your brain know that this touch is in a good context and is in a bad context. There must be some sort of gating in the brain that allows you to quickly like approximate how you should respond. And how does that all work? It's unclear, but I think we have good approaches to kind of study this. Back to the mouse, I talked about those neurons we discovered as part of like that positive valence social reward pathway.

47:06Now, if we give animals, mice, that same stimulation, but we pair it, they've learned to associate with something negative, like a shock. And now we do that optogenetic stimulation to activate the neurons. The animals don't have a positive response, have a negative response. So we can easily like dial in like good touch, bad touch in the animals and read this out. So now we're saying, well, how does this look in the brain? Okay. There's one area in the brain that we've become very excited about called the orbital frontal cortex, the frontal area in the front of the brain that appears to integrate sensory components and high level like learning and planning.

47:45And we think there might be neuro ensembles that are talking to other areas of the brain to let the animal know, like if the animal is in a good state for a touch to be perceived as good, or if the animal is somewhere where they're afraid or anxious or have had a bad experience with it, such that now this gate to like the positive balance networks won't be activated. So early days of this project, but we're trying to figure out how this works at the level of the brain. A lot of what you're raising taps into going back to metaphysics, right? So we began with Descartes. I think, therefore I am, you know, consciousness is all important.

48:25Going down deep into genetics, molecular biology, neuroscience. And now it's kind of, to my mind, the questions start to come back again. Yes, yes. How these neurons translate into this mental world, this interiority, this experience. And I guess I just wonder how much at the scientific level you feel we can approach this really difficult question of why does it feel like something? It is a wonderful question. And one of the things I'll say is that I also have to appreciate my limitations as a molecular biologists, neuroscientists, right? Some of these questions may be slightly outside of the realm of where we can approach, you know, especially using a mouse model, right?

49:09I think there are mechanistic studies we can do in animals, but I do not think we can reach the highest levels of these high level cognition and consciousness in a rodent model. And this is where I think folks like me, we need to be interacting with cognitive scientists, people in psychology, people in other spaces. There's too much of a disconnect between neuroscience and psychology. We're not talking to one another, but we're both studying the brain and the mind. The neuroscientists tend to use animal models and are doing the work I've talked about, very mechanistic, whereas the psychologists are doing really beautiful work, but they're more tapped into the human experience.

49:47The more we can talk to one another, I think we'll be able to address these higher level problems. And this is part of the institute I'm in, the Zuckerman Mind-Brain Behavior Institute. Maybe this is a plug for our institute, but, you know, this is something that we try to do because this is the only way we're going to solve the brain and the mind by bringing people together who think across scales. Fascinating. I think you've portrayed this very well in your responses and in this conversation, which has just been so intriguing. But there's a question we like to ask here at The Joy of Why, and that is, what brings you the most joy or fulfillment in your work?

50:25Yeah, I think I would answer that in two ways. So one is just discovery, okay? When we have that kind of aha moment, that moment of insight where we say, oh, my goodness, this is it. For example, something we're very excited about that we all can relate to is lactation, nursing, that occurs in mammals, right? Now, we've known for a long time that, for example, with nursing, there's a suckling stimulus on the skin from the child to the mom or the pup to the mom. And that physical suckling stimulus is enough to mediate milk release. There's like this neuroendocrine reflex that goes from the skin up to the brain, back to the tissue.

51:06The milk comes down. The baby, the pup gets it. It all is initiated by, in part, by touch. touch neurons that mediate that. In the last few months, we've been able to discover and put in a molecular handle. We found the neurons that mediate this. When we made this discovery, it was just like jumping for joy. It's like the thing that we and others have been looking for for a very long time, like we cracked it. And the data looks so beautiful and convincing. Like those are the moments that I really live for where we can go from just not knowing to at least at that moment, we might be the only people in the world who like have appreciated something.

51:49Those are the moments that we live for. So discovery is the thing that really drives me and brings joy to my life and mentorship, right? Helping people achieve their dreams and goals in life and kind of working alongside them. I also live for that too. And sometimes that's just as like exciting for me as discovery. Thank you so much for taking the time to bring those ideas out of the lab and share them with us and with our audience. It's just been a pleasure, Ishmael. Thank you. Thank you. You've been great. You really pulled a lot out of me today. Thank you. I'm smiling at that. And so are you, Jana.

52:27We can see each other here. And I just, I had a feeling that he would say something about at that moment, I'm the only person or my team is the only team in the world. There is something about that. It's not exactly vanity, but I think every scientist feels that, every mathematician, right? I mean, is that why you were smiling when he said that? Oh, yeah. Well, also, he was such a lovely person, you know, and you just, you enjoyed that he enjoyed it. You know, that he had this wonderful moment of discovery. And I also, that was incredibly fascinating how he was talking about the speciization of the actual neurons, like they're specialized.

53:07And they're not these generic neurons, but they're intended for these purposes. I mean, I just thought that was also really fascinating. And you can imagine that moment of discovery was just tremendous for them. Anyway, wonderful stuff. I'll give you a hug next time I see you. Very good. I might recoil. Touch is a big thing for me, so don't take it personally. Oh my God. That's hilarious. I'm going to come at you with such a bear house next time.

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55:10Thanks for listening.