Chronic Pain Chronicles with Dr Karmy
Join Dr. Grigory Karmy M.D., a distinguished chronic pain management physician with over 20 years of experience, on a captivating journey through the world of pain relief in his podcast series. Delving into the latest regenerative medical treatments like PRP, stem cell injections, and prolozone therapy, alongside educational discussions on pain transmission and various medical options, Dr. Karmy shares invaluable insights and real-life stories, empowering listeners to find relief and regain control over their chronic pain.
Chronic Pain Chronicles with Dr Karmy
Episode 6: Neurobiology of Pain - Exploring Neuropeptides
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In this episode, Dr Karmy is joined by Dr. James Henry, a pioneering expert in the field, where they dive deep into the neurobiology of pain.
Trained at McGill University and with a distinguished career spanning Western University and McMaster's Michael De Groote Pain Center, Dr. Henry brings a wealth of knowledge on the role of neuropeptides in chronic pain.
Join in on their conversation, as they explore how pain signals travel through the nervous system, the discovery and function of substance P, and the intricate interplay between the nervous and immune systems. They also discuss the challenges and limitations of translating animal model research to human chronic pain treatment.
This episode is a must-list for anyone interested in the cutting-edge science behind pain management.
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Hello, this is Dr. Karmy, and today I just wanted to discuss about neurobiology of pain and the role of chemicals called neuropeptides in chronic pain. And we are lucky to have with us Dr. Henry. Dr. Henry is one of the pioneers in the field of neurobiology. He was trained at McGill University, which was one of the big hubs of neurobiology in neuroscience in Canada and even the world when it comes to neuroscience I think of McGill as equivalent to Harvard or Yale in terms of the caliber of researchers that produced in the past. He also went on to have a distinguished career. He was the head of departments, I believe, of both physiology and pharmacology at Western University in London. And he then went on to be the head of Michael De Groote Pain Center at McMaster, which I believe the mission statement for that was to both do research on chronic pain, but also provide education and medical services for patients suffering from chronic pain. Hello, Dr. Henry.
Dr Henry:Hello. It's very nice to speak to you and it's my honor to be able to speak with you.
Dr Karmy:By the way, if I misspeak or I misrepresent something, please correct me. So let me maybe set the scene first before we launch into discussion about neuropeptides. So when you have an injury of some kind, let's say you broke your shin you have chemical changes and obviously anatomical changes in the leg but that by itself does not automatically cause pain. You have to have some way of sensing that you broke your leg. You have to have signals that travel from the broken leg to your brain to make your brain realize there's damage here. The part of the body that's responsible for sending that signal is the nervous system. Normally the signal is electrical it's sent by the nerve cells from your leg all the way up to the brain. Now the thing to keep in mind about cells is that the cells are not very big. Typically, to see a cell, you need a microscope. So it's very hard to have a single cell that goes from your leg all the way up to the brain. And so what the body did was, it essentially has multiple cells transmitting the signal. Think of it as extension cords. If you have a TV set and there's only one outlet on the wall opposite to the TV set and your cord isn't long enough to reach it so that the electricity can go to your TV, what do you do? You get some extender cords. You take your cord from the TV, you plug it into an extendor cord. It's not long enough, you get another extender cord, you plug that one in, all the way until you reach the socket. The body's solution was somewhat similar. You have one nerve, or if you want to think about it as an extender, a cord going from the broken leg into the spinal cord. Part of the spinal cord, there's different parts to it, one that people are interested in in pain is called substantial gelatinosa. Then there's another nerve that goes from the spinal cord to thalamus, which is already part of the brain, but one of the more primitive parts of the brain. And from there, there's another cell that goes to the cerebral cortex, which is the most advanced part of the brain. This is where the consciousness sits. This is where you realize, Oh, I'm in pain. And then there's other cells from there that go to other places; places like amygdala, which actually causes perhaps the emotional reaction like anxiety that comes with chronic pain. It's not enough to have a sensation. I mean, vision is a sensation. Hearing is a sensation. It is important for the pain sensation to be unpleasant because if it's neutral or pleasant, you are not going to change your behavior. There's another little piece, as I mentioned, there's electrical signal that actually goes from the broken leg up and there's multiple, so to speak, nerve cells, or if you want to call it analogous to extender cords. I'm mispronouncing this word, but here's the thing, extensor cords, you typically plug one into the other. And so electricity can travel directly from one extensor cord to the next. With cells, it's not the same way. You can't plug one cell into the other, or generally speaking, you don't do that. So you have a cell, then there's a gap. And there's the next cell and there's a gap. So the question is, how does electrical signal travel across that gap? The name for that gap is synapse. Well, what happens is when the electrical signal reaches the end of the cell and it has to jump across the gap to the next cell. The cell releases a chemical called neurotransmitter. And that chemical, there's multiple versions of it. The first discovered was acetylcholine, and there's dopamine. There's any number of them. So the chemical leaves the first cell, swims across the gap, attaches to the cell neck to the cell next to it and causes that cell to create electrical signal, which then continues up to the brain. So essentially the sequence of events is electrical signal followed by chemical signal, followed by electrical signals, followed by chemical signal, followed by electrical signal, a little bit like a relay race. The interesting thing about neurotransmitters is that they get released, but they also get destroyed very quickly. We're talking seconds, maybe milliseconds from the time they get released to the time they get destroyed. And if you think about it, that's somewhat logical. If let's say, somebody touches you for a minute and then takes away their hand you want the sensation of touch to last the same duration. If, let's say, somebody touches you and that neurotransmitter hangs around for five minutes in the synapse, you would feel like someone is touching you for five minutes, even when they touched you for one minute. And neurotransmitters are not just used to transmit pain. Every single sensation in your body gets transmitted via electrical signal, followed by chemical, followed by electrical, and so on. It's a complete system. It nicely explains how different signals travel up into the brain. The only thing is it's not the whole story. Dr. Henry is an electrophysiologist and electrophysiologists are, at least in my day, there were a little bit of rock stars of neuroscience. They seem to, I would say, have this disproportionate amount of glory in the field. And they use very sophisticated electronic equipment that often they have to make themselves to listen to the electrical signals. So what they do in some of these studies is they will use very fine, very small electrodes, very small pipettes to release various chemicals. In this case, in the substantial gelatinosa of the spinal cord. And then they listen for electrical signal. They want to see whether or not electrical signal is elicited by these chemicals. They can also stimulate touch, heat cold and then see if electrical signals are created. As people continued to do research they found that in addition to different neurotransmitters, nerve cells release other types of chemicals. One very important one is neuropeptides and this is where things started to get more complicated. Dr. Henry was actually quite important in trying to elucidate the role of one particular neuropeptide called substance P. Can you tell me a little bit about how substance P was discovered and how its role in chronic pain was discovered, Dr. Henry?
Dr Henry:Yes, Substance P itself was isolated and the publication came out in 1932 Von Euler and Gaddum were the authors on that paper. They had been looking at extracts of nervous tissue, and then applying them to smooth muscle to see whether there's an effect on smooth muscle. They had earlier found one neuropeptide that they had isolated and applied it to smooth muscle and it caused a very slow contraction of the muscle. It was in the Kinin family of peptides. Since it produced a small slow contraction of the smooth muscle, they called it bradykinin. Brady- meaning slow. And then they had another extract, they found a couple of years later. And it caused a fast contraction of smooth muscle to their surprise. And that was the first one they found that would actually contract smooth muscle quickly. It was a tachykinin It was a powder. They didn't know what to call it. It was just a substance. So they labeled it substance P. P for powder, not for pain, actually. And so they put it on the shelf thinking someday somebody will come along. And it wasn't until the 1970s that Susan Lehman at the University of Boston actually got some of this powder. She first of all identified the amino acid sequence. It's an 11 amino acid peptide. That is, it's 11 amino acids all tied together in a string to create this neuropeptide called substance P and she gave some of that sample to us at McGill University and we tried in our electrophysiological experiments in the spinal cord. And at that time I had been looking at the effects of glutamate, which is an excitatory transmitter. The effects of GABA, which is an inhibitory transmitter. Amino acid glycine, which is another amino acid inhibitory transmitter. I had also been looking at the effects of noradrenaline, dopamine, acetylcholine, and a number of other known transmitters in spinal pathways. And the glutamate at that time was considered to be the universal transmitter in sensory pathways. So it, it was believed that was exciting the second neuron in the pathway. And that was the generally accepted concept. In 1976, I published a paper reporting that when I looked at the role of substance P in the chemical basis of synaptic transmission. It seemed to be involved only in mediating the signal from pain neurons or what we call nociceptive neurons. Noci- meaning pain and-ceptive meaning receiving. So Substance P appeared to be exciting only the nociceptive or pain neurons in the spinal cord. That concept upset the apple card because at that point, as I say, glutamate was considered to be the only neurotransmitter involved in all sensory pathways, so this was an interesting step forward, because all of a sudden now based on what I had found, there was a specificity in terms of different chemicals acting in different sensory pathways. So when we were looking at the hair stimulated sensory pathway, Substance P didn't have any effect on those neurons. When we looked at warmth or touch or pressure, the neurons involved in mediating those modalities were unaffected by Substance P. As I say, that was the beginning of an awareness that more than one chemical may be released from the primary sensory neuron, as we call them. And that different primary sensory neurons release different chemicals. Glutamate and then something else. So that was the beginning and that still is generally thought to be the case.
Dr Karmy:So I guess the obvious question is, why have substance P in the body at all? The system should work fine with just neurotransmitters. They reach, they can swim across the gap, they can stimulate the nerve cells after that. And sometimes there is no answer to these questions, but I'm just wondering why does the body need neuropeptides to transmit pain signals?
Dr Henry:The answer lies in time and space, that when substance P is released, it is degraded more slowly than glutamate, which is degraded immediately and so substance P when it's released, it tends to raise the excitability of all the neurons around it. And where the neurons which have receptors for the substance P these are the pain sensoring neurons. So when substance P is released from the primary or the first neuron, into a region of the second neurons, the pain receiving neurons level of activity or excitability is raised in those neurons. And so that means that there's a tendency for pain to increase disproportionately over time and it also spreads to neighboring neurons. That's the spatial component. So glutamate gives a very acute, very rapid response when it's released from the primary neuron. But the substance P when it's released, it causes a general increase in excitability that goes further over time. It's metabolized more slowly. And therefore you can get a, what's called a central sensitization or a buildup of sensitivity in the region of that first synapse.
Dr Karmy:But I guess from evolutionary standpoint, why would that be beneficial? What you're describing is basically development of chronic pain. Chronic pain is certainly not an evolutionary advantage, right? You would think, in fact, it's a little bit surprising that it's not something that over the course of evolution didn't disappear, because if you have a hunter in prehistoric times with chronic pain, they probably wouldn't get to pass on their genes if you think about it. Is there kind of an advantage to having that sort of persistent sensitivity to pain?
Dr Henry:Yes, I think so. Because the increased sensitivity or the increased level of excitability of the pathway means that if there's a damaged part of the skin, if it's an injured part of the skin, it's evolutionarily advantageous to protect that area of the skin. Let's say you have a burn on your hand, the increased sensitivity means that if you have a task that you need to do manually, you'll use the other hand to protect the damaged area while it's healing over the minutes or hours or days that it's required to recover. Because substance P is involved not only in mediating and carrying the sensitivity into the spinal cord, there's also what's called a retrograde response, and that is a response to substance P in the periphery, in the skin, for example. The substance P plays a role not only in the sensory synaptic relay but it also is involved in modulating immune cell activity in the skin. And it also causes a vasodilatation in the skin, which is the reddening that you see around an area of tissue damage. So that the substance P is involved really at least for acute pains or sub acute pains going for only a few days. The substance P is involved in mechanisms to protect a damaged area from any further damage, that if you have a burn on your right hand, you're going to use your left hand for things that maybe normally you would use your right hand for, but you're protecting that damaged area.
Dr Karmy:So a couple of, comments, retrograde release, correct me if I'm wrong, I think what that means is that the nerve cell itself doesn't just release substance P to stimulate the next nerve in the spinal cord, but it also releases more substance P in the damaged area to cause additional inflammation, because when immune cells come that are attracted, more inflammation happens in the damaged area as well.
Dr Henry:Yes.
Dr Karmy:I guess my question isn't acute pain on its own enough to force a person to rest? Presumably, if let's say you have a broken leg, each time you put weight on that leg, you get a painful signal, wouldn't that be sufficient? Why do you need this additional signal to discourage people from walking on a broken leg?
Dr Henry:Here, I think we'll differentiate between pain from a broken leg and pain from injury to the skin. I think there's not a lot of substance P neuron innervation of bone. But the neurons containing substance P are quite abundant in the skin. And so when substance P is released centrally, it plays more of a protective role so that there's a tendency then to use that part of the skin less. If you have burned your elbow, you're going to be protective in terms of not making that elbow bang into things anymore or if it's particularly severe, then you're not going to wear clothing, that will rub against that part of the skin. And that peripheral effect is called neurogenic inflammation. So in this case, substance P is released in the skin in response to injury or inflammation, and it in fact participates in the inflammatory response.
Dr Karmy:Which brings up another interesting point, and that is the interaction between nervous system and immune system. There are receptors for substance P in some immune cells. Of course, immune system is involved in a broad range of conditions. Do you have any thoughts and interaction between nervous system and immune system? Do you have any thoughts on immune system and chronic pain?
Dr Henry:Yes, substance P actually can directly influence immune cells such as mast cells, macrophages, and T lymphocytes. Substance P also promotes the release of pro inflammatory cytokines such as TNF alpha and interleukins and these, contribute to the immune mechanisms that are triggered by tissue damage.
Dr Karmy:Substance P was discovered almost a hundred years ago. From what you're telling me because it causes central sensitization and central sensitization is thought to have the primary role in why chronic pain develops. It has a primary role in conditions like fibromyalgia. The obvious question is it's been 90 years since the discovery of substance P. Have we tried to find a way of shutting off substance P of developing a drug which would reduce the levels of substance P or blocking it from binding to the nerve cells in the spinal cord as a form of treatment for patients with chronic pain and fibromyalgia?
Dr Henry:Yes, that has been investigated very intensely. Since this was a transmitter that was implicated in acute pain and chronic pain. There was a very intense interest from the pharmaceutical industry to develop an antagonist to block the effects of substance P. At the beginning, the antagonists were all other peptides, but the problem with peptides being given orally, for example, as a medication they're broken down in the gut, so there's very little chance that any of the neuro peptide antagonists will have an effect. Unless they're coupled with a transporter chemical and at that time, those were not available. So then in the eighties and nineties there was a pharmaceutical interest in developing non peptide antagonists, and that, that was very active for a while. So I was running experiments in which I was using products that were produced by Pfizer and Merck because they wanted to know using my technical approach would these antagonists be effective. And they certainly were very effective in blocking the effects of substance P at the cellular level and that the level of neurogenic inflammation. So following the basic science studies, they then got approval to run these non peptide substance P receptor antagonists in human clinical trials. And they were a huge disappointment in terms of pain alleviation. They did not show any promise. And both of these large companies and many other smaller companies running non peptide substance P antagonists, they all came with the conclusion that these were not as effective in treating the pain as they had hoped. They are effective in other uses. For example they can be useful for emesis or vomiting. Whether it's chemotherapy induced vomiting or in pregnant women feeling nauseous. So substance p antagonists can be used. Especially in conjunction with 5 HT receptor antagonists for emesis. But there was also some minor promise that Substance P antagonists might be helpful for depression or other affective disorders. But by and large, the Substance P receptor antagonists have not found any major use for treating human conditions.
Dr Karmy:So this brings up an important point. Presumably, substance P antagonists or blockers were effective in blocking pain in other mammals, rats, cats and yet when you try to apply them to humans. They don't work. Presumably, a mouse or a rat compared to human, if you look at their DNA, they're probably, what, 90 percent similarity. And it is a recurrent theme, actually, in biological research in general, where maybe 90 percent of things that work in rats don't work in humans. Do you have any thoughts as to why that is, given the close similarity and given that evolution presumably makes us on a biochemical level fairly similar to other mammals.
Dr Henry:Yes. The preclinical studies that we were running on experimental animals, we were only looking at the effects of the antagonists on a substance P induced response. We were not able to look at the effects of the substance P receptor antagonists on pain in experimental animals because of ethical reasons. The use of experimental animals is under very tight regulation and that kind of experiment is not allowed in experimental animals. That kind of experiment is not allowed in humans either. The substance P receptor antagonists are used for existing conditions, but not chronic pain induced in humans.
Dr Karmy:But clearly there must be a way to study pain in animals. So animal models?
Dr Henry:Yes.
Dr Karmy:So what would be an example of an animal model of pain?
Dr Henry:We ran an animal model of rheumatoid arthritis. Again the experiments on animals are limited for ethical reasons. So we can only go so far. The restrictions are very tight. In terms of use of animals for any pain research, and we adhered very rigorously to the documented requirements for animal use.
Dr Karmy:You're implying that animals had no pain?
Dr Henry:No, we were not allowed to, it's not ethical to induce pain in an animal.
Dr Karmy:So how can you have an osteoarthritis model or a rheumatoid arthritis model, if you are not inducing pain? Are you taking animals that are just very old and already developed osteoarthritis because they're so old? What does osteoarthritis model look like exactly?
Dr Henry:Our osteoarthritis model, we removed the medial meniscus from the knee and cut the anterior cruciate ligament. And that model then developed a bilateral asymmetry in terms of movement. We looked at the loss of post mortem. We looked at the development of the synovial membrane, looked at the decay of the cartilage in the knee. And we did some behavioral work looking at their mobility. But there was also a limit in terms of how advanced that model could go. As we could not allow the animal to have a kind of pain that is manifest behaviorally. There are a number of very rigid criteria.
Dr Karmy:But I guess what I'm really asking is you can't do research using animals. Unfortunately, as much as some people talk about doing experiments on a computer model of an animal, in real life there would be no biological research and no progress in research without using animals. Whether it's ethical or not, at the end of the day if you want to have science, you have to have animal research and although, one can debate the ethics of research. I think most of us agree that we're very happy that we have been accessed to things like penicillin or immunizations, or any number of other discoveries that science has brought us. So although, it would be nice if there was an alternative realistically, if we want to understand chronic pain, we need animal models of chronic pain. So I understand that it is a little bit of a tightrope or sweet spot that you are looking for where you are causing some pain, but not so much pain that the animal suffers. But by the same token, if you don't do any research, then there's going to be a lot of human suffering. Fair enough, there's more than one way of looking at the field, but I'm very strongly pro doing things that push science forward and get us better approaches to treating medical conditions, recognizing that, things may not be ideal. But I guess what I'm really asking is were these substance P blockers tried in any chronic pain models?
Dr Henry:We did try them in neurogenic inflammation models and they were very effective.
Dr Karmy:Okay. So are you trying to imply that the reason that so few treatments that work in rats and mice but fail in humans, and especially when it comes to chronic pain is because we have really poor animal models of chronic pain?
Dr Henry:No, I wouldn't say that. We did have an animal model of neuropathic pain. In that case, we had some polyethylene cuffs that we put loosely around the sciatic nerve on one side. And we were able to study that model out over several months. Because there were no overt signs of distress of the animal we did see for example the toenails on that one side it became longer than the toenails on the unoperated side because the animal was using that leg less to walk but again, there were no signs of distress in the animal. And so we were able to study that model.
Dr Karmy:So why do so few treatments work in rats but fail in humans?
Dr Henry:Back to the neuropathic pain model we did find that there were some chemicals, that are involved in the early neuroplastic period of the beginning of neuropathic pain before it really becomes chronic. And we found that there are chemicals which will prevent the development of that neuroplasticity. I actually have six patents issued on that approach but that has not been carried to the clinical trial study. It's not that the data from animal models do not apply to humans. It's whether the data from the animal studies are carried forward into clinical trials in humans.
Dr Karmy:Looking at Substance P, it did get carried over in clinical trials in humans, yet it didn't have the expected result.
Dr Henry:But the Substance P antagonists were not studied in a pain condition. In the preclinical studies, they were studied only in response to the administration of Substance P. So they blocked the Substance P effect, but they were not able to be tested in an animal model of chronic pain. So we are quite limited in the ability to study animal models of chronic pain.
Dr Karmy:So presumably because plasticity is I think defining feature of the nervous system, that is how memories are created and just like memories can be forgotten, just because you have a change in plasticity. Presumably some changes in the anatomy or connectivity of the nervous system. If there's a negative change which causes chronic pain, where the nerve system rewires itself to become hypersensitive, presumably there's a way to reverse those changes as well. And I guess the other, at least to my mind, a little bit of a lesson from all of this is Substance P has been studied very intensively for a good 50 years with, I presume, hundreds of papers coming out on it. And sometimes the research does give you a result that's applicable to human disease and sometimes it doesn't, and you just can't predict ahead of time where the field goes. But if you study enough different biological phenomenon some of them will turn into useful treatments like CGRP blockers in migraine headaches.
Dr Henry:Yes. I'll go back to say that I think that if we're talking about use of substance P receptor antagonists in for humans, I think it does lie in a kind of a human condition besides emesis, but and possibly also in a minor role in depression. But I think the real translation of that basic science and into human use would lie more in treating subacute inflammatory responses in the skin and subacute pain, but as I said these are not glaring medical needs since that human condition is not glaringly in need of treatment.
Dr Karmy:So here's a question for you then. You start with acute pain. Presumably a lot of acute pain turns into subacute pain. And then eventually subacute pain turns into chronic pain. So if you block the subacute phase, can you prevent chronic pain from developing?
Dr Henry:That's always possible. That has never been studied.
Dr Karmy:Given that 20 percent of patients with injuries end up with chronic pain, maybe something there.
Dr Henry:Yes. It's quite possible that a clinical study on people who have just just had an injury of some kind that's causing pain and it's a kind of pain that is subacute. Then the way to do that would be to start with early treatment for the patents that I have for myself is a platinum hour, a golden day and a silver week to prevent the development of that plasticity. And I would say there would be a similar time frame for treating the subacute pain. So if we know that there's a kind of chronic pain that typically has a period of subacute pain. Then the idea would be to treat that subacute pain initially aggressively to see if statistically the treated group would not develop chronic pain as much as, or in the same numbers as the untreated group. That would be a very interesting study.
Dr Karmy:All right, so that's it. Thank you very much for talking to me. I learned a lot about substance P and neuropeptides. Have a good day.
Dr Henry:Thank you. Bye bye.
Dr Karmy:So, what are my final thoughts on neuropeptides and substance P interview? First of all, there is a fundamental difference between acute pain, subacute pain, and chronic pain on chemical level. So, one cannot take a finding about acute pain or subacute pain and use it to devise a treatment for chronic pain. Second of all, we really need better animal models for chronic pain. Patients with chronic pain suffer for many years. Their pain is typically severe and debilitating, impacting their ability to work and function normally in society. It is typically caused either by osteoarthritis due to old age or by car accidents. In animals, for starters, the pain seems to be mild discomfort. Second of all, it certainly is not there for many, many years. And the mechanism of pain development is fundamentally different. The pain is not developed because of old age or because of a car accident, but rather typically it develops as a result of some kind of a surgical procedure. Lastly, and that's my last thought, is the chronic pain seems to develop over time. It progresses from acute pain to subacute pain to chronic pain. And by the time it becomes chronic, there are some, anatomical changes on neuroplasticity in the brain and spinal cord, which are very hard to reverse. Perhaps, a more promising approach would be to try to prevent chronic pain from developing in the first place by treating everyone who has acute pain. Clearly, after years of studying chronic pain, Dr. Henry feels this is the most promising approach as he himself patented a treatment which tries to do just that. Time will tell whether or not this is going to be the solution to chronic pain. However, there hasn't been much research on that approach. And so perhaps it has promise. Thank you.
