The Science of Everything Podcast - Episode 121: The Biology of Pain

Episode Date: September 12, 2021

An overview of the underlying mechanisms of pain, including the role of nociception, transduction of nociceptor signals by spinal pathways, the modulatory effects of opioids, and processing of these inputs in the brain. I also discuss phenomena such as referred pain, psychogenic pain, and congenital insensitivity to pain. If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything    

You're listening to The Science of Everything podcast, episode 121, the biology of pain. I'm your host, James Fodor. In this episode, we're going to look at the biology and psychology and neuroscience behind the perception of pain. So this may not necessarily be the most pleasant topic, although I think it is a very interesting and important one. So specifically, I'm going to talk about the underlying mechanisms of pain, transduction and detection of pain signals, so starting with a noceoception, and the transduction of those noceoceptor signals through spinal pathways up to the central nervous system and the brain specifically. We'll then talk about the modulatory effects of chemicals such as

opioids and how all of these different signals and inputs are processed by the brain to actually deliver the percept of pain. In doing so, we'll look at some interesting ideas and phenomena that are relevant, such as the phenomena of referred pain, psychogenic pain, and congenital insensitivity to pain, and I'll talk a little bit about how we actually construct these perceptions or experiences of pain in the cerebral cortex and some of the methodological difficulties with studying pain being a subjective experience. Recommended pre-listening is episode 63 on the nervous system, which will give some useful background, although probably not essential.

All right, that all being said, let's make start and talk about what is pain? The standard definition that you'll find in these sort of introductions is taken from the International Association for the Study of Pain. They would know after all. They define pain as, quote, an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage, end quote. Now, there are a few important aspects of this to note. One is that pain is defined as a sensory and an emotional experience.

So it's not just an issue of what you sense. It's also related to one's emotional, and I would also add cognitive response and reaction to that, which we'll talk more about in a moment. Another aspect here is that it's associated with actual or potential tissue damage, so it's not always the actual experience of damage to tissue, but also the anticipation of that. Or even described in such terms, right? So we may describe pain in terms of burning or throbbing or stabbing, even if there's no actual burn, throb or stab, right? That's the experiential side of what it feels like.

Another key aspect to emphasize here is that pain is defined to be a subjective experience. That means that it is definitionally subjective. So by subjective here, what we mean is that it is necessarily dependent to exist on there being someone who experiences it. Of course, the fact that something is subjective doesn't mean that it isn't real. It just means that there has to be a subject, right? Someone who experiences the pain. and that's one of the things that makes it very difficult to study, because really we can't study pain apart from relying on subject reports.

Now, a lot of what we're going to talk about in the rest of this episode relates to something called noceoception. So noceoception is a particular type of sensory detection, a set of mechanisms, I guess, you could say, that the body uses to detect both internal and external injuries or potential disruptions to tissue in various ways. But it's important to understand that noceoception. is not the same thing as pain. We'll get into more details of how that works in a moment, but noceoception often results in pain, but it isn't the same as pain. So noceoception is a way for

the body to detect noxious stimuli. So noxia stimuli are stimuli or experiences that are potentially harmful or damaging. So that relates to the idea we just mentioned before about the fact that pain is associated with potential or actual tissue damage, right? And that makes clear its connection to noceoception. But again, it is. isn't the same as noceoception. And there's very strong evidence that noceoception, that is the activation of these particular receptors, is neither necessary to produce pain, nor is it sufficient to produce pain. So you can have activation of these receptors and not feel any pain. You can also have pain without activation of these receptors. So there is a bit of a puzzle there about the connection

of these two, and that's something we'll talk about over the course of the rest of this episode. Another thing that we should talk about is what is the point of pain? Like, why do we have it? Pain is something that motivates an individual to withdraw from a damaging situation or potentially harmful stimuli. Also, it helps to protect the damaged part of the body while it heals. So we have a natural instinctive response to cradle or guard damaged areas or parts of their body that are experiencing pain. That's a mechanism to protect from further damage and to help it to heal. Usually pain will resolve when the noxia stimulus is removed and the body healed, although there are types of pain, particularly chronic pain, which persists despite the removal of the stimulus and apparent full healing

of the body. There's also types of pain that emerge even in the absence of any apparent stimulus or damage or disease. These forms of pain are particularly clinically relevant because they result in quite a significant deterioration or quality of life for the patients experiencing them, and they serve as far as we can tell no useful biological purpose. Now, having introduced the idea of pain, Remember, it's a subjective experience, often but not necessarily caused by the activation of noceose receptors. Let's talk about some different types of pain, which will also help us understand this distinction a bit more. So the most kind of basic or easiest to understand type of pain is noceoceptive pain. So this pain caused by stimulation of sensory nerve fibers.

These nerve fibers are embedded in, well, really throughout the body, but particularly in the skin. And when these fibers respond to relevant stimuli, we'll talk a bit about the types of stimuli. later but you know standard sort of cutting or excessive pressure or bruising and other things then that often in healthy individuals leads to the perception of pain now although noceoiceceptes as I mentioned are disproportionately found in the skin and therefore responsive to external types of stimulation there are also noce susceptible fibers found throughout the body in well not in necessarily but surrounding and nearby to ligaments tendons bones blood vessels muscles and other And this pain that is triggered by activation of these noceoceceptors is called deep somatic pain

and often feels, gives rise to a sensation of sort of dull, aching, poorly localized pain. Superficial somatic pain, which is that which is caused by activation of nociceiceceptors near the skin or other superficial tissue by contrast is sharp and well-defined and clearly located. So again, this is the difference between pain that has a very clear sort of external source and pain that sort of comes internally from somewhere that's often harder to localize, but both nevertheless still caused by activation of noceoceptive receptors. So that's the first type of pain, nociceceptive pain, and that's, I think, what most people think about, typically when they think about pain. But that's only one type of pain. There's also neuropathic pain. Now, this is pain that's caused by damage

or disease to the nervous system itself. So contrasts that with noceoceptive pain, where there is tissue damage or disease of some form. But the nervous system, those nerve fibers are doing what they're supposed to do, right? Their job, their purpose is to detect the noxious stimuli that have caused that damage and then essentially to report that to the central nervous system, which then leads to, generally, the perception of pain. But neuropathic pain is different because it is caused by the nervous system itself not functioning correctly or some sort of disease or injury to the nervous system. A very simple example of this is when you bump your funny bone and you get that sort of weird tingling, stabbing feeling. That's a neuropathic pain. Of course, it's a fairly mild form because it's

basically just banging your nerve there and there's no real lasting damage typically. But that's an instance of that sort of feeling that you get when something's gone wrong with the nervous system and it's not reporting any actual tissue damage. It's reporting something having gone wrong with the nervous system. But more extreme forms of that can be caused by various neurodegenerative disorders or other problems affecting the nervous system. And so this is often described as burning, tingling, stabbing, or pins and needles type of pain. Moving on to a third type of pain, psychogenic pain.

This is one of the hardest types of pains to understand. This is also called somatoform pain, and it's pain caused or prolonged or increased by mental, emotional, and behavioral factors. Typically, psychogenic pain occurs without any particular clear, observable tissue damage, either to the nervous system or to any other part of the body. So it's not neuropathic and it's not noososceptive pain,

or if it is the pain that's felt is far in excess of what would be justified by those factors. This type of psychogenic pain often is stigmatized because there's an idea that the pain is sort of not real. And although the tissue damage might not be real, that doesn't mean the pain isn't real, right? So this is an important aspect of what we talked about before, that no secession isn't the same as pain. You can have pain without no seception,

and you can have no seception without pain. get to a bit later. So there's nothing unreal about psychogenic pain. However, it may be the case that the source of the pain that the patient identifies, or the way the patient describes the pain, may not necessarily be accurate in terms of the actual source of the pain. Classic examples of this sort of pain include headaches, back pain and stomach pain. Of course, not that those are always psychogenic, right? But they're very commonly ways that psychogenic pain is expressed or descriptions that patients use to describe their pain. But especially this sort of pain, it's really very unclear why this happens. It seems likely that it is due to some sort of dysfunction

at the central level, at the central brain mechanism level, so basically somewhere in the cortex, rather than at the level of peripheral nerves. But this type of pain is still very poorly understood and is probably one of the contributing factors behind some forms of chronic pain that can't otherwise be identified with any particular organic source. Now, the last type of pain that I wanted to talk about here is sometimes omitted, but I think is very important. And this is sometimes called psychological pain or mental or emotional pain. I don't think mental or emotional pain are good ways to put it, because all pain is mental and emotional. Psychological is probably the best we can do here, even though you might say, well, isn't all pain psychological, but I think it emphasizes

the psychological origins of this type of pain. Note that this is different from psychogenic pain. Again, it's a little unfortunate that the names are so similar. But psychological pain is not pain that appears to originate from somewhere in the body, like a headache or a back pain that doesn't seem to have any particular cause due to tissue damage. Psychological pain isn't that, right? That's psychogenic pain. Psychological pain is, it's been described as mental suffering or mental torment, mental hurt that originates from sort of an experience as a human being. So this is the sort of negative emotional mental experience that characterize certain types of mental disorders, for example, depression and anxiety disorders. Borderline personality disorder is

commonly associated with extreme levels of emotional distress and pain and psychological pain. So this is a form of pain that doesn't seem to really have any connection to noceoception or the peripheral nervous system at all, but nevertheless is a real and important form of pain, but may have quite different mechanisms from other types of pain as well. So we need to be careful there about use of labels. it is nevertheless important, although it might be difficult to exactly demarcate some cases, it is important to keep in mind the different types of pain and the fact that we're using one label to refer to many different things. So noceoceptive pain is pain that's caused by stimulation

of peripheral sensory nerve fibres, and that's typically what most people think about. I think at least at the first outset when they talk about pain, it's also what we have most evidence about, and what most of what we're talking about henceforth will be focused on, although not exclusively. Then there's neuropathic pain which is caused by damage or disease to the nervous system itself, so like pins and needles when you bump your funny bone. Psychogenic pain is caused by some sort of central dysfunction which leads people to attribute pain to peripheral sources, even though there's no actual tissue damage in those places. There's no nociceceptive input, but nevertheless pain is still experienced. And psychological pain, which is not really felt as

or attributed to any part of the body, but it's more sort of feeling mental sense. suffering as a human being, like in terms of anxiety, depression and other mental illnesses, although you don't have to experience, obviously, mental illness, those are just more extreme forms, you know, so this would be also even associated with things like losing a loved one or, you know, grave disappointment or feeling of extreme grief and the pain associated with that. That's psychological pain. All right, so having outlined some of the different types of pain, let's now talk about nocice reception a bit more and explain how these signals are detected and how they convey

to the central nervous system and the brain. So noceoceptors are a particular type of neuron. They're called pseudo-unipolar neurons, which sounds a bit confusing. But basically all that means is that the cell body of the neuron kind of sits off to the side, right? And then you have your dendrites on sort of the one side and the axon on the other side forming kind of like a straight vertical line, if you like, and the cell body sits off to the side. That's relevant in terms of the, the strength. of these neurons and where they sit with respect to the spinal cord, which we'll get to in a moment. But the important part is that the peripheral branch of the axons, so where the dendrites are, free nerve endings, protrusions of the cytoplasm essentially, they project that

into the skin or around other tissues like ligaments and so forth. And essentially, when there is some type of tissue damage, specialised ion channels will be activated, causing a depolarization of the local membrane, which then, if there's sufficient depolarization and sufficient magnitude, it will trigger an action potential which travels down the axon and then passes on information to further synapse neurons, which we'll get to at a moment. But the important point that I want to make here is that most types of noceoceptors just have, the input is just essentially bare nerve endings. So this is distinct from many types of neurons that are associated with detecting signals relating to touch or temperature or vibrations.

which often have very specialized structures. In the case of noose disruption, it's mostly just sort of naked nerve endings. And it's really, therefore, about the particular set of ion channels that are found in those nerve endings rather than specialized cellular structures themselves that make these neurons specialise to detecting tissue disruption or tissue damage. Typically, however, the nerve endings are quite diverse, and the word is polymodal, which means that they respond to a wide range of different stimuli, including temperature, mechanical pressure and various chemicals like capsacin, which gives a burning sensation.

So beyond a certain threshold, these receptors will be activated, like beyond a certain threshold of pressure and temperature and so forth, and these sense, no susceptible sensations will be transmitted up to the brain. Now, these neurons, as I said, that the dendritic projections sit, you know, somewhere near the skin or near other internal organs in the case of the somatic ones. The cell body itself resides in what's called the dorsal root ganglion. So these are protuberances that kind of poke out the backside of the spinal cord. They kind of project through the vertebra, if you like.

And ganglion is just a bunch of nerve fibers and cell bodies kind of packed together. These neurons, remember I said that it's kind of like the cell bodies off to the side, and then you've got the dendrites and the axon sort of an align next door. Well, that's kind of relevant to understanding the structure, because the cell bodies are sitting in the dorsal root ganglion, right, you know, along the spine. And then the input side of them projects out towards the skin, and the output side of them projects back into the spinal cord, which again sits inside the vertebra of the backbone. So basically the point of these neurons is to get any no-susceptive information from the skin or nearby in the skin. And again, there's also there's projections towards internal visceral systems as well.

But let's just talk about the skin here. So it gets the signals from there and transmits them when there's a generation of action potential through to other neurons. that it synapses with in the spinal cord. Different neurons project to different layers within the spinal cord. So there's a fairly elaborate layered structure of different neurons projecting different places. I'm not going to talk too much about that, but bear in mind, there's a fairly elaborate structure here.

Now, these nocice receptors then synapse with what are called secondary neurons or interneurons that project to the dorsal horn of the spinal cord. So that's just the part of the spinal cord where the primary noceosypter, the ones we've just been talking about, synapses with the secondary ones, which then carry the signal up to the brain. So the primary noceoceptors detect the signal, but they don't transfer to the brain directly. They fire an action potential through to where they synapse with a secondary neuron in the dorsal horn of the spinal column, and then that carries the signal up

to the brain. We'll talk more about that transduction process a little bit more, but first there's a few more things to say about noceoception and the receptors. So one important thing, to understand is that there are two main types of nosyiceptors. I mean, there are many types, but there are two sort of big distinctions that are often made. C-fibers and A-Delta fibers. C-fibers have narrow un-milinated axons. You may recall that myelination is a process of basically fatty support cells wrapping around the axons of a neuron, which helps to transmit the signal of an action potential faster. For the details on that, have a look at past episodes that I've done on neurons and the nervous

system. But the fact that C-fibers are un-milinated and also narrow, both of those mean that they're going to transmit their signals much slower than wider, milanated axons. Basically, being narrow means that essentially there's less room for the traffic to get through if you like. It's like a narrower road. There's more congestion, to put it crudely. And un-milinated also slows things down a lot.

Whereas A-Delta fibers are wider and then myelinated, so they're much, much faster. and C fibres project to different layers in the spinal cord compared to the dorsal horn of the spinal cord compared to a delta fibres. So remember I talked about there's layers in the spinal cord where different nociceicepter neurons project to. Again, don't worry too much about that, but just have some idea that there's more structure to it there. Now, this is important because this actually gives rise to something that's called sort of first pain and second pain, where typically if you have some sort of tissue damage, there'll be an initial, very rapid feeling of sort of intense pain. and that is mediated by the A-Delta fibers, right? Because they're very fast, being myelinated and wide.

You get that signal very quickly. And then, slightly after that, you have a slower but longer-lasting kind of duller, perhaps more throbbing feeling of pain. And that's the sort of second pain that's coming from the C-fibers, because they're narrower and un-milinated. It takes longer to transmit the signal. So they give rise to two distinct sensations. Now, as I mentioned, the sensitivity of a particular nociceceptor depends on the population

of ion channels that it expresses. And there are dozens of these different types of ion channels. And so they'll be specialized, these ion channels will be specialized to the detection of specific stimuli, such as excessive cold, excessive heat, excessive pressure, specific types of chemicals like capsaicin or other chemicals that are produced or hormones and things that are released as a result of tissue damage. So there's many different types of stimuli that can cause these particular ion channels to basically open, allowing, they're generally sodium channels, so sodium ions to flow into the cell across the membrane, thereby depolarizing the neuron and causing it to fire an action potential if the depolarization gets to a sufficient level. Although, I mean,

I don't know that they're all sodium channels. I just know that many of them are. A single neuron may express many different of these ion channels, which is why single neurons, as I mentioned, the bare nerve endings for these noceusceptors typically are responsive to many different types of stimuli, but a given ion channel will be specific typically to one particular type stimulus. There's just many different ion channels will be expressed on a single neuron. Now, of these many different ion channels, which I will not get into details of, there is one that I want to mention. This is called the Nav 1.7 sodium channel, which is found in the peripheral nervous system. And it's attracted a lot of attention because it's been found that mutations in the

gene that codes for these ion channels. Of course, each ion channel will have at least one or multiple genes that code for that particular, those particular proteins. So mutations in that particular the gene can lead to congenital insensitivity to pain. Now, this is a rare, but kind of weird and disturbing condition, at least to me, in which you still experience normal stimuli from touch or from cold and vibrations, something like that. So, you know, somaticeception is normal, but there is no sensation of pain. And also typically lacking is any response to the pain. So, you know, if I were to touch a hot stove, there'd be a very rapid reflex to withdraw my hand from the hot stove and I would also feel painful stimuli.

Whereas people with congenital insensitivity to pain may feel the temperature of the stove, but they won't feel pain and they won't have that reflex to withdraw their hand, or at least reflectors like that are severely impaired. And this is why the condition is so dangerous. Very commonly people with this condition die as children or fairly young because of basically tissue damage or other disease that just isn't noticed. It's very common that they have sores in their mouth from biting their tongue or biting there the side of their mouth, things like that that they just don't notice. Damage of the eyes

is also very common from things getting stuck in the eye that, again, isn't noticed because they don't feel the pain. And at least often, I don't know if always is, but it's often associated with the absence of these NAV or NAV-1.7 sodium channels. So this is a very interesting result, but I think it's a bit early to say yet exactly how crucial these receptors are for the, or these particular ion channels, rather, are for the perception of pain, as we'll explain a bit later. But okay, so we've talked about the different types of neurosiseptive fibers and the ion channels that are responsive to different types of stimuli and how these fibers transmit the signal through the dorsal bric ganglion to the dorsal horn of the spinal column, and then they synapse

with secondary neurons, which then carry the signal up to the brain. But let's talk a bit more about this signal transaction through these secondary neurons and how the signal is sort of transduced and transmitted up to the brain, which is the part of the body that actually feels pain. Again, remember that, I mean, as far as we know, and I think that there's a good reason to think this, that the peripheral nervous system itself doesn't feel anything, right? It detects noceasception and, it detects the stimuli that give rise to noceoceptive responses and transduces it up to the brain, but it doesn't feel anything. The feeling, the actual pain, which remember is the subjective sensation, comes only when these signals are processed in a certain way by the brain. So

So here we're talking about the process by which these signals are carried up to the brain, and also a bit about the way these signals are modulated. Now, there are three main tracts, which are basically just bundles of the secondary neurons or the axons of these secondary neurons that carry these no-susceptive signals from the spinal cord up to the brain. And these are called the spinothelamic, spino reticular, and spinomezzapalic tracts. Now, don't worry if you don't remember those words. I'm not really going to belabor the point.

I just wanted to mention them because you might see them sort of in the literature if you're looking into this a bit more. And these pathways carry different types of signals. Remember, I talked about the different layers in the dorsal root ganglion, so there's a connection to that and exactly what type of neurons are carried in which tracks. I'm not going to belabor that point here. It's a bit too hard to explain. Just advise it to say there's a few different pathways,

but all of them involve the secondary neurons that synaps with the actual no-susceptive primary neurons themselves, then carrying the signal up, I mean, in some cases, right from the very bottom of the spinal cord, all the way up to the brain, where they synapse with further neurons. These different tracts here do synaps with different regions of the brain. The spina thalamic and spina reticular tracts both terminate in the thalamus. So that's a fairly low region of the brain, kind of just a little bit above the end of the spinal column. And the thalamus, I mean, it does a lot of things, but one of the things that it is known to do is sort of provide a waystation for a lot of different sensory input.

So many different types of sensory input initially go to the thalamus, whence the information is then projected to higher regions of the brain. So that's what we see there. However, the third tract that I mentioned, the spino-mesoncephalic tract, terminates in the mid-brain, so kind of goes to a different place instead of the thalamus. And then there's a further set of projections that carry the signals to regions like the amygdala and the hypothelmus. So the point to be made here, the lesson to draw from that is that there are different pathways that can carry these no-siceceptive signals to different parts of the brain. And already here we're sort of seeing some of the complexity in it, because it's not like that there's just the pain center of the brain that all the signals go to, and there you feel

pain. It doesn't work like that. The signals go to different parts of the brain and then they're projected into even further parts of the brain. So it's already quite a complex picture. And when we talk about central processing mechanisms, we'll complicate that even further. However, the spinal column isn't just a sort of passive relay station or like a highway. I mean, it does serve as that, but it does a lot more than that as well. It's involved in actively modulating the strength of these nociceoseptive signals. Indeed, most of the neurons in the dorsal horn, remember that's where the primary noceosceptive signals. neurons project to, that's sort of where they end and then the secondary interneurons that go up to

the brain start. But most of the neurons, they actually aren't even doing that, right? They're actually local interneurons, which inhibit the activity of secondary dorsal horn neurons that receive from the neurosioceptors. So there's these very interesting gate mechanisms that have been found, where basically you have this system where there's sort of multiple modulations that go on. First of all, there are interneurons that are inhibitory, right? So that means that if you, if these inhibitory neurons are activated by whatever source, we'll get to that amount, but if they're activated, then when they synapse with, say, the noceoceptive neurons, they will downregulate them or they will reduce their activity. So therefore, they will reduce the intensity or the frequency of the signal sent

up to the brain. So that's what a lot of these sort of local inhibitory interneurons are doing that reside in the dorsal horn. But also you might ask, well, where do they get their input from? Like, how do they know when to be inhibit these no-susceptive signals? And the answer is, again, that there's multiple factors here. One is that there are top-down mechanisms. So these modulatory interneurons receive signals from the brain via the thalamus. So this is top-down control, which serves as a mechanism by which pain can be regulated

or modulated by top-down signals. So it's not all bottom-up. It's also top-down. inhibitary signals sent from the brain and affected locally by these local interneurons in the spinal column, which is really interesting because it's not just an issue that top-down mechanisms can affect how you process the pain or how you experience it, but it actually affects the very signals that are sent up there in the first place. So this is a very interesting phenomenon. But it's not just that. There's also another phenomena which is related to the fact that there

appears to be local inhibitory bottom-up interactions whereby if you have, remember, it's not just nocice exception, there's lots of other neurons there as well that are responsive just to ordinary kind of, you know, somatic sensation, touch and pressure and so forth, types of stimuli, but don't transmit nose deceptive signals. It appears that in many cases, when those are activated, they actually, through these local inhibitory into neurons, actually inhibit the activity of secondary neurons that are carrying the signals up up to the brain. So basically what that means is that when you have normal, normal kind of non-painful stimuli in a particular region, that helps to inhibit the painful stimuli from that region through these local inhibitory neurons. And this is actually

quite a familiar experience, right? So this is, you know, if you bang your hand or something like that, you'll typically rub it or you might shake it or something like that. And this is a phenomenon whereby it appears to be a way of dulling the actual pain signals by activating the non-painful signals which then inhibit the painful stimuli there. I don't know exactly what the hypothesized purpose of this is, but it's a very interesting example of how the spinal column and the nerves therein are actively processing the signals. So integrating bottom-up painful signals, but also bottom-up inhibitory signals with top-down inhibitory signals coming from the brain. So it's all quite interesting and more complicated than you might initially think. But then I'm

going to add another spanner to the works here and talk about another important aspect of modulation of pain, which is the function of opioids. So you've, you've likely heard of opioids before. An opioid refers to any substance that can activate opioid receptors. It's a wide range of substances, including both endogenous and exogenous substances. So basically, there are substances that sort of do that naturally, and then there are substances that come from outside the body that activate these receptors. And typically that's what people mean when they're talking about Opioids is exogenous substances such as morphine, but there are also endogenous opioids such as endorphins, which are going to produce naturally within the body to activate these receptors.

Now, what are opioid receptors? Well, they're receptors on the membrane of the cell, which are a particular type of receptor, or a G-protein-coupled receptor. If you would like to learn more about that, you can have a look at one of the recent episodes, which was episode 118, cell signaling, where I talk a bit about G-protein-coupled receptors. So I won't go into the detail of that now. But the point is that an opioid receptor is just, it's kind of just like many of the other receptors that we have in our body that trigger an intracellular response in response to some particular extracellular signal. In this case, an opioid molecule, whatever that might be. Again, there's many types of these molecules. Now, opioid receptors are found both in the central nervous system, so in the brain itself and also in the peripheral nervous system elsewhere in the body. Peripheral opioid receptors are known to influence or potentiate the activity of inhibitory into neurons. So basically what they do is these peripheral opioid receptors, when they're activated by opioids, they help to boost the activity of inhibitory into neurons. So these are the interneurons that I mentioned

that actually the majority of cells of neurons in the spinal column, it's not the actual no-siceceptor cells or the secondary cells sending the signal up to brain, but these are the inhibitory ones that are kind of modulating the effect there. So many of these have opioid receptors in them, which when activated help to reduce the activity of the interneurons. And therefore it effectively diminishes or reduces the intensity or frequency of the noose receptive signals being sent up to the brain. So this is why opioids are typically used as analgesics, because they can reduce the signals that are then sent to the central nervous system interpreted as pain. But it's also more complicated than that because central opioid receptors in the brain also appear to induce analgesia by inhibiting cortical processing of pain,

as well as activating those descending inhibitory fibres that I mentioned. So there's so many things going on here in the modulation of pain. There's the extent to which the neurosice receptors are active just based on external stimulus or internal dysfunction with organs or tendons. Then there's the extent to which that is being modulated by the activation of ordinary non-painful stimuli, which, as I said, through these gating mechanisms, inhibits the nurse susceptor signals. then there's the extent to which those noceosiceceptive signals are modulated through top-down

mechanisms, including opioid receptor-based mechanisms, as well as other non-opoid-based top-down inhibitory mechanisms. And then that's before we even talk about the effects of sort of emotion and cognition on the central processing of the noceosate stimuli itself. So you can see that it's all a very complicated story, and it's not just a simple story of, oh, there's a noosiceceptive signal that's detected, it sends a signal to the brain, we feel pain. There's a lot more processing integration, top-down, and bottom-up that goes on in the spinal column before we even get to the brain.

All right, but having said that, let's start talking about the brain and the central mechanisms of pain. So remember, all that we've been talking about so far with respect to noceoception, with respect to opioid receptors, with respect to inhibitory interneurons, and the primary and secondary neurons and all that, None of that is actually pain itself. This is just the transmission of noisoceptive signals of varying intensities and different sorts to different parts of the brain. The brain itself is the region where these signals are processed in a particular way to give rise to the sensation of pain. So you might be wondering, well, what part of the brain does that? And I've kind of indicated this before, but although there have been quite a few studies now looking at this from the point of view of lesion studies,

where they look at people who have damaged regions of the brain as well as neuroimaging studies, functional neuroimaging techniques like positron emission tomography and functional magnetic resonance imaging. None of these methods have really been able to identify any particular region that is very specifically only active during pain and not during non-painful stimuli. So there isn't like a pain center of the brain. That being said, there are some regions that are disproportionately more active during perceptions of pain than at other times. And some of the main regions here include the insular, cortex, the anterior singular cortex, the amygdala, as well as various parts of the prefrontal cortex.

So the amygdala is a subcortical structure that is particularly associated with fear responses, as well as negative emotional reactions. So that is not at all surprising that that's involved in pain sensation. These other two areas, insular cortex and anterior singular cortex, don't worry too much if you don't really know where those regions are. They're just parts of the outer cortex, so the folded outer region of the brain. they need to be particularly important. The insular cortex appears to be a region in which there's integration of the emotional and cognitive aspects of the pain.

However, one sort of spanner in the works is that if you directly electrically stimulate these regions such as the anterior cingulate cortex or the insular cortex, you rarely elicit painful stimuli. I mean, sometimes you do, right? But when you electrically stimulate other regions of the brain, you'll often elicit particular sensations of stimuli, like having been touched in a particular place or having a particular the smell or seeing a particular object. But when you activate these parts of the brain, you don't typically get pain.

So it seems that activation of these regions, or at least non-specific activation, isn't sufficient for pain. Of course, our methods of intervening through direct electrical stimulation are quite crude and primitive, so maybe we just sort of don't know how to do it in the right way. Furthermore, there have also been studies that show that regions like the insular cortex and anteriorly-singulate cortex still show activity both in healthy controls and also in subjects who have congenital insensitivity to pain, even though the latter don't have any experience of pain when the activation was measured. So it's a little unclear what these regions are doing. They do seem to be

important in the processing of pain stimuli, but they don't seem to be sufficient for pain. Activating them doesn't necessarily generate pain, and people with congenital insensitivity to pain have these reasons activated, but don't feel the pain. So there's some missing ingredient here, it seems, that we don't understand yet. There's a few other issues, and remember I talked before about the fact that noceoception is not the same thing as pain, and noceoception is neither necessary nor sufficient for pain. I've already talked about congenital insensitivity to pain, as occurring particularly when certain types of these ion channels are missing in noceusceptor neurons, and that leads to the absence of normal painful responses in those who experience

this condition. However, case studies have shown that such people can experience some forms of pain, such as headaches as well as neuropathic pain. Remember, neuropathic pain is that which originates from damage to the nervous system itself. And I assume, although I've not been able to find direct evidence for this, but I assume that such people would also be able to experience psychological pain or mental pain. And so it seems that they can experience some forms of pain, even though they don't have functional noceoception. Furthermore, there's also the phenomenon of phantom limb syndrome.

So this is where you have someone who has a particular part of the body amputated, such as a limb typically, often show normal nociceceptor activity, as well as continual perception of pain from that region. even though there's no limb present, and even in cases where they're severing of the spinal cord, so all of the relevant neurons don't exist anymore, like they've been amputated, but they otherwise show normal nausea activity like in other parts of the body, and they're still feeling pain that they identify as coming from, you know, parts of the body that they don't even have anymore.

So it's clear that pain does not always originate from nerve endings in the stump, because this was an original posture, like when this phenomenon of phantom limb syndrome where people can still feel not just pain, but the positioning, of their limbs or that you've touched their limb or something like that, even though they don't have the limb anymore, this posture that was that, well, maybe it's coming from nerve endings in the stump. But this, as I said, phantom limb syndrome and feelings of pain from the phantom limb occur even in the presence of local anesthesia and even cases of severing of the spinal column, which should eliminate the possibility of any feeling coming from the stump. So it seems

that phantom limb syndrome is not driven by peripheral input, that pain is being generated at some way at the central level. So this combination of the continued presence of some forms of pain in congenital insensitivity to pain, as well as continued pain in the absence of any peripheral input in the case of phantom limb syndrome, both indicates that noososceptive input is not necessary for pain. Conversely, on looking at it from the other side, analgesics and anesthetics can block pain perceptions even without directly inhibiting the function of nociception. And I mean, we just talked about that before, right? You've got this top-down input from the nervous system which can inhibit the actual transduction of these nose-septive signals to the brain. You've also got the

modulatory effect of opioids and other hormones and neurotransmitters as well. So you can have noisitive input with no pain perception and you can have pain perception without no susceptible input. So they're clearly not the same thing. They're dissociable. As I've said, there appear to be particular brain regions such as insular cortex and anterior cingulate cortex and the amygdala, which are preferentially active during perceptions of pain in healthy subjects. But they're also active in people who have conditional insensitivity to pain. So it's not like that they're sufficient to generate perceptions of pain. So where does all this leave us? I mean, where is the pain coming from in a sense? It seems that it's not directly coming from noceoception. We've just looked at the evidence for that.

And it doesn't seem to come from any particular region of the brain, although there are some that are sort of more suspect than others. But at this point, unfortunately, there just isn't a very satisfactory answer to this. We don't have enough understanding of how all of these signals from the nurse reception as well as other sources are being integrated in the brain to generate a painful percept. So in response to some of these issues, some researchers have postulated that, look, maybe this one word pain is actually not the best way to think about it. Pain may not be a unified concept. There may be a bunch of different things going on here. And one sort of easy illustration of this is simply that at the outset, when I talked about four different types of pain, maybe all of these different

types of pain are actually, although they may have some sort of experiential facets in common, like they may feel similar in some respects, may be generated by very different neural substrates or by very different mechanisms. So perhaps we shouldn't even use the same word to describe them, at least at a kind of a biological level. Another way to look at this is an influential decomposition that identifies three different aspects of pain, which have been labeled sensory discriminative, affective, motivational, and cognitive evaluative. So just to break that down a bit, the sensory discriminative aspect is probably the most, again, easiest to understand or the most relatable aspect of pain. It relates to the form, the texture, and the sort of direct feeling of what the pain is like.

So, you know, whether it's burning, stinging, throbbing, or other type of pain. And also, whereabouts it appears to come from the body, you know, whether it's, you know, your thumb or your foot, does it appear to be hurting? So this aspect of it, right, the sensory discriminative part. But that's absolutely not the only aspect of pain. So then we look at the affective motivational aspect of pain, which relates to the emotional aspects of pain, including aversive reaction to pain, motivational desire to end the sensation, aspects of fear or foreboding and so forth that we have with respect to pain or expectation of pain. And those things aren't the same as the sensory discriminative aspect, right?

You know, the aversive reaction to pain and desire to end the pain isn't the same thing as the burning sensation of the pain, right? or the feeling that the pain is coming from a particular part of the body. So that's the idea of this distinction. And the last of these aspects of pain is the cognitive evaluative element. And this relates to how pain is attended to, so attention, you know, what I'm attending to, what I'm not, and also how the person evaluates their experience. You know, so some people may catastrophize, and that sort of makes them attend more to the pain, and that then elevates the sort of extent to which they actually perceive it, and the whole thing

kind of spires out of control, whereas other people may not be attending to the pain, there may be other sensations that sort of subsume that. And an example of this could be both athletes and wounded soldiers have reported that when there's an injury, they don't necessarily immediately feel anything, possibly because of the adrenaline and the sensory overload of the situation. Only afterwards when those aspects are less salient, then they actually feel the pain. So that may be related to the cognitive evaluative component of pain, as well as recognition that I am in pain, right, and I can experience this now.

And that might seem a bit, I don't know, a bit woolly perhaps, but there is an important component between sort of a mere dull indication that you're experiencing something and sort of attending to it and being aware of the fact that you're experiencing something. So, I mean, a very simple example of this is the fact that you can see that many different objects and sort of colors and textures will be part of your visual field currently. So in a sense, you're seeing them. But most of them you're ignoring, like you're not actually paying attention to them. And even without moving your eyes, you can sort of pay attention to this,

object or that object in your field of view and sort of attend to it, process it, think about it, again, even without even looking at it, right? I'm just talking about attending to an aspect of a visual field. So this would be, again, part of the cognitive evaluative component, which is, especially for humans, very important in the way that we experience things. The key aspect of this trichotomy here is that these different aspects of pain may all be processed by different parts of the brain or different processing mechanisms within the brain. There's no particular reason why we would expect them to all be processed in one single region. This may also explain the different experiences of different people and different types of pain and different people

reacting in different ways in different context. So the hypothesis here is that these different facets of pain are the result of patterns of activity produced by different local networks in different parts of the brain, which are then integrated through complex interconnections to form a unified percept. But that unified percept doesn't have to necessarily be localized to any particular brain region. So the idea here is that we should sort of focus less on trying to identify a specific brain region that produces the perception of pain entirely by itself. But it might be more useful to think about what particular processing is being done by particular regions of the brain that's responsible for particular aspects of pain. And there are different mechanisms that could

potentially be used to investigate this. For example, transcranial magnate stimulation, which is a technique that's able to selectively inhibit or activate regions of the brain temporarily that perhaps could be useful for studying which regions of the brain are responsible for particular aspects of pain. It would be interesting, for example, if we could produce clear and reproducible dissociations between some of these different aspects of pain and thereby understand how some of the facets of pain are produced by different parts of the brain and look at what the local networks might be doing. But unfortunately, at this point, we just don't have enough information or enough understanding to explain quite how it happens.

So before we end up, I just want to make a couple of more general remarks because I do get the feeling that people may be bit unsatisfied by this episode because I haven't really explained where pain comes from. I've talked about noceoception and the different signals and how they're transmitted up to the brain and the different regulatory aspects and opioids and the failure to find a signal brain region that is responsive to pain. But I haven't really explained where it actually comes from. Like where does the actual sensation, the experience come from? as far as I can tell, it comes from the brain, right? So it doesn't come from the peripheral nervous system per se, although it's largely, and typically occurs in response to the input from the peripheral nervousism, particularly nocice exception, but it's actually produced by the brain, but not one specific part of the brain. It's produced by many different regions

of the brain interacting in a particular type of way that we haven't been able to figure out yet. Now, one question that we might consider is, why does pain feel like anything, right? Why don't we just have, I mean, clearly we need to be able to detect aversive stimuli, but why does there need to be a feeling that's associated with it? Why doesn't it just sort of elicit the right response? I think one partial answer to this is that there are instinctive responses that we have. For example, if you're touching a hot object, you'll instinctively pull back your arm. And that's not something, the signal there doesn't even, I believe, for that reflex,

I don't think it has to even go to the brain. I think that one, well, at least some reflexes are purely spinal reflexes. I'm not 100% sure about that one. But the point is that we don't need to consciously think about those sorts of reactions. They just happen, right? And so for things like that, you don't actually need to feel anything, right? But for a lot of experiences, there's no sort of clear one behavioral response that's just sort of always going to be the right one, or almost always, like it is in the case of the hot stove.

For a lot of things, it's going to be an issue of we're going to need to sort of think about and process at a cognitive level what the appropriate response is to avoid that situation or two to help protect from further damage. And so it seems that there needs to be some sort of more generalized signal that's accessible to our conscious awareness that we can then respond to in a deliberative way. I mean, and this is probably true for other animals as well, right, although perhaps at a reduced level because they have a reduced capacity for integrative reflective thought,

but they still have some capacity for that. Although the extent to which other animals experience pain in the way that humans do is a is a controversial and difficult issue, but I'm not going to talk about that here, other than just to say that remember pain is defined as a subjective sensory and emotional experience, and therefore, in some sense, no amounts of comparing the no-susceptive pathways can directly tell you whether another type of organism is experiencing pain, and that's a major limitation of current methodologies. But anyway, the point there is that it seems that the role of pain may be to provide some sort of more generalized signal that's accessible to our awareness and at an emotional

level as well, that then prompts us to respond to that. And I suppose you could still ask, well, yeah, but couldn't there be such a sort of signal that still doesn't feel like anything? And at that point, again, this really moves us into the realm of philosophy rather than science. But at least I would say, well, look, it seems that all of our other sensations are, at least when we're consciously sort of attending to them, you know, sight, sound, touch, and so forth, I mean, they all feel like something. They feel like different things, of course, because they're different, but they all feel like something.

There's a sort of a qualier to them, as a philosopher's say. So it's not really clear that why pain would be different in that respect. And perhaps there's nothing more to say about it other than, look, it just turns out that when you are an organism with a nervous system operating in such and such a way, then there just is such a thing that it feels like to be that, to be that system. I mean, it's sort of no more obvious that there should be something that it feels like than that there shouldn't be, right? I mean, why would you think either way that there should be a thing that it feels like to be in pain

versus not a thing that it feels like to be in pain? So I think that we can understand why we need more than just mere reflexive responses to pain, and that's why there maybe needs to be something more sort of generalized signal that we can respond to. In terms of why does that feel like something, it seems that there's not much that we can say at this point other than, well, sensation just turns out to feel like something when you're that sort of thing. Perhaps one could build organisms that behave similarly but didn't have any sort of. sort of experience, but we don't really know that. And that's something that perhaps it will take a long time to figure out. Although, I suspect that if you try to build anything that even works remotely

like a human in terms of the internal operation, that it will feel like something to be that thing. And so therefore, it would be capable of experiencing pain. Although, as we know, there are weird cases like congenital insensitivity to pain and like referred pain where people experience pain in different parts of their body to where the stimuli actually comes from or in cases of phantom limb syndrome. So there are interesting cases there that, I think causes to rethink some of our maybe preconceptions about how pain works. But anyway, that's enough speculation for now. Hopefully you found this episode interesting, if maybe not entirely satisfying in all respect.

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