Welcome back to Medical Neuroscience. Today, we're going to talk about the Pain Systems. This topic is one of the most complex that we can conceive in the whole field of Medical Neuroscience. So it's not surprising that we're going to be once again reinforcing our core principles that the brain is the body's most complex organ. We're going to be talking about the circuits that arise in early brain development that give rise to our perceptions of pain. And then what we do with those perceptions as pain becomes part of what our cognitive faculty now integrate into our integrated perception of self. And, of course the human brain endows us with a natural curiosity to want to know how all of this works. And, as we begin to discover more about the nature of pain processing. And the interactions between our pain systems and other aspects of cognition. We're on the threshold I believe to really understanding how to best manage individuals who suffer from pain of various sorts. So it's a very exciting time To be learning about neuro science and it's applications in the world of healthcare. Our learning objectives today are to be able to discuss with some foundation the complex phenomenology of pain. I want you to specifically be able to describe the two basic categories of pain that we often differentiate clinically. They're called first and second pain. And explain the neural foundation of each. I want you to be able to characterize the peripheral and the central mechanisms underlying hyperalgesia. I want you to be able to characterize the neural mechanisms for the feedback modulation of nociceptive processing. And I also want you to consider the feed forward modulation of pain processing. And lastly, I want you to be able to discuss the effective dimensions of pain. And identify the neural systems that are involved in pain affect. It might be useful in our discussions to consider that no nociceptive aspects of pain from the affective or the emotional aspects of pain. And it's from the latter that we believe arise the notion of suffering. So let's begin by discussing the complex phenomenology of pain. Well, we're going to spend a little bit of time on the neurophysiology of pain systems. And we will begin by considering pain as one submodality of somatic sensation. And the word we use to describe this is called nociception, which means pain perception. But we know that the phenomenology of pain goes well beyond nociception. There's an affective component to pain that has bearing on our emotional lives. And then there's a phenomenon that we call secondary affect, which refers to how the impact of chronic pain begins to work it's way into our emotional life. Especially as we consider the future consequences of living in pain. And all of this, of course, happens within the psychosocial context that can have a significant impact in modulating the experience of pain. So I think you get the idea. That, to understand pain. One needs to understand the transduction of signals in our nociceptive pathways. But one needs to go well beyond the concept of nociception. Well, for those of you that are headed towards careers in the health care systems. There is, quite a lot of change that has taken place over the last decade. And will likely to continue to take place, as the impact of pain in health care management, continues to evolve. We've seen, a, a, a radical, change in the way that we assess pain. At least here in the United States thankfully. Assessments of pain is now part of standard procedure. Every time a patient enters the health care system. But even the best practice for how we assess pain is not so clear. There are changing strategies for pain management. And I think we're seeing A welcomed introduction of interdisciplinary approaches in pain management. And I think that's going to be a key strategy towards dealing with not just nociception but the consequences of pain as well. And as a result of all of this I think we will continue to see a changing role for health care professionals. In the management of pain. Well, I share this with you just to give you the broader context of the problem of pain in medical neuroscience. Okay, well, let's begin to talk about the neurophysiology of pain beginning with the neurophysiology of nociception. Well, as you remember from last time nociception begins at the peripheral ending of a dorsal root ganglion neuron. And in the case of our pain and temperature afferent fiber, that dorsal root ganglion neuron grows an axon that ends a structure called a free nerve ending. The central process extends into the spinal cord where there is a synaptic connection with a neuron in the dorsal horn. And note, that's an important distinction between our mechano sensory pathways and our pain and temperature pathways. The mechano sensory pathway extends essential the central process, then enters the dorsal column. And then grows up to the caudal level of medulla before making a synaptic connection along the mechanosensory pathway. But for pain and temperature the first synapses right here at the dorsal horn, we will come back to that point. For now, let's turn our attention to this receptor ending. And what we discover Is that within the tissues of the body, there is a type of ending that we call a free nerve ending. Because these free nerve endings are not encapsulated. They're not associated with any particular specializations of Schwann's cell, Lamelly, nor are they affiliated with special cells, such as Merkel discs cells. So they're free nerve endings. Thy distribute fairly broadly within the tissues. Suggesting that they have a fairly large, receptive field size relative to some of our finer processes, like these Meissner's corpuscles, for example. So these free nerve endings. These are the structures that will transduce the signals the signals that lead to the generation of action potentials in our pain and temperature fibers. Well let's look at those fibers. The pain and temperature fibers are among the smallest sensory fibers that we have in our spinal and cranial nerves. They come, basically, in, in two classes, one of which can be further sub-divided. Those classes are the A delta fibers and the C fibers. The A delta fibers include axons that end in receptors that are sensitive to mechanical stimulation that can lead to nociception. There's also a type of delta fiber that is sensitive to both mechanical energy and thermal energy when it threatens to damage tissue. Now, notice that these A delta fibers are a little bit thicker. They have in axons that diameter a couple of microns, they tend to be lightly myelinated. In contrast our C fibers on the other hand, are very small indeed. And most of these are very poorly myelinated or perhaps unmyelinated all together. So that suggests that the conduction velocity of the A delta is going to be greater than the conduction velocity of the C fibers and indeed that's the case. We'll come back to that point about speed in just a moment. So these C fibers they are polymodal. And what we mean by that is that they respond to multiple modalities of energy or of chemical conditions that potentially can signal damage to the tissues of the body. So they respond to thermal, mechanical and chemical stimuli. So lets think now about the transduction mechanisms at the ends of these axons. So what we find at the end of these axons is a type of channel that was discovered not too long ago. And it's a type of channel that is a member of the Transient Receptor Potential family of ion channels. So we call these TRP channels for short, and there's a whole variety of TRP channels that have since been characterized. These TRP channels. Might be sensitive to one of a variety of stimuli. They may be sensitive to heat. There are TRP channels that are sensitive to cold. There are TRP channels that are sensitive to the presence of protons indicating acidic conditions developing, often. Secondary to tissue damage and inflammation. And then there are modulatory sites on these channels that combine organic compounds such as Capsaicin. So Capsaicin is a substance in chile peppers that give it its heat. And isn't it interesting. That we've come to use this word to describe the experience of eating a chile pepper. We say that it's hot we say that my mouth is burning. When in actuality this substance is modulating the activity of a TRP channel that otherwise might very well be sensitive to heat. So, it seems like we've gained some insight into nueroscience through the culinary arts, so I think that's, that's a wonderful idea. Okay. So, these TRP channels then can be modulated by a variety of substances. And they can be gated via the interaction of these channel proteins. With, protons, heat, cold. Other factors that are released by the mediators of inflammation in damaged tissue. And what these channels do when they are open, is they allow for the passage of cations, like sodium and calcium. So as sodium enters the cell it will depolarize the cell. Produce a generator potential. And potentially an action potential if the threshold is crossed. Calcium as you will recall, is an important mediator of second messenger signaling within the cell. So as calcium levels change within the terminals of these free nerve endings, then there may be a variety of consequences which respect to protein posphorylation and deposphorylation. And that will be important for understanding the impact of inflammation and the sensitivity of these free nerve endings. Now, let's move to consider what happens in the central nervous system. When the cental process of these first order axons enters the spinal cord. So, here, we're looking at a cross section through the lumbar level of the spinal cord. And we imagine that somewhere out here is a dorsal root ganglion cell that ends in a free nerve ending. And the central process enters this dorsal root entry zone and synapses on neurons in the dorsal horn. And I'll just highilght one very interesting part of the dorsal horn. I've told you elsewhere that the dorsal horn is a series of layers of cells. And one layer that's very important in processing signals related to pain is called layer two or laminae two. And it's identified on the left side of this panel. This is called the substantia gelatinosa for the appearance of this layer in a myelin stain such as what we're seeing here. So it appears rather bright. Meaning that it's densely populated by small cell bodies. With the exclusion of most heavily myelinated axons. So, within this region, this laminae two. We have a rich assortment of projection neurons and interneurons that are going to be receiving the input from these first order axons. The circuitry of the dorsal horn is going to be an important mediator of signals coming both down from the brain as well feeding forward into the spinal cord that will modulate the transmission of pain signals. From the first order axon, to the second order cell body, so we'll come back and talk more about that circuitry near the end of this tutorial. Here's yet a more schematic look at this circuitry here the dorsal horn. So there are, are pain and temperature afferets, are C fibers or a delta fibers coming in to the dorsal horn. And here's our substantia gelatinosa, our layer two. And deeper down we have additional cells that receive this incoming Information about pain and temperature. Near the base of the dorsal horn in laminaes five and six. And notice that the C fibers they tend to terminate more superficially. Mainly in what's called the marginal zone and in the substantia gelatinosa, this more posterior cap of the dorsal horn. Whereas the delta fibers tend to terminate more deeply, on these large projection neurons that are found in laminae five and six. The delta fibers might also give rise to a superficial collateral. So I think it's helpful to just remember that the C fibers predominately terminate out in the region of the substantia gelatinosa. Whereas the A delta fibers tend to project more deeply at the base of the dorsal horn. Well, from both places from the more superficial parts of the dorsal horn as well as the deeper part second order axons arise from neurons that will then project all the way up through the brain stem. And terminate among targets there and in the thalamus, as we'll see in more detail in a different tutorial. But for now, what I want to do is highlight the difference we think, from a functional and clinical perspective between the signals conveyed via the A delta fibers and those conveyed via the C fibers. Now, imagine the unpleasant scenario of banging your thumb with a hammer. Or perhaps, closing a door on your fingers. That's going to hurt. And the way it's going to hurt is that there will typically be a very rapid, sharp shooting pain. So we call that first pain. And that first pain typically subsides in just a matter of seconds. And what's left is more of a throbbing pain, that we call second pain. So there's this first pain and a second pain. And we think that these two qualities of pain that follow slightly different temporal dynamics correspond to signals that are transduced by A delta fibers and C fibers. We think the A delta fibers are associated with the first pain. And the C fibers are associated with transducing the second pain. We know that because in experiments when it's possible to silence or to take out the a delta fibers, all that's left is the second pain. And in complementary experiments, where the C fiber has been silenced. What we have is the sharp shooting pain, but not so much this dull, aching pain that evolves more slowly and persists for a longer period of time. Well, as it turns out, the dorsal horn neurons that are receiving this input from the A delta and the C fibers seem to give rise to different connections. The dorsal horn neurons that sit down in those deeper layers, layers five and six of the dorsal horn, give rise to projections that travel directly to, to the thalamus. And from there, there is a relay in the ventral posterior complex. Sending signals into the somatic sensory cortex In the post central gyrus. So this is a relatively rapid pathway for the transmission of signals from the A delta fiber to the thalamus, and then on to the somatic sensory cortex where the localization of injury can be quite precise. Because this information is now being elaborated within the context of this exquisite map of the contralateral body surface that's found in the post central gyrus. Now, in contrast, the C fiber system gives rise to much more diffused set of projections. And we might have inferred that, that would be so if second pain is associated with more of an emotional or affective component. One might imagine that the C fiber information should gain access to those parts of the brain that are concerned with emotion. And indeed they do. The c fiber pathway enters the dorsal horn synapses in the more superficial parts. Like the marginal zone, and the substantia gelatinosia. And from those more superficial layers, projection neurons grow axons through the spinal cord into the brainstem. And along the way, these axons terminate among a variety of structures in the brainstem. Structures that have widespread influence over the activity of cells in the forebrain. Some of these fibers will also make it to the thalamus. But rather than synapsing in the ventral posterior complex, they tend to synapse in medial nuclei in the thalamus. Those that, likewise, give rise to widespread projections to parts of the brain that are more concerned with aspects of cognition, than they are with the localization of somatic sensory stimuli. Those regions are in the ventral and medial parts of the forebrain, what we might call the limbic forebrain. So, these pathways then suggest something about the functions of our A delta and C fibers. They seem to provide information that runs in parallel, but serves quite different purposes. With the first pain pathway helping us to localize the source of the injury to our tissues. Whereas the C fiber pathway seems to motivate in response to that injury.