So now let's have a different schematic look at these pathways. So on the left side of this figure, we have an illustration of the first pain pathway. So again, this begins with an A delta fiber that is going to provide input into the dorsal horn of the spinal cord. And then from there, there will be a direct projection from spinal cord to thalamus. This side of our anterolateral system, is called the spinothalamic tract, because it's a direct shot between the dorsal horn of the spinal cord. And the principal thalamic nuclei that then relay signals up into our somatic sensory cortex. Now, as you might imagine things are a little bit more complex on the other side of this figure. The other side of this figure is intended to illustrate the second pain pathway. So here's our second pain pathway, which begins with C fibers that provide input into dorsal horn neurons. That then give rise to projections that terminate in a variety of structures throughout the brain stem. And even on up into the forebrain. The structures such as the amygdala and the hypothalamus. Now, we won't talk in depth about all of these targets, but I do want to highlight two in particular. The reticular formation refers to a broadly distributed set of cells in the core of the brain stem. And among those cells are multiple small nuclei. That are involved in very particular kinds of functions. And some of these functions are those that influence our overall level of arousal and our overall level of attention. And it's through such mechanisms, we think, that the reticular formation can receive information about pain and thereby modulate our cognitive states. There's another interesting structure in the brain stem that receives this information. It's called the periaqueductal gray. The periaqueductal gray is a structure in the midbrain that surrounds the cerebral aqueduct. We'll come back and talk more about the periaqueductal gray in a few minutes. This is a structure that's critical for the top down or the feedback modulation of pain transmission in the dorsal horn of the spinal cord. Now, over here on the right side of this bifurcating input is nuclei of thalamus that is on the middle side of that y-shaped lamina. And particularly nuclei right along the mid-line, and nuclei actually buried within that lamina. These nuclei give rise to cortical projections that are accessing part of the brain. They're involved in processing emotional signals. As well as singles that help build up an image of our body that is especially informed by our internal state. That seems to be what's going on here in the insular. Whereas the anterior singular cortex is a very interesting part of the brain. It participates in pre frontal cortical networks that are involved in evaluating the significance or the consequence our actions. And we know some from some very interesting studies that activation of the anterior singular cortex seems to be associated with the burden of our pain. And this can be modulated in experimental studies through hypnotic suggestion. And it's been demonstrated that the more we feel pain as an unpleasant experience the greater is the activity in this part of the cingulate gyrus. Okay. Well I just want to review for you again the overall organization of somatic sensory pathways. And I'm going to refer you to a separate tutorial to go into more detail about the organization of the pain pathways. But I'll just remind you that for the conscious awareness of somatic sensation, we have two pairs of pathway. One pair of pathways serves the post-cranial body and another pair that serves the region of the anterior cranium, including the face. So for the post-cranial body then, we have pathway that is concerned with. Somatic sensory experience in the domain of mechanosensation. And this would be the dorsal-column medial lemniscal system that we discussed in a previous tutorial. Our system that conveys pain and temperature signals for the post-cranial body is called the anterolateral system. And now, for the anterior cranium for the region of the face, are mechanosensory pathway runs through the principal or the chief sensory nucleus of the trigeminal complex, as we saw in a previous tutorial. But for pain and temperature signals, the processing runs through a different division of the trigeminal brain stem. It runs through the spinal nucleus of the trigeminal complex. So at this point I would encourage you to just hold the thought about the pain pathways. And we'll take that up in a separate tutorial. But for now, let's move on. And consider some topics of particular interest concerning how nociception is processed and modulated by both local factors as well as neural factors. So, let's consider the phenomenon of hyperalgesia. Hyperalgesia refers to inflammatory pain. This is a condition of enhanced sensitivity to mechanosensory stimulation that follows the onset of injury. And the development of a response in the tissue, that engages the immune system and other mediators of inflammation. So hyperalgesia is due to the peripheral sensitization of our nociceptors. Largely due to the action of paracrine mediators of inflammation. So following tissue injury, there's an immune response to that injury. And there are immune cells that will infiltrate the area such as our macrophages and our mast cells or our neutrophils. And they begin releasing immune mediators that can have an impact on, the vasculature. That supplies this region and have impacts directly on the free nerve endings of our first order nociceptive axons. Many of these mediators are those that will modulate the activity of our TRP channels. Things like ATP bradykinins, protons, histamine, prostaglandins. All these mediators can increase the currents that flow through those TRP channels. And thereby increase the sensitivity of those free nerve endings. Well, notice what else is happening here. The free nerve ending itself can release neuroactive peptides that then interact with these immune cells or the vasculature. So, there is in a sense a bit of bi-directional signaling here between the inflamed tissue, and the free nerve ending itself. These interactions can lead to an increase in sensitivity of that free nerve ending to the signals that are being transduced into pain. Well, in addition to peripheral sources of modification that can lead to hyperalgesia, there can also be changes within the central nervous system itself. Specifically in the dorsal horn or in the spinal trigeminal nucleus that can lead to central sensitization. So this can contribute to the phenomenon of hyperalgesia. So there may be activity-dependent increases in the excitability of these second-order neurons, following high levels of nociceptive activity. And this increase in the excitability of these second-order neurons might generalize. From nociceptive inputs to collaterals of other polymodal inputs that might respond to, mechanical stimulation. And this can be a problem, this can lead to a phenomenon called allodynia which means that a normally innocuous stimulus might be perceived as being painful. And perhaps this is happening because these second-order neurons now have generalized their excitable state. Now there seems to be a two forms of central sensitization that reflect the mechanisms of long-term potentiation. So you'll recall from our discussion of synaptic plasticity, that with a coordination of activity across a synaptic connection. That connection can strengthen. There is an early form of long term potentiation that's transcription independent. So, this is what we consider to be a phenomenon that's called wind up in the field of pain management. So this is when there's repeated activation of nociceptors and it leads to the sustained depolarization of that second-older neuron. If there is an NMDA receptor dependent mechanism at play, you can imagine that sustained depolarization. Might be sufficient to remove magnesium block aligned for the influx of calcium. And the establishment of long-term potentiation and such synaptic connections. So, we know that, that the postsynaptic conductances that are dated by glutamate can become more effective now and these neurons that have undergone these sorts of wind-up phenomena. And so, presumably the reflects an activity dependent plasticity at the connection between these first order nociceptive afferents and their targets in the dorsal horn. There's also a transcription dependent form central sensitization that we imagine might be triggered through that influx of calcium. And that requires the mediation of transcription factors that can modify the expression of genes in the nucleus of cells there in the dorsal horn. So changes in gene expression can lead to a longer term maintenance of that hyper-excitable state. So now, let's turn our attention to the central regulation of nociception and pain. And let's consider the phenomenon of analgesia, which refers to the absence of pain. Despite the presence of nociceptive stimulus. Well, as I mentioned at the onset. Pain is a complex phenomenon. And it's subject to all kinds of modulatory influences. For example, context is very important. The emotional context of the trauma. Such as stress during injury can lead to a heightened sense of the experience of pain associated with that injury. Your cognitive understanding can have a profound impact on your experience with pain. Perhaps many of you have been injured during some athletic competition. And perhaps you were aware of the injury at the time, but you quickly, reentered the game and continued to participate. And it was only sometime later that the full impact of that injury was experienced. So somehow, you had the ability to allow context to help you suppress your experience of pain. And then there are cultural differences in the experience of pain. And we, we know this from studies across the world that have looked at the experience of pain in, in different people groups. And we know there can be incredible variation in how different cultures establish their norms for the response to pain. We don't know the explanation for most of these phenomenon but at least some of them seem to be attributable to the feedback or the descending modulation of pain transmission. And we are now getting some insight into the circuitry that's involved. So the feedback pathways that modulate pain are depicted in this figure. And there are a number of structures that are highlighted here. And I'd like to draw your attention to a few of them. One right in the middle is called the periaqueductal gray. This is the gray matter that surrounds the cerebral aqueduct in the midbrain. The periaqueductal gray is really a key node in a network that allows for the feedback modulation of pain. The periaqueductal gray is receiving input from structures in the fore brain such as the amygdala and the hypothalamus. These are structures involved in our emotional experience and expression. The periaqueductal grey receives input from the somatic sensory cortex, and from the insular cortex. And together these inputs are integrated. The output of the periaqueductal grey goes to other parts of the brain stem. In particular, the reticular formation that's present in the medulla. And from this part of the reticular formation, we have inputs that terminate in the dorsal horn of the spinal cord. In addition to the medullary reticular formation, there are really interesting inputs that come from some of the nuclei of the brain stem. That release biogenic amine neurotransmitters, such as the locus coeruleus and the raphe nucleus. The locus coeruleus releases norepinephrine in the dorsal horn of the spinal cord, and the raphe nuclei release serotonin. And these neuromodulators can influence the excitability of the dorsal horn neurons. Well this figure is far from complete. And we don't really understand how all of this works. But the basic principle at play here, is that there are projections from the brain stem to the dorsal horn. That can impact the transmission of nociceptive signals right at the very first synapse in the pain pathway. Also present in that circuity of the dorsal horn of the reason substantia gelatinosa. Are interneurons that release neuropeptides such as enkephalins. And other kinds of endogenous opioid substances. What these neuropeptides seem to do is inhibit the activity of the nociceptive afferent as it makes synaptic contact with the dorsal horn neuron. So we can imagine that descending inputs from structures like the raphe nucleus and the locus coeruleus in the medullary reticular formation can drive the activation of these local circuit neurons. With the effect of turning off the output from that dorsal horn. And that, we think, is one way that the brain can produce an analgesic effect right at the very first synaptic junction along our nociception pathway.
