The Neurobiology of Pain by Dr. Clifford Woolf. Hello. My name is Clifford Woolf, and I am director of the program in Neurobiology at Boston Children’s Hospital. And I’m going to talk today about the neurobiological mechanisms that are responsible for the generation of pain and the implications of these mechanisms for both the prevention and treatment of pain. Introduction. I think it’s reasonable to ask first the question, why do we experience the sensation of pain What particular functional role does it have And perhaps the best way to answer that is.
To look at those patients who lack sensitivity to pain. And this occurs in rare cases of mutations to particular genes which result in a congenital insensitivity to pain. One of the more recent such genes is a voltage gated sodium channel called Nav1.7. And loss of function mutations in this channel result in individuals who experience no pain whatsoever. The consequences of this are really quite severe. These individuals not only demonstrate a lack of pain in response to noxious stimuli, but actually damage themselves because they are unaware of the potentially damaging features of their environment.
For example, we explore the world with our fingers. And if we are not aware that something is potentially dangerous, we may actually injure ourselves. Equally, when we eat, part of the way we detect whether food is too hot is by our pain mechanisms. And if we lack this, we are at risk of scalding our mouths and our tongues, and indeed, even chewing our lips and tongues. So individuals who lack the sensitivity of pain typically have severe tissue injury, and indeed, their life expectancy is reduced. So the protective qualities of pain are really.
The Neurobiology of Pain by Dr. Clifford Woolf, for OPENPediatrics
Essential as an early warning device to tell us about impending danger in the environment. And this early warning device is mediated by a specialized sensory apparatus that is activated only by intense or potentially damaging stimuli, stimuli that we call noxious. And the sensory fibers that mediate this function are called nociceptors, which is another way of saying these are sensory neurons that respond only to noxious and not to innocuous stimuli. One of the big breakthroughs in our understandings of the mechanisms of pain have come from the recognition that the sensory neurons, the nociceptors that respond to noxious stimuli,.
Have particular proteins, called transducers, which encode features of the environment particularly those associated with intense or damaging stimuli and convert these stimuli into electrical activity, which activates these nociceptor fibers and carries information to the central nervous system where it can elicit both the sensation of pain, which we call nociceptive pain pain evoked by a noxious stimulus as well as withdrawal responses. When we analyze the pathways that are responsible for nociceptor receptive pain, we need to appreciate that the actual sensory experience of pain itself occurs within the brain. This.
Is where the conscious sensation arises from an activation of several major cortical areas. And the flow of information that leads to this conscious awareness goes through several levels of the nervous system, including subcortical thalamic regions, regions of the brain stem, as well as a major processing within the spinal cord. And indeed, it is activity in the spinal cord which is really the gateway to the activation of those pathways that lead to the sensation of pain. And as we’ll see later, changes in the function of the spinal cord can lead to both increases.
Or decreases in our sensitivity to pain, and central modulation is a major contributor to several clinical conditions associated with pain. But in the end, the major driver of nociceptor pain is activation of the peripheral sensory neurons, the nociceptors. And this occurs in response to noxious heat, intense cold, mechanical stimuli, such as a pinprick, as well as a variety of chemical irritants which produce, typically, a burning sensation. So this then is nociceptor pain, the pain that helps inform us about damage and helps us to avoid such damage.
This particular slide now just illustrates the way in which a peripheral stimulus acting on the nociceptors through the protein transducers results in the activation of nerve fibers which carry action potentials from the periphery to the central nervous system, eventually to those parts of the brain which lead to the conscious awareness of a noxious stimulus that unpleasant sensation that we feel as pain. The reason is the sensation is unpleasant is because that is a major driver of our learning to avoid such stimuli. So part of the protective mechanism of pain is the immediate unpleasantness.
Of a noxious stimulus, but also the fact that we then learn to avoid such stimuli in the future. And absence of the capacity to feel pain in patients with congenital insensitivity to pain results in them failing to learn this and damaging themselves repeatedly. Clinical Pain Syndromes. Nociceptive pain is a physiological pain. It’s the pain that all of us experience in our daily lives. However, there are, obviously, many clinical pain syndromes and a major feature of all of the pain syndromes is that, instead of being activated only by noxious stimuli,.
In clinical pain situations, pain may arise spontaneously, in the absence of any stimulus. So, normally, in order to feel pain, you need an intense stimulus, such as touching something that is too hot, but in patients, the pain may arise in the absence of any detectable stimulus. So spontaneous pain is one of the major features of clinical pain syndromes. Another major feature is heightened sensitivity. Normally, to feel the sensation of pain, we need to be exposed to an intense or damaging stimulus, a noxious stimulus, whereas in patients,.
A stimulus that would normally produce in us an innocuous sensation, such as light touch or pressure or movement of a joint, now can be intensely painful in a patient. And a big feature, mechanistically, about how pain is generated is to understand this transition from a high threshold pain, which is nociceptive pain, to low threshold clinical pain syndromes, because it is this hypersensitivity which is the feature that makes pain so difficult for our patients. We can further look at clinical pain syndromes as having several major subtypes. One subtype.
Is inflammatory pain, the pain associated with tissue damage and inflammation. Another is neuropathic pain, which is the pain that occurs in the presence of damage to the nervous system itself. And this could be damage either to the peripheral or to the central nervous system. And then finally, we have a group that is only relatively recently been recognized, and these are patients who are not exposed to a noxious stimulus, so they do not have nociceptive pain. They have no tissue damage or inflammation, so they do not have inflammatory.
Pain, and there is no detectable damage to the nervous system. And, instead, these patients seem to have an abnormal functioning of the nervous system and this is why we call this group of patients as having dysfunctional pain. What I will now do is go through some of the major features of these different clinical pain syndromes and highlight some of the mechanisms that have been identified as contributing to these particular kinds of pain. So to start off with will discuss inflammatory pain, the pain that is associated with inflammation, for example, associated with a bacterial infection.
Or tissue damage, fine tissue damage, which could be post surgical or post trauma. And the feature here is that the peripheral inflammation activates immune cells, which are both recruited and activated, and these produce a variety of chemical signals, inflammatory modulators, some of which are lipids, some are ions, and some are proteins. And these act on nociceptors to change their function. And a major feature of the changes that occur are an alteration in the excitability of nociceptors, such that their threshold is reduced. They can now be activated by less intense stimuli then what occurs in normal noninflamed tissue.
So inflammatory pain is a consequence of changes in the sensitivity of the nervous system, both the peripheral nervous system what we call peripheral sensitization as well as changes that occur within the central nervous system what we call central sensitization. And I’ll explain a little later exactly what occurs and how these changes manifest. The next kind of pain I wish to discuss is neuropathic pain, which as I’ve indicated earlier, is pain associated with damage to the nervous system itself. And the neural lesion result in pathological changes in the function of the nervous system. So this is.