Hello again amazing nerds. In the previous text I went through what is nociception and how our bodies are able to take a stimulus from our environment, for example heat from a fire, transform it into nerve signals and interpret it. I also explained that many brain areas are involved in interpreting this potentially threatening information and that the outcome of this interpretation is not always pain, despite the nociceptors being activated. So let’s pick up from there.
The interpretation of nociceptive signals is done by the synchronous activity of multiple brain areas, which include areas associated with sensation (somatosensory cortex), emotion (anterior cingulate cortex and insular cortex), fear and anxiety (amygdala and limbic structures), as well as others (Gore, 2022; Hudspit, 2019; Hudspith, 2022). As you can see, a lot of these areas are also involved in functions that are not related to the interpretation of noxious stimuli (Hudspith, 2022). This is theorised to be because all our bodily systems have the ultimate function of ensuring our survival, primarily by maintaining homeostasis (Hudspith, 2022). It has also been theorised that the most efficient way for the body to maintain homeostasis is to answer its needs before they even arise, in other words, prediction (Hudspith, 2022).
In order to predict what our body will need, multiple areas of the brain are linked in a network that allows it to create an auto-representation of states of our body in the environment and circumstances we currently inhabit – what can be called an ‘integrated self’ (Hudspith, 2022). This representation is dynamic because the internal state of our body as well as what is happening in the environment around us will change. In order to keep up with this our body continuously probes for information from the environment, and from inside itself, using our senses and sensory organs, which include the nociceptors (Hudspith, 2022). However, this representation of an integrated self does not appear to be just a result of the information the brain receives, as there is evidence that the network involved in the representation will display spontaneous activity not linked to any stimuli (Hudspith, 2022). This is theorised to be a sign of the previously mentioned prediction, technically called ‘predictive processing’ – the brain is changing its own representation of the body (which includes the brain) based on what it predicts is likely to happen (Hudspith, 2022).
How does the brain predict what is likely to happen? Remember above when I said that multiple areas of the brain are responsible for interpreting nociceptive and other sensory information that the brain receives? This includes areas linked to our memory, emotions, as well as conscious thinking (Gore, 2022; Hudspith, 2022). I hope you’re already seeing where we are getting to. The brain makes predictions based on past experiences which, together with our current emotional state and thoughts, will shape how the information received about the current body state and the environment is used in the prediction (Hudspith, 2022). What if the brain predicts there is a high probability that there is going to be an injury or another threat to homeostasis (independently of if it actually happens or not)? It will make the experience of pain emerge as a way of prompting us to action to reduce the consequences of the threat that is already present (injury) or the predicted threat (Hudspith, 2022).
In this same line, and based on these predicted body states, the brain and body can also decide not to respond with pain to noxious stimuli, even being able to modulate the activation threshold for the Aδ and C-fibre nociceptors (Hudspith, 2019). This modulation can be achieved through both bottom-up (from tissues in limbs and organs to the brain) and top-down processes (from the brain to the tissues on limbs and organs) (Gore, 2022).
At the periphery, the activation of nociceptive fibres can be modified by several biological molecules, such as those released during the inflammatory response that occurs during a tissue injury (Gore, 2022; Hudspith, 2019). This inflammatory cascade starts with the release of certain molecules from the injured cells as well as the gathering and activation of immune cells such as lymphocytes and macrophages (Hudspith, 2019). These immune cells also release their own molecules, creating what is often termed ‘inflammatory soup’, a concentration of the following molecules, among others (Hudspith, 2019):
- Bradykinin;
- H+ ions;
- ATP;
- Purines;
- Prostaglandin E2;
- Leukotirenes;
- Cytokines (e.g. TNFα and IL-1β);
- Nerve Growth Factor (NGF)
These different molecules produced by our body can modify how nociceptors respond to noxious stimuli, making them easier to activate through noxious stimuli and decreasing their threshold for sending a signal to the spinal cord in two ways (Hudspith, 2019):
- Affect the electrical charge of the membrane of the nociceptor nerve cell, reducing the threshold for activation and for sending a nerve signal.
- Influencing the expression of genes in the nerve cell, which regulates the synthesis of receptors, in practice increasing the literal number of receptors that nerve cell has got.
In addition to what happens peripherally, the activity of nociceptors can also be modulated by higher brain centers (Gore, 2022). The brain can increase the sensitivity of nociceptors through a process called ‘central facilitation’(Wallden and Nijs, 2021b), but it can also reduce their activation through anti-nociceptive cerebral structures and descending pathways that use inhibitory interneurons at the level of the spinal cord (Gore, 2022).
As you can see, processes occurring both at the level of the tissues as well as regulation by the brain can increase or reduce the activity of nociceptor nerve signals. It is theorised our body does this based on the probability of predictions mentioned above. This could lead to there being a lot of tissue changes and noxious stimuli causing nociceptor activation, but the body doesn’t interpret those symptoms as dangerous, so it dials down nociceptor activity, and the pain response isn’t produced. At other times the body has such a high expectation of a threat, making the nociceptors so sensitive, that the minimal noxious stimulus (knocking or shoulder on the door frame) is sufficient to make the body produce a very intense pain response without any actual tissue damage present.
Just to make things more complex, the inflammatory soup described above can result from tissue damage, however, it can also be caused by other factors such as psychological and emotional stressors (Wallden and Nijs, 2021a). You read that right. When we are exposed to psychological and emotional stressors that we struggle to cope with, particularly over a long period of time, this causes physiological stress in our body, triggering the production of stress hormones such as cortisol and noradrenaline, which can drive inflammation through activation of immune cells such as macrophages and release of cytokines, which in turn increases the inflammatory soup and creates a state of low-grade grade inflammation in our body (Hudspith, 2019; Wallden and Nijs, 2021a; Wallden and Nijs, 2021b). Like before, this leads to sensitization of nociceptors – an increase in the number and/or intensity of signals (Hudspith, 2019).
The areas of the brain mention above to be involved in the regulation and processing of nociceptive inputs, as well as in the pain response, have been shown to be more active in people with depression and anxiety in a pattern that overlaps with the one shown by people suffering with chronic pain (Gore, 2022). This link, which we still can’t with all certainty say it’s a causal one, has been reinforced by several authors who have found that psychological factors like depression, anxiety, fear of movement, and catastrophising of pain lead to increased sensitivity to feeling pain, the intensity of pain felt and risk of developing chronic pain (Gatchel et al, 1995; Kehlet et al, 2006; Linton and Shaw, 2011; Merlijn et al, 2003; Tang and Gibson, 2005; van Wijk and Vedhuijzen, 2010).
I hope that I have managed to help you understand at a basic level the anatomy and physiology behind pain, but also that this isn’t a direct one-way process. As you can see, pain is a complex experience that is influenced by anatomy and physiology, including what is happening in the tissues and what the brain does with that information and tells the tissues to do, but also by other physical and mental factors, including our emotions and psychological well-being. And these processes are present in both a simple ankle sprain done yesterday as well as chronic multiple-joint pain that has been lasting for years.
Let me know if you have any further questions and please share this text if you found it interesting and informative.
I hope to see you on the next one,
The Physiolosopher.
References
Gatchel RJ, Polatin PB, Mayer TG. The dominant role of psychosocial risk factors in the development of chronic low back pain disability. Spine. 1995;20:2702–2709.
Gore, D. G. (2022). The anatomy of pain. In Anaesthesia and Intensive Care Medicine (Vol. 23, Issue 7, pp. 355–359). Elsevier Ltd. https://doi.org/10.1016/j.mpaic.2022.04.002
Hudspith, M. J. (2019). Anatomy, physiology and pharmacology of pain. In Anaesthesia and Intensive Care Medicine (Vol. 20, Issue 8, pp. 419–425). Elsevier Ltd. https://doi.org/10.1016/j.mpaic.2019.05.008
Hudspith, M. (2022). The genesis of pain. In Anaesthesia and Intensive Care Medicine (Vol. 23, Issue 7, pp. 360–364). Elsevier Ltd. https://doi.org/10.1016/j.mpaic.2022.03.007
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Wallden, M., & Nijs, J. (2021a). Applying the understanding of central sensitization in practice. Journal of Bodywork and Movement Therapies, 27, 723–730. https://doi.org/10.1016/j.jbmt.2021.04.004
Wallden, M., & Nijs, J. (2021b). Before & beyond the pain – Allostatic load, central sensitivity and their role in health and function. In Journal of Bodywork and Movement Therapies (Vol. 27, pp. 388–392). Churchill Livingstone. https://doi.org/10.1016/j.jbmt.2021.04.003
van Wijk G, Veldhuijzen DS. Perspective on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes. J Pain. 2010;11:408– 419.
The Physiolosopher 