An introduction to the stress response systems

In modern society, we have to deal with daily stressful events challenging our own body and its capabilities¹. Think about posting something on Instagram and waiting for that first like, managing a heavy workload with strict deadlines, or worrying about the things you will have to do tomorrow. These situations are called stressors and the physiological changes in response to these stressors shape the stress response². Is this harmful? Well, a short-term stress response to a stressor (either painful or non-painful) is adaptive and essential for survival because it prepares you to act³. Try to imagine walking in a forest, and suddenly, you cross paths with a hungry-looking grizzly bear. Here, a stress response would be essential to survive. Your autonomic nervous system will lead to a very rapid, short-term increased secretion of (nor)adrenaline, resulting in increased heart rate to pump more blood to the working muscles, increased breathing rate to take in more oxygen, increased glucose release in the bloodstream to provide energy, etc. Another major stress system is the hypothalamus-pituitary-adrenal (HPA) axis which increases the secretion of catecholamines (e.g. cortisol, often referred to as the “stress hormone”) that also helps regulate the stress response and can be sustained over a longer period of time⁴. Encountering a grizzly bear was an example of an extreme situation that (luckily) does not occur on a daily basis, but the physiological mechanisms are similar in response to day-to-day stressors.

What happens to the HPA-axis when stress becomes chronic?

Well, chronic reactivation of the stress response may result in a dysregulated stress system³, leading to either a hypo- or hyperactive system⁵. HPA-axis activation in response to acute stress results in higher levels of cortisol. However, in chronic pain conditions, both increases and decreases in cortisol have been reported⁶. The functioning of the HPA-axis might depend on the extent and chronification of pain. Chronic localized pain conditions, e.g., low back pain, seem to be associated with repetitive overstimulation of the HPA-axis with excessive release of cortisol, while, on the contrary, chronic widespread pain conditions, e.g., fibromyalgia, seem to be associated with lower cortisol levels⁶ and might be explained by downregulation of pituitary receptors, increased negative feedback sensitivity, reduced cortisol production, hormone depletion or changes in the adrenal cortex^7,8.

Hypothesized characterization of the HPA-axis functioning in chronic pain

Since the functioning of the HPA-axis seems to be associated with the extent and chronification of pain, it is hypothesized that chronic localized pain groups have higher basal levels (before a stressor) of cortisol, an increased reactivity to an acute stressor, and a slower recovery from that stressor compared to pain-free controls, whereas chronic widespread pain groups have lower basal levels of cortisol, a blunted reactivity to a stressor, and a slower recovery.

Recap: What is the influence of chronic stress on cortisol levels and what is its association with chronic pain?

Chronic overuse of the stress system can result in a dysregulated HPA-axis that is either hyperactive or hypo-active, and is possibly dependent on the chronification and extent of pain. However, more research is needed to map the functioning of the HPA-axis in different (chronic) pain groups divided by their pain distribution and duration. My (stressful) doctoral thesis focuses partly on mapping the HPA-axis functioning and its association with chronification and expansion of locations of pain. It is postulated that the functioning of the stress systems play a key role in pain, and in particular interactions between stress and pain confer vulnerability for spreading and chronification of pain.

Final note: Curious about the methods of measuring cortisol in human research?

Cortisol is often measured in saliva, serum and urine representing short-term levels whereas cortisol can also be assessed in hair assuming that hair grows at one cm per month. A sample of three cm determines cortisol secretion of three months retrospectively, which is suited for investigating long-term endocrine responses⁹.

Feel free to ask for more information by sending me an email: Joren.Vyverman@UGent.be

Interesting literature:

• Timmers, I., Quaedflieg, C. W., Hsu, C., Heathcote, L. C., Rovnaghi, C. R., & Simons, L. E. (2019). The interaction between stress and chronic pain through the lens of threat learning. Neuroscience & Biobehavioral Reviews, 107, 641-655.
• Sapolsky, R. M. (2004). Why zebras don't get ulcers: The acclaimed guide to stress, stress-related diseases, and coping. Holt paperbacks.

Joren Vyverman

Joren Vyverman is a joint predoctoral researcher at Ghent University and Tilburg University investigating the interaction between stress and pain.

2024Pain in Motion

¹https://pubmed.ncbi.nlm.nih.gov/?term=stress+socie...

²https://pubmed.ncbi.nlm.nih.gov/29614900/

³https://www.researchgate.net/publication/264056771...

⁴https://europepmc.org/article/nbk/nbk541120

⁵https://pubmed.ncbi.nlm.nih.gov/27262345/

⁶https://pubmed.ncbi.nlm.nih.gov/21764519/
⁷https://www.sciencedirect.com/science/article/pii/...

⁸https://www.sciencedirect.com/science/article/pii/...

⁹https://www.sciencedirect.com/science/article/pii/S0009912018307306#:~:text=Hair%20cortisol%20analysis%20is%20a,its%20use%20in%20wider%20settings.