Knowing Neurons
Sensation and Perception

The Mystery of Chronic Pain: When your body goes past the “Ouch!”

By Anastasiia Gryshyna

Have you ever wondered why some of us have chronic pain while others do not? Most of us have experienced the awful sensation when you burn your finger or stub your toe. But can you imagine having this feeling constantly? Chronic pain, defined as pain that lasts more than 3 months, brings a significant negative impact on a person’s quality of life (IASP, 2022). Chronic pain also has been associated with the development of mental health disorders, such as depression and anxiety (Dominick et al., 2012). Therefore, understanding the root of chronic pain and how it develops is currently a “hot” topic of pain research. This article will explore some of the recognizable theories of acute-to-chronic pain progression, as well as what neuroscientists are doing now to possibly prevent and treat chronic pain.

What is Pain and Why Do We Need It?

According to the International Association for the Study of Pain (IASP), “Pain is an unpleasant sensory or emotional experience that is associated with, or resembling that associated with, actual or potential damage” (IASP, 2022). Pain can be further divided into three types: protective, adaptive and protective, and maladaptive (Prescott & Ratté, 2017; Linton et al., 2018). Protective pain, also called nociceptive pain, is important for detecting the potentially “dangerous” sensations (Woolf, 2010). This is the type of pain that tells you not to keep a hand on a hot surface and say “Ouch!” when touching something sharp.

Similar to protective pain, adaptive and protective pain protects our body from damage. However, it does this by recruiting immune cells that cause inflammation and pain. Therefore, this pain is also called “inflammatory pain” and its the one you might have after surgery. The inflammatory pain is necessary in order to encourage the patient not to move the damaged region post-operation (Woolf, 2010).

Maladaptive pain…causes persistent pain even if there is no physical damage.

Lastly, the third type of pain is maladaptive (chronic) pain, which is the one that many scientists are trying to understand because it serves no benefit to the individual (Linton et al., 2018). Maladaptive pain results from abnormal functioning of the nervous system, which causes persistent pain even if there is no physical damage. This makes the treatment of maladaptive pain very difficult because, quite frankly, the specific source of the pain is unknown (Turk, 1990; Carnago et al., 2021).

Acute to Chronic Pain Progression

Development of chronic pain is often attributed to the body’s pain inputs becoming more sensitive. This process is called central sensitization of pain inputs. In other words, exposure to persistent pain can increase the sensitivity of the neurons in the central nervous system (Woolf, 1983). This increase in neuronal firing can result in hyperalgesia (increased pain to painful stimuli) and allodynia (increased pain to normally non-painful stimuli; Latremoliere & Woolf, 2009). Hyperalgesia and allodynia are normal phenomena, and are necessary to promote good tissue healing and often resolve overtime. However, the process of increased sensitivity may lead to persistent hyperalgesia and allodynia, which marks the transition from acute to chronic pain (Lavand’homme, 2011).

But how does our system become chronically sensitive even after the damaged tissue heals? The answer lies in a phenomenon called long term potentiation (LTP). LTP refers to prolonged strengthening of the neuronal signals that transmit information between synapses, such as pain (Rygh et al., 2005). As a result of LTP, your body increases the release of neurotransmitters, signals that transmit information about pain. Over time, there is a substantial increase in these pain-inducing neurotransmitters and, therefore, you have a lot more “painful” signals coming to your brain even in the absence of nociceptive stimuli (Rygh et al., 2005). This persistent release of neurotransmitters also results in prolonged hyperalgesia and allodynia, making it a maladaptive disease on its own (Sandkuhler, 2009).

Exposure to persistent pain can increase the sensitivity of the neurons in the central nervous system

You can think of of LTP as a sort of “memory” of the painful experiences. In fact, LTP is also observed in our hippocampus, a region of the brain responsible for memory consolidation. So, chronic pain might actually be a persistent memory of the pain we’ve had in the past! However, although some mechanisms are very similar between hippocampal LTP and central sensitization, there are major differences that distinguish memory formation and chronic pain development (Ji et al., 2003).

Although the central nervous system plays an important role in the amplification of pain signals, another important component of chronic pain is peripheral sensitization. Peripheral sensitization occurs in the peripheral nervous system, which is composed of nerve fibers outside of our spinal cord and brain. This sensitization happens when there is an increased immune response at the site of an injury. An increase in the inflammation in the peripheral system can result in the recruitment of many other signaling molecules that can increase the sensitivity of the sensory nerves (Gangadharan & Kuner, 2013). As you can imagine, this can create a positive feedback loop where more inflammatory molecules are released because more pain receptors are stimulated.

Chronic Pain Management

As mentioned previously, chronic pain has a large impact on individual’s mental and physical health. Therefore, appropriate pain management is important to improve quality of life for individuals with chronic pain. When it comes to medical interventions, opioids have been used for many years. However, the problem with opioids is their high potential for addiction; for someone who has had pain for years, taking opioids every day may not be the best management technique. Nanotechnology is a growing field which shows a lot of promise when it comes to pain management. Nanoparticles that carry analgesic drugs show increased efficacy and decreased incidence of addiction, as they can deliver relief via more controlled release of the drug. Additionally, some nanomedicines are designed to decrease sensitization, treating the direct cause of chronic pain rather than just masking its symptoms (Bhansali et al., 2021).

Another exciting chronic pain management tool uses monoclonal antibodies. Antibodies are naturally-produced immune proteins that help our bodies fight infections and detect pathogens. Antibodies have high affinity, or, in other words, they are very good at finding the “right” stuff to bind to. Unlike naturally-occurring antibodies, monoclonal antibodies refer to antibodies engineered in the lab. In pain-related research, monoclonal antibodies can be engineered to recognize specific pain signals and, therefore, recruit our own immune cells to remove pain-inducing molecules. Monoclonal antibodies provide several advantages over current treatments, such as decreased risk of addiction and lower frequency of medicine administration (Sánchez-Robles et al., 2021). However, there are still some disadvantages when using monoclonal antibodies, one of which is that these antibodies cannot cross the blood brain barrier (BBB), a protective cellular layer that prevents circulating blood from entering the central nervous system. Amazingly, some nanoparticles can be engineered to carry a drug though the BBB (Wohlfart et al., 2012). Maybe one day scientists will be able to combine these two promising pain management techniques together!

Conclusion

Many factors contribute to the transition from acute to chronic pain, and, it can be difficult to treat. Besides physiological differences in the course of pain progression, it is also important to acknowledge psychological and social differences between individuals. However, with new innovations in technology, the management of chronic pain may soon become universally effective.

 

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Written by Anastasiia Gryshyna
Illustrated by Nadia PenkoffLidbeck
Edited by Sarah Wade and Mary Cooper

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References
Bhansali, D., Teng, S. L., Lee, C. S., Schmidt, B. L., Bunnett, N. W., & Leong, K. W. (2021). Nanotechnology for pain management: Current and future therapeutic interventions. Nano Today, 39, 101223.

Carnago, L., O’Regan, A., & Hughes, J. M. (2021). Diagnosing and Treating Chronic Pain: Are We Doing This Right? Journal of Primary Care & Community Health, 12, 1-4.

Cohen, S. P., Vase, L., & Hooten, W. M. (2021). Chronic pain: an update on burden, best practices, and new advances. The Lancet, 397(10289), 2082-2097.

Dominick, C. H., Blyth, F. M., & Nicholas, M. K. (2012). Unpacking the burden: understanding the relationships between chronic pain and comorbidity in the general population. Pain, 153(2), 293-304.

Gangadharan, V., & Kuner, R. (2013). Pain hypersensitivity mechanisms at a glance. Disease Models & Mechanisms, 6(4), 889-895.

International Association for the study of pain: IASP. International Association for the Study of Pain (IASP). (2022, December 8). Retrieved December 13, 2022, from https://www.iasp-pain.org/

Ji, R. R., Kohno, T., Moore, K. A., & Woolf, C. J. (2003). Central sensitization and LTP: do pain and memory share similar mechanisms?. Trends in Neurosciences, 26(12), 696-705.

Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: a generator of pain hypersensitivity by central neural plasticity. The Journal of Pain, 10(9), 895-926.

Lavand’homme, P. (2011). The progression from acute to chronic pain. Current Opinion in Anesthesiology, 24(5), 545-550.

Linton, S. J., Flink, I. K., & Vlaeyen, J. W. (2018). Understanding the etiology of chronic pain from a psychological perspective. Physical Therapy, 98(5), 315-324.

Melzack, R., & Katz, J. (2004). The gate control theory: Reaching for the brain. Pain: Psychological Perspectives, 13-34.

Prescott, S. A., & Ratté, S. (2017). Chapter 23 – Somatosensation and Pain. In P. M. Conn (Ed.), Conn’s Translational Neuroscience (pp. 517-539). Academic Press.

Rygh, L. J., Svendsen, F., Fiskå, A., Haugan, F., Hole, K., & Tjølsen, A. (2005). Long-term potentiation in spinal nociceptive systems—how acute pain may become chronic. Psychoneuroendocrinology, 30(10), 959-964.

Sánchez-Robles, E. M., Girón, R., Paniagua, N., Rodríguez-Rivera, C., Pascual, D., & Goicoechea, C. (2021). Monoclonal antibodies for chronic pain treatment: present and future. International Journal of Molecular Sciences, 22(19), 10325.

Sandkuhler, J. (2009). Models and mechanisms of hyperalgesia and allodynia. Physiological reviews, 89(2), 707-758.

Turk, D. C. (1990). Customizing treatment for chronic pain patients: who, what, and why. The Clinical Journal of Pain, 6(4), 255-270.

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Author

  • Anastasiia Gryshyna

    Anastasiia Gryshyna is a doctoral student in the Departments of Anesthesiology and Psychology at the University of Alabama at Birmingham (UAB). She received her master’s degree in nanotechnology at University of Central Florida and became fascinated with neuroscience and techniques that can be used to study our brain. Her current interests are in basic science and pelvic pain. Anastasiia uses electrophysiology and optogenetics to examine how pain signals travel to the central nervous system and how we can address issues associated with urologic conditions using optogenetics. Outside of the lab, she enjoys hiking, training Jiu jitsu, and spending time with her family.

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Anastasiia Gryshyna

Anastasiia Gryshyna is a doctoral student in the Departments of Anesthesiology and Psychology at the University of Alabama at Birmingham (UAB). She received her master’s degree in nanotechnology at University of Central Florida and became fascinated with neuroscience and techniques that can be used to study our brain. Her current interests are in basic science and pelvic pain. Anastasiia uses electrophysiology and optogenetics to examine how pain signals travel to the central nervous system and how we can address issues associated with urologic conditions using optogenetics. Outside of the lab, she enjoys hiking, training Jiu jitsu, and spending time with her family.