Nociception: Things We Don't Know about Pain

People with congenital insensitivity to pain can feel temperature, but not when it's bad. But those with congenital insensitivity to pain with anhidrosis can't feel temperature at all, and so are at risk of overheating as well as getting cuts, bruises, burns etc. Image credit: Hobbes vs Boyle

Pain evolved as a necessary evil. It tells us when we've done something damaging, or are on the brink of causing more serious harm. It's tempting to wish away pain after stubbing your toe or burning your hand, but life without pain is far from pleasant. People born with very rare genetic conditions giving complete insensitivity to pain end up spending most of their lives in hospital for injuries they simply didn't know they were getting. They must actively learn and constantly be thinking about what things are "bad" to touch, such as knives or boiling water, because they will never feel the warning signs of a light prick or rising warmth.

These people have no trouble experiencing the touch and feel of their surroundings, showing that pain isn't just an excess of touch. Instead, there are nerves which specialise only in detecting and transmitting harmful stimuli. These nerves are called nociceptors.

After the first stage of the transmission of pain signals, our knowledge comes to an end. Image credit: Carlos Martinez

The first step of nociception, how receptors in our skin respond to painful stimuli, is probably the best understood aspect of pain - both mechanical and temperature-based. We know which of the heat-detecting nociceptors^[1] can also be activated by capsaicin, the painful component of chillies that makes us feel like our mouth is on fire despite all evidence to the contrary. We also know which gene is mutated in many people who cannot feel pain.

Yet after the first stage, our understanding wanes considerably.

The nerves which first receive the harmful signal (called primary nociceptors) deliver their signal to a region of the spinal cord called the dorsal horn. Unfortunately, the arrangement of neurons within the dorsal horn appears chaotic at best. The complexity is so great that even categorising the different cell types^[2] and functions is proving challenging, and this is before the nociceptive signal even reaches the brain.

Why can we feel pain without reason, or be injured without pain?

A further complication is that nociception does not necessarily equal the experience of pain^[3] - you can have one without the other. Pain is a product of the brain, and psychology is just as important as neuroscience in understanding it. The same painful procedure can be experienced so differently according to our moods and surroundings. If we play a video game for distraction or are asked to swear profusely^[4], we find ourselves much better able to withstand acute pain.

One key disease where nociception and the pain experience fall out of healthy alignment is in chronic pain, a condition felt by millions of people which includes lower back pain, arthritis and fibromyalglia. People with these conditions may experience pain from the lightest touch or even with no stimulation at all. It can be stressful, unrelenting and debilitating, and there is relatively little that can be done to help sufferers.

Some chronic pains arise out of acute injuries, where the tissue heals but the pain never leaves. Why the pain of some injuries leaves with the wound and others linger for months, years or a lifetime is not clear, and the risk factors are not fully understood. It is also possible they may be psychological rather than physical, or perhaps a combination of both. Either way, chronic pain sufferers are often passed between physical and psychiatric doctors because neither can find an identifiable root cause, and hence are offered just symptom management rather than the chance of a real cure.

It is vitally important that we come to understand any physical characteristics of chronic pain.
Image credit: Steven Depolo

Therefore it is vitally important that we come to understand any physical characteristics of chronic pain that are found. One of the most significant recent observations was made in 2004 when it was found that chronic back pain sufferers also had significant reduction in grey matter volume throughout the brain^[5] compared with non-sufferers. This atrophy was most significant in parts of the brain known for relaying pain-related signals and processing the emotional and cognitive elements of the pain experience. The researchers noted that those suffering from back pain for longer periods of time showed more brain atrophy.

This may be a very significant finding, but little is understood about why this would be the case, and if there is a causal relationship between the two. Are the physical changes in the brain caused by, or the cause of the long-term unavoidable pain? Or could the relationship be of an entirely different nature, perhaps even a coincidental finding? This can only be determined by more studies with larger cohorts.

Pharmaceutical products can help mitigate symptoms, but are not a permanent cure. Image credit: Megan Hodge

Current treatment for chronic pain focuses around a combination of painkillers and various pain management therapies. Unfortunately many chronic pain sufferers develop tolerances to the most accessible painkillers, and the stronger ones like morphine are plagued with side effects and are therefore heavily regulated. What's missing is an in-between drug; one which can combat the abnormal pain while leaving the healthy pain pathways intact.

It can take years or even decades to develop brand new drugs from scratch. For this reason, there is also research into treating chronic pain with pharmaceuticals already on the market (and so known to be safe), but used for other conditions. These include anticonvulsants (primarily used to treat epilepsy) and antidepressants. The relationship between chronic pain and depression is complicated. Suffering with one makes you far more likely to suffer the other but antidepressants appear to work whether or not the pain sufferer also has depression - how exactly it does this is not known^[6].

How can there still be so much we don't know? The study of pain is fraught with difficulties, not least because of how hard it is to measure scientifically. While the initial nociception may be easy to track, pain itself is a personal, subjective experience which does not readily convert into numerical data for analysis.

Furthermore, the experimental study of pain is quite the ethical minefield for obvious reasons, and there's also a big difference between "laboratory pain" and the injuries people experience in everyday life. While researchers from many scientific disciplines are working on understanding pain, it may be a while before we can keep pain as the helpful health and safety officer it evolved to be without it turning into the lifelong demon on the backs of millions.

Emily Coyte helps teach biochemistry at the University of Bristol. She tweets as @EmilyCoyte and blogs about many aspects of science at Memetic Drift.

Recommended Further Reading

Neuroscience: Exploring the Brain, 3rd edition Bear. MF., Connors, BW. and Paradiso, MA. (Lippincott Williams and Wilkins)

Understanding Pain: Exploring the Perception of Pain Fernando Cervero. (MIT Press)

References
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[1] Welch, JM, SA Simon, and PH Reinhart. “The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat.” Proceedings of the National Academy of Sciences 97.25 (2000): 13889-13894. doi:10.1073/pnas.230146497

[2] Todd, Andrew J. “Neuronal circuitry for pain processing in the dorsal horn.” Nature Reviews Neuroscience 11.12 (2010): 823-836. doi: 10.1038/nrn2947

[3] Bushnell, M Catherine, Marta Čeko, and Lucie A Low. “Cognitive and emotional control of pain and its disruption in chronic pain.” Nature Reviews Neuroscience (2013). doi:10.1038/nrn3516

[4] Stephens, Richard, John Atkins, and Andrew Kingston. “Swearing as a response to pain.” Neuroreport 20.12 (2009): 1056-1060.

[5] Apkarian, A Vania et al. “Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.” The Journal of Neuroscience 24.46 (2004): 10410-10415. doi:10.1523/JNEUROSCI.2541-04.2004

[6] Sansone, Randy A, and Lori A Sansone. “Pain, pain, go away: antidepressants and pain management.” Psychiatry (Edgmont) 5.12 (2008): 16. PMCID: PMC2729622