Neural Mechanisms of Pain

Pain is one of the body’s most ancient and essential defence mechanisms. Acting as an alarm system, it detects noxious (harmful) stimuli, transmits a warning signal, and forces us to react before greater injury can occur. At its core, pain exists to protect us, and its existence is crucial for survival. An extremely rare and dangerous genetic condition, congenital insensitivity to pain (CIPA), prevents people from feeling any pain. People with this condition often sustain repeated injury without noticing, and self-mutilation of the eyes, lips, and fingers is common. As a result, the life expectancy for patients with CIPA averages only 25 years. 

Because of pain’s vital role in survival yet the suffering it causes, research has long been motivated by the goal of understanding and reducing it. Over time and across cultures, the study of pain has evolved, allowing scientists to map its fundamental biological processes. It involves specialised receptors that detect danger, then signals that travel through nerves, and finally the brain interpreting them to produce a conscious experience of pain. While unpleasant, pain ultimately serves a protective role, guiding our actions to prevent further harm to the body.

The Pain Pathway: Nociceptors

Pain is part of the somatosensory system, which processes sensory information such as touch, pressure, and temperature. The detection of painful stimuli begins with nociceptors, specialised free nerve endings located in the skin, viscera, muscles, and joints. Compared to mechanoreceptors, nociceptors are approximately nine times more dense, but transmit signals more slowly. They lack encapsulated structures, and are instead classified by axon properties such as myelination, conduction speed, and the  types of stimuli they detect. Two main nociceptor fibres exist:

1. Aδ class (average 25 m/s conduction speed)

   1. Mechanosensitive: responds to physical pressure.

   2. Mechanothermal: responds to hot or cold temperatures.

2. C class (average 1 m/s conduction speed) 

   1. Polymodal: responds to mechanical, thermal, and chemical.

These fibre types explain the distinction between “first pain” and “second pain.” Aδ fibres produce the fast, sharp, and localised pain felt immediately after injury, while the unmyelinated C fibres generate slower, duller pain that follows.

Importantly, nociceptors differ from other sensory receptors in their activation thresholds. A warm surface, for example, activates non-nociceptive thermoreceptors. Only when the surface reaches a temperature capable of causing tissue damage do nociceptive receptors fire. At that point, their action-potential frequency rises in proportion to stimulus intensity, allowing the nervous system to gauge threat level and trigger the appropriate reaction.

The Pain Pathway: Central Nervous System

Once nociceptors are activated, their signals travel along axons that enter the spinal cord through the dorsal roots. In the dorsal horn, the signal is passed to second-order neurons, which cross the spinal cord and travel through the spinothalamic tract up towards the brain. These fibres reach the thalamus, a central relay station for sensory information. From there, third order thalamic neurons project to the somatosensory cortex, where discriminatory components of pain- location, intensity, features- are mapped. Pain signals also reach the limbic system, which creates emotional response to pain, and the brainstem, which coordinates protective reflexes and other autonomic responses.

Why does pain feel different?

Despite the common pathways, not all pain feels the same. Even identical stimuli can be perceived differently, depending on the circumstances. This difference can arise from both biological and psychological influences.

Biological

Two mechanisms occur at a past injury site in the body:

1. Primary hyperalgies

Following injury, nociceptors become sensitised, meaning their activation threshold is lowered and their responses are amplified. This occurs because inflammatory mediators, such as cytokines and potassium ions, are released at the site of damage. These molecules bind to receptors and open ion channels, increasing neuronal excitability. As a result, stimulus that was previously mildly painful is now perceived as more intense, reflecting a heightened interpretation of danger.

2. Allodynia

Normally innocuous stimuli, such as normal touch or warmth, can be perceived as painful. This results from maladaptive changes within the central nervous system, where signals are misinterpreted. For example, a light touch on a bruise can provoke pain, whereas the same stimulus on uninjured skin is not painful.

Psychological 

Pain is not only a biological signal, but also a subjective experience shaped by the brain. Here are two factors that determine whether a noxious stimulus is consciously experienced as painful, and how intense that pain feels:

1. Motivational-affective. The emotional response can amplify or reduce the perception of pain. Where attention is focused also matters: concentrating on the source of pain can intensify it, while distraction can reduce it. For example, an athlete might not feel an injury until after the race.

2. Cognitive-cultural. Beliefs, expectations, and cultural background influence how pain is experienced. Past experiences “train” the brain to interpret noxious stimuli, while cultural or religious frameworks can shape tolerance and response. (For example, the Thaipusam Festival. Read more at Thaipusam Festival Body Piercings)

Works Cited

Armstrong, S.A., 2023. Physiology, Nociception. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK551562/.

Chen, J.S., 2023. Physiology, Pain. StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK539789/.

Kenshalo, D.R., et al., 1980. Responses of Spinothalamic Neurons to Noxious Stimuli. Journal of Neurophysiology, 43(6), pp.1537–1549. Available at: https://pubmed.ncbi.nlm.nih.gov/7411178/.

Willis, W.D., 1985. The Anatomy and Physiology of Pain. In: Osterweis, M., ed. Pain and Disability. Washington, D.C.: National Academy Press, pp.1–26. Available at: https://www.ncbi.nlm.nih.gov/books/NBK219252/.

Coghill, R.C., 2020. The Distributed Nociceptive System. Journal of Neurophysiology, 124(3), pp.741–758. Available at: https://pubmed.ncbi.nlm.nih.gov/32642392/.

Dubin, A.E. & Patapoutian, A., 2010. Nociceptors: the sensors of the pain pathway. Journal of Clinical Investigation, 120(11), pp.3760–3772. Available at: https://doi.org/10.1172/JCI42843.

Auvray, M., Myin, E. & Spence, C., 2010. The sensory-discriminative and affective-motivational aspects of pain. Consciousness and cognition, 19(3), pp.1055–1063. Available at: https://doi.org/10.1016/j.concog.2009.12.015.

South China Morning Post, 2020. No pain? How extreme body piercing of Thaipusam Hindu festival devotees works. South China Morning Post. Available at: https://www.scmp.com/lifestyle/travel-leisure/article/3048074/no-pain-how-extreme-body-piercing-thaipusam-hindu-festival.