A Project Encephalon & The Science Paradox Collaboration article
One of the most important forms of sensory perception, the one responsible for an organism's survival, is pain. Pain is not a one-dimensional experience, it is nuanced and complex, both in the ways in which it is transmitted through our body and in the manner that we perceive it. What is the neuroanatomy of pain perception? Over millennia, several pathways have evolved for its signals to travel through our body, which are a combination of different kinds of sensory fibres, neurotransmitters, and locations that these signals are relayed to. These differences in structure and function enhance our perception of pain and enable us to assess its location and severity. In this article, we will explore two of the main pain pathways, what makes them unique, and how that translates to our own experiences of pain perception.
As a kid, I remember a frequently asked question in exams - “What distinguishes a living being from a non-living one?” While the younger version of me would have probably answered on the lines of movement, metabolism etc, as I grew older and became familiar with the concepts of sensation, an important difference began to make sense to me - the ability to sense and react to stimuli. Almost all life forms one way or the other respond to various stimuli around them, whether it’s internal or external. We have various receptors present in our body such as mechanoreceptors, olfactory receptors etc. which connect themselves to the nervous system and the brain, which then further directs the response in the effector organs because of this stimulus. Of these, the ability to sense pain is very important as it can prevent or minimise tissue injury.
Our experience of pain occurs in two phases, first, a fast, sharp, localized sensation of it, and later, a slower, duller sensation that we aren't quite able to pinpoint to a specific area. These differences in our perception aren't merely a coincidence; they are part of a complex system of transmission that has evolved over several millennia, which helps us appreciate the most subtle differences in our environment.
Sensory neuron receptors that are responsible for transmitting pain signals are called nociceptors. Unlike other kinds of nerve fibres, they do not have specialized receptors but have free, unmyelinated nerve endings that branch out and form networks in the organs they innervate. Further, they only get activated and transmit an impulse when a noxious stimulus reaches or surpasses a certain threshold level.
There are primarily two types of fibres that transmit pain: A-delta and C-fibres. A delta fibres are myelinated and have a larger diameter than C-fibres and thus, conduct nerve impulses faster. C-fibres are unmyelinated, have a smaller diameter, therefore, have a lower conduction velocity. C-fibres respond to more than one kind of stimulus, like thermal, mechanical, or chemical, and thus, are "polymodal" in nature. In contrast, A-delta fibres only respond to one kind of stimulus.
Both these kinds of fibres achieve the same outcome, so why are their modalities different? The answer comes down to the evolutionary timeline of these pathways, which has enabled us to perceive one kind of pain sooner than the other and be able to localize certain impulses and not localize others precisely.
The pathways through which pain signals travel from the spinal cord to the brain are called spinothalamic pathways. All first-order sensory fibres, including nociceptive fibres, enter the spinal cord's dorsal (posterior) grey horn, which is composed of several laminae. Here the fibres synapse with the second-order neurons, which cross over to the other side of the spinal cord and then relay messages to the thalamus and other areas of the brain. Hence this pathway is known as the spinothalamic tract. In the brain, these fibres synapse with the third-order neuron, which relays signals to the somatosensory cortex, each point of which is correlated with a specific area of the body.
Through evolution, two primary pathways for this process have come into existence: the more primitive paleospinothalamic pathway, and the more recent neospinothalamic pathway.
The A-delta fibres terminate at lamina 1 of the spinal cord and release glutamate at this synapse. It activates the second-order neuron of pain, which terminates in the ventro-postero-lateral (VPL) and ventero-posteromedial nuclei (VPM) of the thalamus. This second-order neuron is a part of the neospinothalamic pathway of pain. From here, the third-order neuron will convey these impulses to the somatosensory cortex. The VPL and VPM are significant for the localization of pain. Thus, the localization of pain occurs at the level of the thalamus and not the cerebral cortex, which is responsible for assessing the quality (type) of the pain, not its location.
In contrast, the C-fibres largely follow the same path but have a few interruptions along the way. They terminate in lamina 2 (substantia gelatinosa) and lamina 3 (nucleus proprius) of the dorsal horn, where most of the signals they convey then pass through one or more additional short fibre neurons/interneurons within the dorsal horn before entering mainly lamina 5, also in the dorsal horn. From lamina 5, they synapse with the second-order neuron, which is part of the paleospinothalamic pathway of pain. At all three laminae, though, the C-fibres secrete both substance p and glutamate as neurotransmitters, but the amount of the substance p is greater than that of glutamate. Glutamate acts instantaneously and lasts for only a few milliseconds, while substance P is released more slowly, building up in concentration over a period of seconds or even minutes. Also, as part of the paleospinothalamic tract, the pain impulses are modulated by neurotransmitters of the descending tract and the interneurons before reaching the thalamus. So it is partly due to the multisynaptic nature of this pathway, the various modulating factors, as well as the differences in neurotransmitters that pain signals travel slower through this route.
The poor localization of pain, however, is explained by where these fibres ultimately end up. Most of the fibres of the second-order neuron of slow pain, i.e., the paleospinothalamic pathway, end in one of three areas in the brain stem: the reticular nucleus, the tectal area or the periaqueductal grey matter. Only 1/4th - 1/10th of these fibres end in the thalamus. As the thalamus is largely responsible for the localization of pain, while these fibres are widespread in other areas, the pain relayed by this pathway is poorly localized.
From those three main areas, the fibres also extend to the hypothalamus and intra-thalamic nucleus. This explains why if we experience "slow pain" due to a chemically mediated injury, we experience a slew of other symptoms alongside, such as insomnia and other autonomic symptoms, like sweating or headaches.
To conclude, the neospinothalamic tract is responsible for the conduction of fast pain with the help of A-delta fibres and thus plays an important role in providing information about the location of the noxious stimulus, helping us quickly move away from it. On the other hand, the multisynaptic paleospinothalamic tracts are responsible for the conduction of slow pain with the help of C-fibres and thus conduct pain which is mostly poorly localised in nature.
Pain is an inevitable part of human life. In simple terms, it's an “ invisible disability” (Quoted from the Harvard Health Blog). Pain activates many different areas of the brain which ultimately link the whole paradigm of sensation, perception, memory, emotion and motor reaction, helping us make sense of the world around us and keeping us safe within it.
Dafny, N. (2020). Pain Tracts and Sources (Section 2, Chapter 7). Retrieved from Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston website: https://nba.uth.tmc.edu/neuroscience/s2/chapter07.html
Al-Chalabi M, Reddy V, Gupta S. (2020). Neuroanatomy, Spinothalamic Tract. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507824/
Dubuc, B. (n.d.). Ascending Pain Pathways. Retrieved from The Brain from Top to Bottom website: https://thebrain.mcgill.ca/flash/a/a_03/a_03_cl/a_03_cl_dou/a_03_cl_dou.html#paleospino
Hasudungan, A. (2018). PAIN! Physiology - The Ascending Pathway, Descending Pain Pathway and the Substantia Gelatinosa. Available from https://youtu.be/5c8maFAhqIc
World Heritage Encyclopedia. (2021). Paleospinothalamic Tract. Retrieved from: Paleospinothalamic tract | Project Gutenberg Self-Publishing - eBooks | Read eBooks online
Harvard Health. (2017, April 28). Chronic pain: The “invisible” disability. https://www.health.harvard.edu/blog/chronic-pain-the-invisible-disability-2017042811360