I started to get to know my body through pain and illness. I lived the first thirty years with relative abandon, but I soon discovered that my head and what was inside it, as well as being a source of pleasure and knowledge, also carried within it endless possibilities for pain.

Pedro Almodóvar, Pain and Glory
© 2019, Pedro Almodóvar
Publishing licence granted by Penguin Random House Grupo Editorial, S.A.U.

Nobel Prize in Physiology or Medicine 2021.
David Julius and Ardem Patapoutian

Temperature, touch, pressure, pain

With this article we recall that the Nobel Assembly of the Karolinska Institute in Stockholm awarded the 2021 Nobel Prize in Physiology or Medicine jointly to David Julius (renowned biochemist at the University of California in San Francisco, USA) and Ardem Patapoutian (molecular biologist, researcher in the Department of Neuroscience at the Scripps Research Institute in California, USA), for their discovery of temperature and touch receptors.

We will also try to shed some light on this research and its more significant applications in pain management.

More than twenty years ago, Julius had already discovered how stimulation of temperature receptors in our nervous system can be perceived as pain.

One of his fields of study is the molecular analysis of pain neurons (nociceptors), and his great achievement has been the identification of a specific protein (called TRPV1) as the neuronal receptor for noxious stimuli.

We invite the reader to join us on an exciting journey into the past to better understand this momentous discovery.

I soon became acquainted with insomnia, chronic pharyngitis, otitis, reflux, ulcer and intrinsic asthma. Nerves in general and sciatica in particular and all types of muscular pains: lumbar, dorsal and tendonitis in both knees and shoulders.

Pedro Almodóvar, Pain and Glory
© 2019, Pedro Almodóvar
Publishing licence granted by Penguin Random House Grupo Editorial, S.A.U.

Now, for a little bit of history. Santiago Ramón y Cajal
Nervous system. Basic building blocks

The year was 1889 when Santiago Ramón y Cajal, a young Spanish doctor and researcher who was as-yet totally unknown on the international scene, stepped out of a second-class carriage at the Berlin railway station. He was carrying a briefcase with a Zeiss microscope and a box with carefully packed slides. He had paid the registration fee for the annual congress of the German Anatomical Society out of his own pocket and also paid for the trip.

This young doctor, who at that time was a professor in the Faculty of Medicine of the University of Barcelona, was determined to divulge and assert his theories on the nervous system, and for this purpose he had sought out the meeting place that attracted the most brilliant medical researchers.

Nervous system. Basic building blocks
Cajal and the neuron

The nervous system (brain, spinal cord and peripheral nervous system) was perceived as a tangled and complex web whose secrets had yet to be discovered.

The prevailing theory led, among others, by Camillo Golgi (an Italian physician who ironically was to receive the Nobel Prize for Medicine jointly with Santiago Ramón y Cajal in 1906), was based on a simplistic view of the nervous system as a whole, according to which everything effectively formed a real network and all those thousands of cells or nerve units were physically connected.

Ivan Ilyich went out slowly, climbed dejectedly into the sleigh, and drove home. On the way he kept going over what the doctor had said, trying to translate all those complicated, vague scientific terms into simple language and read in them the answer to the question: bad—is it very bad for me, or still all right?

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

Cajal and the neuron
Tell me what languages you speak

On the contrary, Cajal, after many years of study and observation under the microscope and of drawing precisely in Indian ink, one by one, the nerve units under study, with each and every one of their ramifications and paying the utmost attention to the smallest details, was convinced of the opposite: of the individuality of the nerve cells.

Tell me what languages you speak
On neurons and synapses

Since German was the language of science and Cajal could hardly understand enough to read it, let alone write it, his theories and discoveries could not be made widely known.

And so it was that he managed to get to Berlin and take part in the annual International Medical Congress of 1889, which was attended by the great medical researchers, pathologists, physiologists and other eminent people of the time.

And that pain, the obscure, gnawing pain, which did not cease for a moment, seemed to have acquired, in connection with the doctor’s vague words, a different, more serious meaning. With a new, heavy feeling, Ivan Ilyich now paid heed to it.

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

Somehow, with some rudimentary French, Cajal was able to make himself understood and took advantage of the occasion to approach the famous and influential Swiss medical researcher Albert Kölliker, to take him by the arm, bring him to his microscope and his drawings and introduce him to what would later be known as neuronal theory, the main basis of all current neuroscience.

No more, no less!

An astonished Albert Kölliker, who was certainly able to glimpse the potential there before him, did not hesitate to say: “It gives me great satisfaction to tell you, Mr Cajal, that it is I who have just made a great discovery: You. And I would like to spread the word about my discovery in Germany.” And he did. Neural theory had just taken flight and would now spread rapidly around the world.

On neurons and synapses
New vocabulary

The great interest aroused by these discoveries was reflected in a multitude of studies, observations, research, articles and exchanges of ideas on the nervous system and its constituent cells, as well as the way in which they communicate with each other.

The pain did not diminish; but Ivan Ilyich tried to make himself think that he was better.

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

New vocabulary
Neuron

It was Waldeyer-Hartz, a well-known German doctor and researcher, very interested in the new theory and a great disseminator of this and of the work of Cajal, who coined the term neuron in 1891 to name the nerve cell, taking up the old Greek word néuron (nerve unit). Waldeyer decided to learn Spanish in order to follow the enormous amount of information in Cajal’s studies and became his friend, mentor and promoter among German scientists.

New vocabulary
Synapses

Sir Charles Scott Sherrington, also a Nobel laureate in medicine, postulated the synaptic hypothesis as early as 1897.

Sherrington approached the functioning of the nervous system from a dual perspective: the neuron and the synapse. This way of thinking not only distinguished him from all the neurophysiologists of his time, but also helped him to underpin Cajal’s theory of the neuron.

Sir Charles enlisted the help of a classical language expert named Arthur Verrall to name the hiatus, or active separation between one neuron and another. The neologism that this collaboration produced would not only become famous for its precision, but would eventually become a cornerstone of modern neurophysiology. The synapse was thus born.

These are wheezes and whistles, I also suffer from them. In addition to the tinnitus and wheezes, my speciality is headaches, migraines, tension headaches or cluster headaches, and back pains.

Pedro Almodóvar, Pain and Glory
© 2019, Pedro Almodóvar
Publishing licence granted by Penguin Random House Grupo Editorial, S.A.U.

Nobel Prize in Physiology or Medicine 2021
David Julius and Ardem Patapoutian

Some figures
We are very numerous

It is in the brain that we find the greatest number of neurons. A human being has about 86 billion neurons in the brain, connected to each other by a trillion synapses. Each neuron connects with some 30,000 neighbours. The spinal cord has about 13 million neurons and the rest of the neurons are spread throughout the human body forming the so-called peripheral nervous system.

Some starring neurons
The sense of touch

The organ with the greatest abundance of nerve endings is the skin and it is precisely where research in recent decades, in particular by David Julius and Ardem Patapoutian, has focused on understanding how pain, and more specifically nociceptive pain, is generated and transmitted.

And again, right there, along with this course of recollection, another course of recollection was going on in his soul—of how his illness had grown and worsened. … “As my torment kept getting worse and worse, so the whole of life got worse and worse,” he thought.

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

My favourite neuron: nociceptor (noxious stimulus detector)
Sir Charles Sherrington again

As a result of physiological experiments that he conducted more than a century ago, Sir Charles Sherrington concluded: “There is considerable evidence that the skin is provided with a set of nerve endings whose specific office it is to be amenable to stimuli that do the skin injury, stimuli that in continuing to act would injure it still further” (Sherrington, 1903). Based on these observations, Sherrington proposed the existence of the nociceptor (noxious stimulus detector), a primary sensory neuron that is activated by stimuli capable of causing tissue damage (or skin damage).

Thus, this concept of nociception (from the Latin nocere, to damage), coined by Sherrington, is intended to point out that pain is a specific sensation with its own sensory machinery.

After the spinal fusion operation (which immobilised more than half my back), I discovered that my life would revolve around my spinal column. I became aware of each one of my vertebrae and the number of muscles and ligaments that make up the mythology of our organism and that, as with the Greek gods, our only way of relating is through sacrifice.

Pedro Almodóvar, Pain and Glory
© 2019, Pedro Almodóvar
Publishing licence granted by Penguin Random House Grupo Editorial, S.A.U.

Pain, where are you?

Pain is a complex experience that involves not only the transduction of noxious environmental stimuli, but also cognitive and emotional processing by the brain.

Always the same thing. A drop of hope glimmers, then a sea of despair begins to rage, and always the pain, always the pain, always the anguish, always one and the same thing.

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

The senses: Sight, hearing, smell, taste, touch

All sensory systems must convert environmental stimuli into electrochemical signals. In the case of sight or smell, primary sensory neurons only need to detect one type of stimulus (light or chemical odorants, respectively). In this sense, nociception is unique because individual primary sensory neurons in the ‘pain pathway’ have the unique ability to detect a wide range of stimulus modalities, including those of a physical and chemical nature.

Unlike vision, smell or taste, the sensory nerve endings that detect painful stimuli are not localised in a particular anatomical structure, but are dispersed throughout the body, innervating skin, muscles, joints and internal organs.

Pain pathway

Pain usually starts in the periphery: in the skin, an internal organ or any other site outside the central nervous system, i.e., outside the brain and spinal cord.
Contact with a hot stove or a stubbed toe triggers the activation of nociceptors, neurons that respond to stimuli that are damaging for tissue. These neurons (thanks to certain sensing molecules that find the noxious agent on the skin or in an organ) fire an electrical impulse that travels through the neuron and a signal is transmitted through the synapse to the spinal cord, where other neurons are then activated to carry the signal to the brain.

Although known as pain-sensing neurons, nociceptors merely signal the presence of potentially harmful stimuli, but it is the brain that interprets the pain signal and generates the pain.

But not everything is so physical and illustratable. I also suffer from abstract hardships, pains in the soul, such as panic and anxiety, which add anguish and terror to my life. And naturally I’ve dealt for years with depression.

Pedro Almodóvar, Pain and Glory
© 2019, Pedro Almodóvar
Publishing licence granted by Penguin Random House Grupo Editorial, S.A.U.

Pharmaceuticals

In the search for new analgesics, much effort has been directed towards the site where pain signals originate: the periphery.

Some of the specialised molecules used by nociceptors to detect noxious stimuli rarely exist elsewhere in the body. Blocking these molecules would presumably turn off pain signalling without altering other physiological processes, thus causing no side effects.

Aspirin and ibuprofen

The most popular current remedies – aspirin and other non-steroidal anti-inflammatory drugs such as ibuprofen – operate mainly in the periphery. These drugs inhibit the activity of certain molecules that nerve cells use to generate pain signals. But they also inhibit the synthesis of these molecules elsewhere in the body, often causing side effects such as stomach pain, diarrhoea and ulcers. However, they do not relieve the most acute forms of pain.

It was impossible to deceive himself: something dreadful, new, and so significant that nothing more significant had ever happened in his life…

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

Nobel Prize in Physiology or Medicine 2021.
David Julius and Ardem Patapoutian

Capsaicin receptor (spicy ingredient in chillies)

As early as 1997, David Julius and his team were working on the discovery of certain molecules that reside almost exclusively in nociceptors, opening up a great opportunity for the development of more specific analgesics. One of these is the capsaicin receptor molecule.

Julius found that this receptor responds not only to capsaicin but also to painful heat. The receptor stimulated in this way generates a signal that translates into a burning sensation induced by heat or spicy food.

Substances that inhibit capsaicin receptors should dampen inflammatory pain.
Today, several pharmaceutical companies are studying the development of capsaicin receptor antagonists.

The doctor said that his physical sufferings were terrible, and that was true; but more terrible than his physical sufferings were his moral sufferings, and these were his chief torment.

The Death of Ivan Ilyich, Leo Tolstoy (1886, translated by Richard Pevear and Larissa Volokhonsky, Knopf 2009)

Other possibilities

The possibilities for manipulating the receptor molecule do not end here. Paradoxical as it may seem, in some cases intentional stimulation of capsaicin receptors relieves pain. A variety of topical creams containing capsaicin are available to relieve the itching, stinging and prickling that accompany the postoperative wound healing process or nerve disorders resulting from HIV infection, herpes attacks or diabetes.

Wasabi and inflammatory pain

Later, Julius also identified the receptor for the pungent compound wasabi, from the mustard family, again turning to nature: “For years, mustard extract has been used for pain testing: it is rubbed on the patient’s skin to irritate it and test its response to pain; this also causes inflammation, increasing sensitivity to temperature and touch. It is a model for investigating inflammatory pain, such as that of a joint with arthritis. By investigating how the process worked, we identified a receptor on nerve cells, and that’s the mechanism by which wasabi and other mustard plants cause a sharp sensation.

The same wasabi receptor has been found to be involved in the itch that makes you cry when you cut an onion, but it is also activated by the venom of some animals, such as the scorpion. However, “the most important thing” about this mechanism, Julius explains, is that “it is very important for understanding the pain of an inflammatory lesion” and can be used “to understand how lesions cause not only acute but also persistent pain, which culminates in chronic pain syndromes”.

Summary

Our little journey is coming to an end but not before we express our deepest gratitude to these great researchers, whose dedication and tenacity allow us to alleviate our physical aches and pains as well as our deeper kinds of pain. Our leading figures Salvador Mallo and Ivan Ilyich, who have accompanied us on our expedition, can bear witness to this.

On the nights when various pains coincide… those nights I believe in God and I pray to him. The days when I only suffer one kind of pain, I’m an atheist.

Pedro Almodóvar, Pain and Glory
© 2019, Pedro Almodóvar
Publishing licence granted by Penguin Random House Grupo Editorial, S.A.U.

The recognition by the German scholars was the key to the major awards Cajal received in the following years, the Moscow Prize (1900), the Helmholtz Gold Medal of the Berlin Academy of Sciences (1905) and the Nobel Prize (1906). But something even more important was that Cajal had opened the doors to modern neuroscience.

If you wish to learn more about Nobel Prizes, you can check our blog to read about the Nobel Prize in Physics 2021 and the Nobel Prize in Chemistry 2021.

Bibliography:

Almodóvar, P. (2019). Dolor y gloria. Reservoir Books.

Baliki, M., & Apkarian, A. (2015). Nociception, Pain, Negative Moods, and Behavior Selection. Neuron, 87(3), 474–491. https://doi.org/10.1016/j.neuron.2015.06.005

Bole, K. (2021, October 4). David Julius Wins Nobel Prize for Work on Pain Sensation. UCSF. Retrieved October 5 2021, from https://www.ucsf.edu/news/2021/09/421481/david-julius-wins-nobel-prize-work-pain-sensation

Julius, D., & Basbaum, A. I. (2001). Molecular mechanisms of nociception. Nature, 413(6852), 203–210. https://doi.org/10.1038/35093019

Kuffler, S., & Nicholls, J. (1981). De la neurona al cerebro. Reverte.

Peña, J. R. A., Segovia, J. A., Alonso, J. R., & de Carlos Segovia, J. A. (2018). Cajal : un grito por la ciencia. Macmillan Publishers.

The Nobel Prize. (s. f.). The 2021 medicine laureates. NobelPrize.Org. Retrieved 5 October 2021, from https://www.nobelprize.org/prizes/medicine/

Tolstói, L. (2011). La muerte de Iván Ilich. Jadzhí Murat. Alianza Editorial.

Valderas, J. M. (2017, September). Charles Scott Sherrington, sinapsis y reflejos. Investigación y Ciencia. Retrieved 5 October 2021, from https://www.investigacionyciencia.es/revistas/mente-y-cerebro/los-lmites-del-ego-721/charles-scott-sherrington-sinapsis-y-reflejos-15793

Woolf, C. J., & Ma, Q. (2007, August 2). Nociceptors—Noxious Stimulus Detectors. ScienceDirect. Recuperado 5 de octubre de 2021, de https://www.sciencedirect.com/science/article/pii/S0896627307005375