Neural Mechanisms of Analgesia
A short story in the genre of academic neuroscience horror.
This story comes from my horror story collection No One Came For Me: weird and primal horror stories.
Dear Ms. Hollow. You don’t know me, but you and I share a mutual acquaintance, through whom I had the opportunity to read the draft of your horror story about the exotic fruit that turns pain signals into pleasure. I much enjoyed the prose of your story, but I have some relevant information that I would like to share with you.
You may use this entire letter however you wish – perhaps the easiest thing from your point of view would be to simply ignore it. But I get the sense that you are a curious-minded lady, and perhaps it will interest you to learn something new, even if I’m afraid it does collapse your entire story.
You see, I am a neurosurgeon specialized in pain – indeed that is why our mutual friend passed your story on to me – and the fruit you describe is not just far-fetched (which I would have considered acceptable for a work of horror fiction) but it is fundamentally incompatible with scientific fact. In this letter I shall explain to you why this is so, and I hope that you shall find it educational.
You describe your mysterious fruit as analogous to the West African “miracle berry”, synsepalum dulcificum, which has the astonishing ability of temporarily making sour foods taste sweet. This real-world plant functions, as you correctly describe, by way of a protein which binds to taste receptors on the tongue, causing its sweet receptors to be activated by the acids in sour foods (Nakajima et al., 2008). From there you make the – not in itself unreasonable – leap that there might exist hypothetical substances which similarly bind to receptor neurons of other sensory modalities and distort them – for instance, and with horrifying consequences for your main character, turning pain into pleasure. However, this is where I am the bearer of bad news. The central premise upon which your story rests is unfortunately a misunderstanding, albeit one that you share with perhaps most laypeople: that pain is a function of haptic perception, that is, the sense of touch. In fact, from a neurological point of view, pain is more than merely a sensation. It is more accurately defined as an experience (Afifi & Bergman, 2005).
Perhaps I should first say a little more of what it is I do. You see, sometimes when I say I am a pain researcher, people think I am a torture engineer of some kind. Far from it. For one thing, inducing pain is not that difficult. Humans perfected their methods of physically hurting one another before the dawn of recorded history, and there is really nothing new to be discovered (Anderson, 2013). If you are looking for a torture engineer, I suggest you turn to the field of psychology and leave us neuroscientists alone. No, my interest is in relieving pain, which turns out to be considerably more challenging than inducing it. Would that your fruit could truly exist, even though it would put me out of a job! But yes, now that I’ve hopefully clarified that I am a morally sound individual, let us continue this mini-lecture of sorts.
So: if pain is not a sensation, then what exactly is it that happens when, for instance – now using for an example an actual case with which I am familiar (and which is described in Stubolsky (1992)) – a foolish teenage boy gets his hands on The Anarchist Cookbook and sets himself on fire trying to generate an electro-magnetic pulse from an electrical substation (Powell, 1971)? Well, the processes that allow him (or any of us) to experience pain are astoundingly complex and involve nearly all of the brain (Kolb & Whishaw, 2021). This complexity is the reason why chronic pain is so difficult to treat, as well as why scientists have yet to develop a fully satisfactory measuring instrument for pain (Wood, 2018). Let me briefly introduce you to the neuromatrix of pain.
The neuromatrix (Melzack, 2001) is a theoretical model of the neurological mechanisms of nociception, that is, pain perception. The model was originally developed by my hero in the field, Dr. Ronald Melzack, and postulates a set of three interconnected aspects of the nociceptive process; sensory, cognitive, and affective. These three together constitute the neuromatrix of pain.
The sensory aspect of the neuromatrix deals with the raw, neural information about the pain – its location in your body, its intensity, what “flavor” of pain it is, and so on. The cognitive aspect is your awareness of the pain and your conscious and unconscious mental processes in response to it. The affective aspect is your attitude and emotional response to the pain. All of these three aspects engage specific, and in part overlapping, areas of the brain, and also feed back into one another – the output of the neuromatrix becomes new input, creating a recursive explosion of complex neural activity. All of this happens behind the scenes of something so superficially simple as experiencing pain.
With all that in mind, what about our burning teenager? First, it’s important to remember that pain does not begin in any one aspect of the neuromatrix – it begins in all three of them simultaneously. That said, the constrictions of language mean that we need to begin this explanation somewhere, so let’s begin with the one that requires the most detail – the sensory aspect.
The basal level of the sensory aspect of the pain neuromatrix is a specific category of nerve endings called nociceptors, which are located throughout most parts of the body (Belmonte & Cervero, 1996). These nociceptors can react to three types of stimuli — mechanical, such as being cut or crushed; chemical, such as coming in contact with a toxic plant or a strong acid; and thermal, such as being burned. Interestingly, most of the body’s nociceptors are specifically tuned to just one of these three types, and they are not all evenly dispersed. This is why some body parts can be, for instance, painlessly cut, but not painlessly burnt, and so on.
When the boy’s clothes first catch on fire, for a brief moment his haptic thermoreceptor neurons will register warmth but no pain, until the temperature becomes high enough to activate the thermal nociceptors. When activated, these neurons release a mixture of numerous different molecules which we neuroscientists refer to as “inflammatory soup” (Wood, 2018). These substances facilitate the activation of nearby nociceptors. In addition to that, the activated nociceptors also relay pain signals to the brain via the spinal cord.
Now here is a moment to point out something truly fascinating. Remember when I said that pain is neurologically distinct from touch? For a striking demonstration of this, if I were to surgically sever the left side of your spinal cord with some precision, your left leg would lose sensation of touch below the laceration, but still be able to feel pain – and your right leg would still feel touch, but not pain! This condition is called Brown-Séquard paralysis, and it occurs because the axons – nerve fibers – that transmit pain signals to the brain travel contralaterally along the spine – that is, on the opposite side of the nociceptors that register the pain – while the axons for touch ascend ipsilaterally – on the same side (Kolb & Whishaw, 2021). So you see, from the first moment that pain “enters” your body, it is wholly distinct from non-painful touch stimuli even on a neuronal level. We are not even inside the brain yet, and you are already beginning to understand why your miracle fruit as a concept does not agree with biological reality.
Now, the brain. The sensory aspect of the neuromatrix can be said to consist of two neural pathways, one ascending and one descending (Yam et al., 2018). What I have thus far described is the ascending pathway of pain, which is essentially the way the body communicates to the brain that something hurts. Another astonishing piece of pain research trivia is that for a surprisingly long time, scientists believed that humans were born with this pain pathway undeveloped, and that it was only fully formed around the age of two years. In other words, infants were thought unable to feel pain. For this reason, surgery on infants was once routinely performed without anesthesia and infant burn victims did not receive pain medication. This was the case until the late 1980s, but fortunately we know better today (Anand & Hickey, 1987).
Let us move now to the descending pathway. In contrast to the ascending pathway, which informs the brain of pain, the descending pathway is how the brain communicates back to the body to manage the pain. These two pathways are integrated by neurons in the dorsal horn of the spine, an integration which allows for the brain to modulate the ascending pain signals to a certain extent – for instance decreasing pain through the endocrine secretion of endogenous opioids (Wood, 2018). This pathway is crucial for the pain regulation system that is inherent to the neuromatrix. It is also the reason why we are not very good at sensing where in the body organ pain is located. You see, the nociceptors do not communicate directly with the brain, only these integrating neurons in the spine do. And a side effect of this integration is that internal pain is “mapped” somewhat crudely into a neural body representation. This explains the phenomenon of “referred pain”, such as when your left arm hurts during a heart attack, or why a stomachache seems to originate from a point somewhere behind the navel rather than behind the lower left rib, where the stomach is actually located (Kolb & Whishaw, 2021). The interplay between the two pain pathways is also one reason why pain tends to exhibit a pulsating quality at various scales (Melzack, 2001; Wood, 2018).
By the time the nociceptive information reaches the brain, it actives an entire network of neural structures, located across several areas of the brain: the brainstem and thalamus, the limbic system, and the cortex.
There are three structures I would like to point out as being of particular importance. There is the PAG, or periaqueductal grey – a nucleus in the central brain, densely packed with opioid receptors. It is crucial for the descending pathway of pain modulation. Then there is the anterior cingulate cortex – a part of the limbic system and the integration of emotional and somatic experience. And third, there is the prefrontal cortex – the seat of cognitive function and interpretation of experience.
Let us now look quickly at the affective and cognitive aspects of the neuromatrix. The purpose of the affective system is to direct your attention toward the pain and its source. It is also what infuses the experience of pain with negative valence – i.e., invests our teenager with the awareness that his being on fire is, in a word, undesirable.
The aspects of the neuromatrix are tuned to one another and thus come into activation on similar scales, which means that the more pain is relayed to the sensory aspect, the more intensely the affective aspect urges the organism to initiate behaviors that aim to restore its previous state of non-pain.
The cognitive aspect deals with the organization of that behavior, and of course with conscious thought. If the affective system is screaming at our young man on fire to “Act!” then the cognitive system determines how he acts. He could try to run away from the pain. He might remember the old “stop, drop, and roll” and try to do that. If his screams are in the form of language at all, then the words are formulated here. As it was, none of his behaviors helped, which is often the case when it comes to burn victims in particular. Luckily for the boy, he was not alone, and a friend was eventually able to put out the fire. But not before the kid had suffered extensive and severe burns to his torso.
I hope you are not getting put off. To me, this entire subject is endlessly fascinating. And you must keep in mind that the topic of this letter is still analgesia, that is, pain relief. I only bring up the neuromatrix and the burning youth because you must intimately understand the pain experience before you can understand pain relief. As I said before, the complexity of what constitutes pain is precisely the reason why it is so difficult to alleviate. But now that you are acquainted with the neuromatrix, let us finally move on to the much happier matter of treating pain.
With the three aspects of the pain neuromatrix in mind, you could classify pain treatments according to which aspect of the matrix they primarily target. The most obvious interventions are aimed at the sensory aspect, and if I asked you to list some pain treatments, you would probably start by naming a number of sensory medications.
Aspirin, for instance, targets the sensory aspect of pain by blocking the production of certain substances included in the “inflammatory soup” previously mentioned, thus lowering the activation threshold of surrounding nociceptors (Wood, 2018).
Opiates, on the other hand, also target the sensory aspect but in a wholly different way, binding to the opioid receptors in the PAG to produce an extreme activation of the descending modulatory pathway – you will remember this is the body’s built-in pain suppression mechanism. The PAG can also be activated by a deep brain stimulation implant, which can be seen as an alternative to opioids for patients who suffer chronic untreatable pain (ibid). Unfortunately, the body builds a tolerance to endogenous opioids as well as exogenous.
Less dramatically, physiotherapy to correct poor posture and so forth could also be considered an intervention targeting the sensory aspect of the neuromatrix (ibid).
Now, while these sensory methods may be the most obvious, they are by far not the only ways to address pain. Laypeople might be aware of cognitive methods such as mindfulness meditation and reframing, but might wrongly assume that these are merely ways to cope with pain. In fact, thanks to the interconnected nature of the three aspects of the neuromatrix, cognitive interventions actually do relieve pain even on a sensory level. In other words: the human brain is able to initiate, on its own initiative and by means of language, the activation of the PAG and the descending pain modulation pathway in the same way that ingesting opiates would. Just not to the same extent.
What’s even more interesting is that studies have shown once you have learned a cognitive strategy for pain relief, you experience less pain whether or not you actually use the strategy (Wood, 2018). The mind is truly a remarkable thing.
Of course, “cognitive” doesn’t necessarily refer to just internal-monologue type procedures. Consider lobotomy, for instance. In this day and age with the medical achievements we have available to us, we may scoff at the crude days of ramming ice picks through eye sockets to whisk out the frontal cortex more or less at random, but in its heyday, the method was in many respects an improvement over the even more barbarous, or at best nonexistent, methods of previous generations (Terrier, Lévêque, & Amelot, 2019). Treatment resistant pain was a frequent ailment for which the ice pick was prescribed, and many of those patients who survived the procedure did indeed improve after the lobotomy. You may ask yourself: why did it work? Answer: because of the neuromatrix. Remember, the experience of pain is generated by an intertwined feedback loop of sensation, affect, and cognition. The prefrontal cortex is home to much of higher cognitive function, and damage to this area leads to impaired cognitive function – which alleviates pain because one third of the experience of pain is cognitive function (Melzack, 2001).
Today, prefrontal lobotomy is practically nonexistent. However, if you are unfortunate enough to suffer from treatment resistant pain, your doctor may suggest to you – finally, as a last resort, when all other avenues have failed to relieve you of your constant suffering – a rare treatment targeting the affective aspect of the pain neuromatrix: the surgical removal of your anterior cingulate cortex (Wilson & Chang, 1974).
Incidentally, this was the treatment ultimately received by the burning teenager. Some people are under the impression that severe burns are only painful while they are happening and while they are healing, because the nerve endings are literally burnt away and those that aren’t, are able to heal. Unfortunately, the truth is that about half of burn victims suffer chronic pain long after the injury (Griggs et al., 2017).
But what, then, is an anterior cingulectomy? This procedure severs the connections in your brain that allow the limbic system to communicate with the sensorimotor cortex – literally cutting out your ability to have an emotional response to the unrelenting pain signals feeding into your sensory system. In other words, you would still physically feel the pain, but you would be emotionally numb to it. You would in fact have no emotional connection to the entire concept of pain. And thanks again to the interwoven workings of the pain neuromatrix, this isolation of emotion from the physical sensation would in fact lessen your sensory experience of pain as well. (But you wouldn’t care.) This unusual procedure was what finally worked for the burn victim in our example, and he even went on to have a successful career.
The main downside of a cingulectomy is the same as for any major surgery – the problem of general anesthesia.
The problem with general anesthesia, acknowledged by most if not all surgeons but rarely if ever conceded within earshot of their patients, is that to a troubling extent, it is unclear whether it actually works (Cascella & Muzio, 2018). Let me explain.
First, you need to understand that anesthesia is not just one thing. When we put you under, we give you a cocktail of drugs designed to achieve exactly four separate goals, which could be said to cover all three aspects of the neuromatrix. First, affective: sedation – so that you are not awake during the surgery. Second, sensory: analgesia – so that you cannot feel the pain. Third, also sensory: paralysis – so that you cannot move. And fourth – this is the one that your surgeon doesn’t tell you about. Cognitive: amnesia – so that in the case that any one of the aforementioned effects for any reason fails to occur, you will not remember it afterward (Bischoff & Rundshagen, 2011). This is not, as a cynic would say, to protect hospital staff from malpractice suits. This is for your benefit. This is because of the neuromatrix.
The problem with this anesthetic cocktail is that amnesia is much more reliably induced than analgesia (Alkire, Hudetz, & Tononi, 2008).
The technical term for waking up during surgery is “anesthesia awareness with recall”, and as the name indicates, it’s not just about waking up during surgery. It’s about knowing that you woke up during surgery. Unfortunately, precisely because the medically induced amnesia usually does work, we simply do not know how common it is for patients to retain some awareness during surgery, or even what degree of awareness is retained (Chung, 2014). Obviously, if your body physically moves while you are under my knife, that instantly alerts me that you are not sufficiently paralyzed. But in the case where paralysis is present but analgesia is not, I can only become aware of your predicament after the drugs wear off and you verbally report what you have gone through. And of course you cannot do this if amnesia is present – and it nearly always is.
We are aware of this issue, and many studies have been conducted to try to ascertain if pain awareness is present in a paralyzed patient, but it has proven quite a challenge, thanks to the complex nature of the pain experience with which you are by now familiar (Linassi et al., 2018; Alkire, Hudetz, & Tononi, 2008).
The prevalence of anesthesia awareness with recall is said to be around one or two cases per thousand surgeries, which is not ideal but also not very high (Bischoff & Rundshagen, 2011). However, the prevalence of anesthesia awareness without recall is far less certain, and some estimates go as high as one third of all surgeries (Hill, 1999). In other words, one in three patients might be experiencing their surgery, but only one in a thousand remember it afterwards. If this alarms you, consider this: would you rather they did remember? Thus, amnesia is a cognitive intervention to decrease the experience of pain, for the benefit of the patient.
As a writer of weird horror, perhaps you have read The Arabian Nightmare (Irwin, 1983). If not, the titular nightmare is an unfathomably terrifying dream which is never remembered in the waking state. Whoever falls victim to the Arabian Nightmare can go the rest of their life never consciously knowing that they are victims to it, yet vividly experiencing the dream every night. The book offers up the philosophical conundrum of what it means to have an experience that evaporates as soon as it is over. But while Irwin presents the dilemma as a fantastical thought experiment, it turns out to be viscerally relevant to anybody who has ever had surgery.
And now that you know the detailed workings of the experience of pain as well as the limitations of the best medical analgesia in current existence, you undoubtedly see why your miracle fruit will sadly never be discovered outside of your imagination, as wonderful as that would have been.
Thanks for taking the time to read my letter. I hope you found it interesting and enlightening, and I am sorry that I had to ruin what was otherwise not a bad idea for a horror story.
Sincerely yours,
Dr. R—.