What Is Modulation?
Modulation is defined as the exertion of a modifying or controlling influence on something. Similarly, pain modulation is a complex process involving various neural pathways and mechanisms that can either amplify or diminish the perception of pain. This modulation occurs at multiple levels of the nervous system, from peripheral to central pathways.
It explains why different individuals respond to the same stimulus (input) differently and also how pain can be altered/ helped using different modalities like heat, ice, massage, and electro/manual therapy.
Ever noticed how a small cut feels worse when you're stressed but barely noticeable when you're distracted? This is pain modulation in action. It hurts extra when your annoying brother hits you for fun and less when your friend does it. It hurts even more when you have work the next day and less when you have a party to go to. If pain was just something mechanical or a result of tissue injury it would’ve hurt the same amount, even in different individuals and circumstances.
Key Mechanism Of Pain Modulation
There are two primary mechanisms through which pain can be modulated: the gate control theory and the descending analgesic system (Endogenous Pain-Inhibitory Pathways).
To understand it better let's discuss the gate control theory, developed by psychologist Ronald Melzack and neuroscientist Patrick Wall that first challenged the dogma of pain as a direct result of tissue trauma/damage and changed how pain was seen as a linear process.
The Gate Control Theory
The gate control theory of pain asserts that non-nociceptive input closes the nerve "gates" to nociceptive input, which prevents nociceptive sensation from traveling to the central nervous system. The gate control theory was the first theory that recognized the influence of psychological factors on pain perception.
We all know that information is carried through nerves from our surroundings via sensory organs like the eyes, nose, ears, mouth, and skin which is then processed in our brain. But along with it, information is processed at the level of our spinal cord which also acts as a link between the body and the brain.
Understanding Nociception v/s Pain
Nociception is the process by which the nervous system detects and encodes painful or harmful stimuli through nociceptors, in simpler terms, nociception is how our nervous system detects harmful stimuli. However, not all nociception results in pain—pain is the brain’s interpretation of those signals. Hence, pain is not an initial information that enters our brain, it is an output that can later on also become an input for a future instance.
For example, burning your finger (nociception) on a hot stove can cause pain and make you careful the next time you use a stove again. Here the output of the pain acts as an input as well. Although there could’ve been a possibility that you were running late for work and burning your finger (nociception) on the stove doesn’t lead to any pain as a result of your brain modulating the pain out to prioritize work. In this instance, the nociception does not lead to pain.
There are many instances in our daily lives where minor injuries do not cause pain, likely because our brain decides that it's not worth paying attention to at that moment.
Sensory Nerve Fibres And Their Functions
Moving on with the gate control theory, the central nervous system (brain and spinal cord) receives information from the periphery through nerve fibers (k/a sensory afferent nerve fibers). There are three primary types of these sensory fibers:
A-beta fibers: Large-diameter myelinated fibers
A delta fibers: Smaller myelinated fibers
C fibers: Unmyelinated fibers
The A beta fibers (non-nociceptive sensory fibers) are generally not associated with the processing of pain but rather they make us aware of our surroundings by sending in harmless information about proprioception (position of the body), light touch, pressure, vibration to the central nervous system. They work constantly to let you know the position of your limbs, and the different types of textures or sensations you feel when interacting with different things in your surroundings.
The nervous system processes different types of sensory input, not just pain, which explains why the same action can feel different in different contexts. For example, lying down on your bed feels more comfortable than lying down on a friend’s bed, or a friend giving you a hug versus your partner versus a stranger hugging you, all of these feel different though they involve the common act of hugging a person.
Modulation processes complex sensory inputs and assigns meaning to them based on various factors.
Besides, the other two sensory nerve fibers, the A-delta and the C fibers (nociceptive sensory fibers), which are the “tissue monitoring” fibers that constantly inspect (not active only during an injury which is a general belief) the state of our tissue but somewhat anxiously. They report all kinds of dangerous information to the central nervous system from a small nick to a large cut or a bit of stretch while doing yoga to a complete muscle pull, leaving it to the CNS to decide (modulation, again) which of these information is worth paying attention to and taking some action about, especially if it's dangerous.
The authors of this study quote, “On the other hand, ample evidence indicates that nociceptors can be active in the absence of pain perception. For example, any pain psychophysicist would agree that applying a 50 kg weight on a 1 cm area of skin would evoke excruciating pain. Yet, experienced ballerinas dance with pointe shoes for many hours, reporting deep positive emotional satisfaction while their toes carry the weight of their body, an activity that must massively and continuously activate their toe nociceptors. Therefore, at least ballerinas with intense training are capable of dissociating pain from nociception.”
These C and A delta fibers release the chemical substance P and glutamate respectively when they synapse in the spinal cord. These chemicals are responsible for activating the second-order neurons/ transmission cells (T-cells) from where the signal travels up toward the brain. Substance P leads to a slower activation of second-order neurons as compared to glutamate leading to slow pain vs fast pain on activation of respective nociceptive fibres.
Let's say, you do get an injury in the form of a cut on your finger. This will lead to inflammation causing the release of chemicals (eg. substance P) through the local blood circulation and immune cells. These inflammatory chemicals activate the A-delta and C fibers to bombard the CNS with messages of damage.
Pain Gating At The Level of Spinal Cord
These danger messages first arrive at the Rexed lamina II (Substantia Gelatinosa) of the spinal cord. Remember, that the A-delta and C fibers are the anxious kind and continuously send in danger signals to the CNS, however, in case of potentially real danger these nerve fibers amp up the intensity of their impulses to draw the attention of the CNS towards them. In addition, the release of chemicals like substance P at the site of injury can further decrease the firing thresholds of these nociceptive neurons.
Whereas the A-beta fibers arrive at the dorsal column of the spinal cord from where they travel up to the brain through the ‘dorsal column medial meniscal pathway’. But, these fibers also give off collaterals to the lamina.
When an impulse travels through the A-beta fibers and the collateral fibers it activates the inhibitory interneurons present in the lamina. This activation leads to the release of a chemical called GABA (Gamma-Aminobutyric acid) which in turn INHIBITS the stimulus coming from the nociceptive A-beta and C fibers from traveling up the brain leading to modulation and a decrease in pain perception.
In other words, stimulation of A-beta fibers can "close the gate", while C and A-delta fibers can "open the gate" causing pain. This mechanism explains why rubbing a painful area can provide relief—stimulating A-beta fibers to compete with nociceptive signals, reducing pain perception.
The Descending Analgesic System
While the Gate Control Theory explains how pain is regulated at the spinal cord level, the descending analgesic system explains how the brain further modulates pain perception by involving signals that originate in the brain and travel down to the spinal cord.
Let's say a nociceptive stimulus comes in and travels through the Substantia Gelatinosa in lamina II and ascends upwards through the lateral spinothalamic tract. This can activate the descending analgesic system/ endogenous opioid system leading to the release of chemicals like norepinephrine and serotonin through the PAG, PVG, raphe nucleus magnus, etc.
This release of chemicals activates the inhibitor interneuron which in turn releases special chemicals like enkephalins, endorphins, and dynorphins, which are endogenous opioids similar to morphine that inhibit the Substantia Gelatinosa from sending nociceptive signals upwards again leading to decreased perception of pain.
Brain's Role In Pain Modulation
Who decides these chemicals get released which would in turn inhibit pain? The higher brain centers like the hypothalamus, cingulate gyrus, thalamus, sensory cortex, etc can regulate the PAG and other areas involved in the descending pathway of pain.
This decision by the brain is made by collecting inputs, weighing in all the information from different centers on several cognitive and emotional factors, such as the prior experience of pain, context of the situation, beliefs about pain, environment, nature, and intensity of the injury/damage, etc. As Dr. Lorimer Moseley rightly said, “Pain is an unpleasant conscious experience that emerges from the brain when the sum of all the available information suggests that you need to protect a particular part of your body”
Practical Application Of The Descending Inhibitory Control
This is the basis of how rubbing a painful area feels good and also how modalities like TENS, IFT, cold, heat, dry needling, acupuncture, and manual therapies like massage, and manipulation work can “feel good” even without the use of “correct technique” (even so it is advertised otherwise).
The above-mentioned modalities hardly change your muscle imbalances, fix your joint position, break down knots, or put your discs into place, but they modulate out the pain through counter-irritation by competing with the nociceptive stimulus, decreasing pain and hence helping you move better.
Diving A Bit Deeper
The nociceptive information from the periphery can be inhibited at the level of the spinal cord (pain gating) and this is where the gate control theory ends. However, there is more to pain modulation. The nociceptive information coming in can be excited further up to the brain through the terminals of second-order neurons or T cells.
Thus, the dorsal horn of the spinal cord has excitatory and inhibitory connections. Therefore, the dorsal horn also receives INPUT from the brain (descending pathway/modulation) on whether to let the sensory information from the periphery to come in, if so, then how much, or let it stay out, which ultimately decides what and how we feel.
What we tend to learn in school tends to stop here at the transmission cells and how they can inhibit or carry the stimulus to the brain leading to pain.
However, there are two types of T-cells, nociceptive specific cells (NS) and wide dynamic range cells (WS). As the name suggests, NS cells only respond to noxious stimuli. If I hit my toe at the edge of my bed, the A-delta and C fibers will carry this noxious stimulus to the dorsal column which will activate the NS cells from where the information will be carried to the centers in the brain that process the threat, giving rise to pain that’d make me for careful.
WDR cells on the other hand get activated with a wide range of stimuli from non-noxious to noxious. So in a controlled state of things, if you scratch yourself mildly things would be fine and you’d experience no pain, although, if you keep scratching yourself at the same spot continuously or aggressively, things will get uncomfortable and painful, urging you to stop.
But, things can get out of control like in cases of an injury or when things get “dangerous” where the nervous system can shift up or down (modulation) from the regulated state depending on the level of injury, context, environment, etc.
For example, if you twist your ankle while crossing a busy road (a pretty dangerous situation), the excruciating pain that usually comes along with an ankle twist would be unhelpful and would even hinder survival. In such a case, modulating down the pain and shifting to a desensitized state such that it allows you to cross the road and is not only just helpful but also aids survival (a priority). So the central nervous system can adapt to a temporarily desensitized state and get back to a sensitised state when you are in a safe environment.
Additionally, a common misconception is that this gating occurs in certain instances or potentially painful situations, though it is a constant process. If our body wasn’t able to modulate our nociceptive information we’d be in constant agony and pain and if there wasn’t any continuous inspection happening in our body we’d be injured often. Imagine if a chef could feel all their minor burns and cuts, and what if a gardener could feel all the bruises and scratches, they'd never be able to go back to work the next day!
Pain Modulation Can Malfunction
In certain cases, like chronic pain, this fine-tuning of the brain to switch between the sensitized, controlled, desensitized state along with the normal firing threshold of sensory fibers, gating out of pain and the descending analgesic pathway can be disturbed and the person can stay stuck in a persistent sensitized state. No wonder people with chronic pain find everything to be painful most of the time.
In Conclusion
Many mechanisms influence nociception and pain and theories that collate it better ( like ‘The Neuromatrix Theory of Pain’ or ‘The Mature Organism Model’). Pain is more complex than just a direct response to injury or tissue damage. It is a subjective, dynamic, and constantly modulated experience influenced by multiple factors, including cognitive, emotional, contextual, and environmental aspects. Understanding pain modulation helps us better navigate our own experiences with pain, and provide support to those who suffer from it beyond just addressing physical injury.
As Dumbledore wisely said, “Of course, it is happening inside your head, Harry, but why on earth should that mean that it is not real?” Pain is real, no matter its origin, and by understanding how modulation works, we can approach it with greater awareness and compassion.
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