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Pain – A Surprisingly Complex Experience

Pain seems pretty elementary – it hurts! When it really hurts, you want to throw yourself out of your skin. It’s actually not so simple. Pain is often described as a complex, “biopsychosocial phenomenon“. The International Association for the Study of Pain describes pain as an “unpleasant sensory and emotional experience”.

There’s the sensory side of pain – how the pain signals get to the brain and are processed – and the sensations they produce.  We know those processes are damaged in fibromyalgia, but that’s not nearly the end of the pain situation for those with fibromyalgia or chronic pain.

pain complex experience

Pain is more than a body sensation: it’s a complex experience put together by several different parts of the brain.

There’s also a cognitive element to pain. Triathletes, marathon runners, swimmers and other athletes, for instance, are able to push through high levels of pain partly because they know it’s going to be limited in duration; i.e. it’s controllable. Simply believing that you can control or handle or withstand your pain actually makes the pain less severe.  Pain levels spike, on the other hand, in people who do not believe they can handle their pain.

That emotional aspect – the fear and other emotions associated with pain –  also plays a major role in how we experience pain.  Emotions and pain are necessarily hard-wired together.  Pain, after all, is the stimulus our bodies use to tell us an injury has occurred. Our brain uses emotions like fear to ensure that we get the message, respond to and resolve the situation. The fear, anxiety, anger, etc. – what researchers call the “unpleasantness factor” – that pain arouses in us makes up the second major part of pain.

It turns out that pain sensations – surprise, surprise – are not necessarily unpleasant – they’re just very strong sensations.  Patch them together, though, with a bunch of unpleasantness, and you get PAIN… Without that unpleasantness aspect, people with FM or ME/CFS might be distracted by the intensity or bizarreness of their sensations, but they won’t necessarily be bothered by them.

The sensation+unpleasantness=PAIN patch is usually quite effective at prodding someone to take the actions needed to relieve their pain and return to health. But what about someone sitting in a toxic stew of pain and fear for years on end. They’re certainly not experiencing an adaptive or effective pain response. They’re in the midst of a chronic pain response that has run amok, is causing pain for no good reason, and is doing no one – not the person experiencing it nor the community they live in – any good.

Finding out how all that “unpleasantness” – a typically mild scientific word for a pretty darn torturous situation – occurs, then, is a big deal. If we knew how unpleasantness got mixed in with pain, we might be able to make pain a heck of a lot easier to deal with.  Earlier this year some Stanford researchers made a breakthrough in understanding this core aspect of pain.

Tracking Down the Hurt That Comes with Pain

Researchers have pretty well mapped out how the sensory aspect of pain occurs. Tracking down the origins of the “unpleasantness” aspect of pain – which turns out to be buried deep in the brain – has been considerably more difficult. Some of the pathways have been mapped, but finding neurons which start the process off has proved elusive.  New technology developed at Stanford, however, is tracking them down.

Science. 2019 Jan 18;363(6424):276-281. doi: 10.1126/science.aap8586. An amygdalar neural ensemble that encodes the unpleasantness of pain. Corder G1,2,3,4, Ahanonu B5,6,7, Grewe BF5,7, Wang D1, Schnitzer MJ8,6,7,9, Scherrer  G10,2,3,4,11.

As reported in Science in January, Stanford researchers used a miniaturized microscope, called a “miniscope”, which is able to probe deep into the brains of mice and determine which neurons are turning themselves on in response to a painful stimuli. They charted two responses – a response when their paw was pricked with a pin and the animals’ attempts to avoid further pin-pricks or their licking the pricked paw.

The first response indicated that the pin-prick did indeed induce a pain sensation. The second response indicated that it was associated with unpleasantness.  They found that repeated pin-pricks caused the animals to attempt to escape from the pin-pricks and/or lick the pricked paw.  The pin-pricks were clearly unpleasant to them.

unpleasantness pain

It’s the “unpleasantness” part of pain which makes pain so difficult to tolerate. Turn off the unpleasantness factor and what is experienced as pain might seem like just another body sensation.

Using what one reviewer called “some of the most advanced techniques” in neuroscience, the Stanford researchers were able to turn on and off neurons associated with pain response.  Turning off one set of neurons in the basolateral amygdala (BLA) maintained the animals awareness of the sensation but left them utterly unconcerned about it. The researchers could prick the animals again and again without the animals showing any signs that it was unpleasant to them.

After reviewing the study, Benedict Kolber, Duquesne University, stated that the “full flavor” of pain had been lost. The lead author of the study, Grégory Scherrer, simply stated that the animals  “essentially didn’t care about pain anymore”.

Then they exposed the mice to high levels of heat and cold.  Again, the mice with the BLA neurons turned off exhibited fewer signs that the temperature changes were unpleasant compared to normal mice.

The researchers then induced a short-term course of sciatica in the mice to see if being in acute pain affected the BLA region. It didn’t – suggesting that acute pain does not, by itself, necessarily cause the amygdala to up the unpleasantness factor.  Interestingly, though, light touch did increase neuronal activity – which indicates that this part of the amygdala probably plays a role in the development of allodynia and chronic pain.

They then let the mice develop a full course of allodynia. After they’d become sensitive to even the lightest of touches, the researchers turned off their BLA neurons and saw the animals’ distress levels plummet. When they did the same process with cold-induced allodynia, the animals’ aversion to cold completely disappeared.

The researchers had found a way to take the hurt out of pain.

 

Chronic fatigue syndrome (ME/CFS) and Fibromyalgia (FM)

While the focus on the basolateral amygdala is new, the amygdala and the limbic system have quite a history in ME/CFS and FM. Back in the 1990’s, in “The Chronic Fatigue Syndromes: A Limbic Hypothesis”, Dr. Jay Goldstein proposed that the amygdala – with its connections to the brainstem, hypothalamus and other cortical areas – was likely part of the “final common pathway”, where a damaged limbic system induced changes in ME/CFS patients’ brains.

In 2002, Ashok Gupta proposed that amygdala activation causes immune reactivation/dysfunction and chronic sympathetic nervous system stimulation, which produces mental and physical exhaustion and other symptoms. His Amygdala Retraining Program – now called Gupta Program Brain Retraining – attempts to tame a hyperactive limbic and brain through neurolinguistic reprogramming and meditative and mindfulness practices.

A recent fibromyalgia Israeli study touted the success of a neurofeedback protocol aimed at the amygdala.  Another recent study suggested that when milnacipran works, it does so in part by altering activity in the amygdala. Grey matter alterations, increased glutamate, functional and structural alterations, overactivity at rest, and reduced opioid binding potentials have all been found in the amygdalas of people with fibromyalgia.

Location Matters

This study is a reminder why it’s so good to have ME/CFS researchers working at places like Stanford and Harvard. It’s no surprise that this study – which was published in the journal Science – happened at Stanford. For one, Stanford is known for its pain research. (It’s where Jarred Younger did his post-graduate explorations into pain and fibromyalgia.)

More importantly, places like Stanford and Harvard are where top scientists and their toys meet up and produce creative new studies. Reviewer after reviewer applauded the new techniques used in the study, which one said “will be very valuable to the pain field in the future”.

The study happened because Scherrer – the senior author interested in the unpleasantness aspect of pain – happened to work next door to Mark Schnitzer, the developer of the miniscope. It resulted from the “many conversations” the two next door neighbors had over the years.

Next Steps

Now that the researchers have determined where in the brain sensory sensations get turned into fear and churning, painful experiences, the next steps include better mapping of the pathways involved, one of which involves the nucleus accumbens – a part of the basal ganglia which has been highlighted in ME/CFS.

receptor to reduce pain

The next step is to try to isolate a receptor which a drug could attach to and shut down – and turn down the hurt in chronic pain.

Researchers also want to learn how this particular region of the amygdala gets altered in the first place, but uppermost on the Stanford researchers’ list is looking for receptors or ion channels on the BLA neurons which could be targeted with drugs – which could shut down the unpleasantness factor that makes chronic pain so very painful.

It will take time to unravel all this, but the implications of the study – to be able to turn off the hurt that comes with pain – are enormous. Kolber in The Pain Research Forum stated:

“From a therapeutic perspective, these findings could be extremely powerful, because if we could just get rid of the negative valence of pain, then even a patient with a 10 on an intensity pain scale could say it doesn’t bother them—that it’s a 1 on an unpleasantness scale—which would greatly increase their quality of life.”

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