Sustained Stimulation of β2- and β3-adrenergic Receptors Leads to Persistent Functional Pain and Neuroinflammation. Xin Zhang, MD, PhD, Jane E. Hartung PhD, […], and Andrea G. Nackley PhD, PhD. Brain Behav Immun 2018 Oct;73:520-532.  doi: 10.1016/j.bbi.2018.06.017. Epub 2018 Jun 20.

There’s neuroinflammation and there’s the stress response. Recently, we saw Mackay and Tate propose that neuroinflammation in ME/CFS and FM was linked to a whacky stress response centered in the hypothalamus.

In 2018 Chinese-Duke University collaboration suggested that the stress response and neuroinflammation are linked as well, although in a different way. The appearance of these hypotheses and findings is good news given that neuroinflammation appears (but has not been definitively proven) to be present in these diseases, and evidence suggests that the stress response is certainly off.

Studies suggest that the activity of the “fight or flight” (sympathetic nervous system) response is increased and/or that the activity of the “rest and digest” (parasympathetic nervous system) response is decreased in ME/CFS and FM.

This Chinese-Duke collaboration proposed that an overactive stress response system (“enhanced catecholamine tone”) has triggered the neuroinflammation in fibromyalgia (FM), chronic fatigue syndrome (ME/CFS) and similar disorders. No injury was necessary to start the  just a really amped up fight/flight system.

Norepinephrine breakdown by the COMT enzyme. Problems with norepinephrine breakdown by the COMT enzyme are suspected in FM and ME/CFS.

The inability to find an immediate physical origin for the pain in FM and other “functional pain” diseases (temporomandibular joint syndrome (TMJ), vulvodynia, irritable bowel syndrome, interstitial cystitis, chronic fatigue syndrome (ME/CFS)) has thrown the medical profession for a loop. Too often, that has led doctors to dismiss the pain and other symptoms in these disorders as psychological or to treat it as something not significant.

Over time, however, consistent problems in the HPA axis, the sympathetic nervous system (SNS) and central nervous system have been found which could help explain the pain. While it’s possible that the body pain in FM is to some extent being generated in the body, it’s clear that it is also being generated in the brain;; i.e. pain is being brought to the body by the brain.

The Gist

  • Many studies indicate that prolonged activation of the sympathetic nervous system (SNS) can result in increased pain sensitivity
  • The researchers in this study amped up the SNS system of rodents by inhibiting the activity of an enzyme called COMT that breaks down norepinephrine – the main driver of SNS activity.
  • It took from 2-3 weeks for a chronic pain state and signs of neuroinflammation to appear – a state which remained even after the researchers turned off the sympathetic nervous system activation.
  • That indicated that while the SNS activation was needed to trigger the chronic pain state, something else, after a time, maintained it in the brain.
  • The authors found that three cytokines (TNFα, IL-1β, and IL-6) were driving the chronic pain state in the brain.
  • They were able to stop the pain by inserting a TNF-a blocker called etanercept (Enbrel) into the rodents spinal cords.
  • That suggested that while the SNS activation triggered the pain state, attacking the neuroinflammation may be the key.
  • Enbrel is used to combat pain in several autoimmune diseases but does not work in everyone and can have significant side effects.
  • The authors proposed that drugs which target specific parts of the TNF-a immune pathway would work better.
  • Dr. Nancy Klimas’s modeling efforts suggest something similar is happening in ME/CFS and FM. She’s using Enbrel plus an HPA axis drug to tamp down the neuroinflammation first and then hopefully reset the HPA axis in GWI and ME/CFS.



Heart rate variability (HRV) studies suggest the sympathetic nervous system (“fight or flight”) is hyperactive or always on in FM and ME/CFS. That hyperactivity has made an exploration of the COMT enzyme which breaks down norepinephrine – the driver of SNS activity – a long-standing pursuit. A balky COMT enzyme could lead to high norepinephrine levels and an always on fight or flight system. Other studies have focused on the beta-2 adrenergic receptors that bind to norepinephrine (and epinephrine).

Well over a dozen studies have explored whether a COMT polymorphism – an unusual form of the gene – could be playing a role in fibromyalgia. Most studies have found links to COMT polymorphisms in FM, but not all. (It was remarkable to see two meta-analyses done a year apart come to opposite conclusions concerning whether the val(158)met COMT polymorphism plays a role in FM.)

The geneticists are not giving up, though.  One of the latest studies, which examined almost 3,000 people with FM, gave a nudge to the COMT/FM hypothesis and concluded that, yes, more studies were necessary.

Possible problems with both COMT and the adrenergic receptors have shown up in ME/CFS, which also appears to share the fight or flight system activation found in FM. Wyller found an increased incidence of unusual forms of the B2AdR and COMT genes (polymorphisms) in adolescents with ME/CFS in 2011.  The next year, the Lights found that exercise dramatically increased the expression of beta adrenergic and other genes in ME/CFS patients, but not in healthy controls. Just recently Loebel and Scheibenbogen found increased antibodies to B2 receptors in a subset of ME/CFS patients.

Both Loebel and Scheibenbogen and Wyller’s findings suggest that the SNS problems don’t stop at that system and that an SNS/immune connection is present in ME/CFS. These Duke/Chinese researchers would agree.

Sympathetic Nervous System – Neuroinflammation Connection Found

“In line with findings from studies of inflammatory and neuropathic pain (Latremoliere and Woolf, 2009), our results suggest that functional pain is maintained in the central nervous system long after the precipitating cause is removed. This phenomenon may explain why patients with FPS (fibomyalgia pain syndrome) experience sensory abnormalities at regions remote from the original painful site.” The authors

The Duke/Chinese researchers were intent on determining how sympathetic nervous system activation could lead to immune activation, long-term neuroinflammation and chronic pain.

They turned up the dial on the sympathetic nervous system by inhibiting the COMT enzyme that breaks down the norepinephrine and then they waited and watched. Fourteen days later, their subjects – rodents – were demonstrating signs of widespread pain.

This was not a surprise. Numerous studies have linked the activation of the adrenergic B2 and B3 stress receptors that drive the fight or flight system with increased pain sensitivity. These receptors appear to be producing pain by increasing the excitability of pain signaling neurons and by activating T-cells, mast cells and others. (Interestingly, this study found that activated B2 and B3 receptors in the body – not in spine or supraspinal regions – triggered the increased pain sensitivity.)

SNS body

Mostly we think of the sympathetic nervous system’s effect on the body, but these researchers found that chronic SNS activity in the body could affect the brain as well.

Importantly, they showed that constant sympathetic nervous system activation induced a chronic pain state that had a life of its own. Even after the COMT inhibitor was removed the rodents’ pain levels remained high.

Next, they tried to determine what was driving the chronic pain state. Turning off the B2 and B3 AR activation with antagonists didn’t do anything to the pain. That indicated that while the adrenergic receptor activation played a critical role in triggering the development of the pain state, and had apparently strengthened the “pain-coding pathways”, something else was now driving the chronic pain state in the brain.

That something else proved to be three cytokines: TNFα, IL-1β, and IL-6. As the brakes were taken off the COMT enzyme the cytokine levels in the plasma decreased but 1-3 weeks later continued to increase in the cerebral spinal fluid. About the same time, the immune cells in the brain called microglia and astrocytes showed signs that they were activated.

The researchers had just shown how to induce a state of neuroinflammation and chronic pain without ever causing a physical injury. Note that the neuroinflammation in the rodents’ brains was simply initiated by increasing the levels of epinephrine and norepinephrine (by inhibiting the COMT enzyme).

Tricky Situation?

Wyller showed how much of a difference a slightly altered gene can make – and just how tricky this situation may be in ME/CFS. He found that the activity levels of ME/CFS adolescents with a high activity (Rs4680) form of the COMT gene tanked when given Clonidine.

That was a fascinating result given that Wyller believed the opposite would happen. With his data indicating that high norepinephrine levels were present in ME/CFS, Wyller believed that Clonidine would decrease the adolescents’ sympathetic nervous system activity, increase their parasympathetic nervous system activity – and provide them with more energy. Clonidine did decrease the SNS activity of this particular group of patients, but to such low levels that they actually got worse. It turned out that this group already had lower NE levels.

Wyller’s finding in two groups of ME/CFS patients, one with higher and one with lower NE levels, and each with different immune factors at work, suggests that the situation may be quite complex.

Treatment Possibilities


Enbrel – injected into the spinal cord – was able to turn off the pain state in the rodents.

The researcher were able to stop the pain by administering either of two substances – the TNFα inhibitor etanercept (Enbrel) or the p38 inhibitor SB203580. That indicated that TNFα and p-p38 were driving the chronic pain state in the brain.

Enbrel is used in the treatment of inflammatory pain conditions, such as arthritis and inflammatory bowel disease, and neuropathic pain conditions, such as lumbar disk hernia and sciatica. About 40% of the patients, however, do not respond to TNFα antibodies and long-term use is associated with an increased risk of infection and other adverse events.

The authors suggested that drugs which selectively target parts of the intracellular TNFα signaling network could produce better results and fewer side-effects for people in chronic pain.

Dr. Klimas’s models, however, suggests that using etanercept (Enbrel) first and then using the HPA axis modulator next, Mifepristone, could flip the systems of Gulf War Illness and ME/CFS patients back to normal. She is testing that model now.

Dr. Klimas’s Big Win and What it Means for Chronic Fatigue Syndrome (ME/CFS)


The sympathetic nervous system route to chronic pain is being increasingly well documented, with the authors able to provide many citations to support it.

It should be noted, though, that this was a rodent study, not a human study. Except for Enbrel, the authors were unable to point to TNFα altering drugs that might work. The authors’ ability to insert Etanercept straight into the brain obviously also couldn’t be repeated in humans.

Nor have the genetic issues with the COMT enzyme or the functioning of the beta adrenergic receptors been completely fleshed out in FM or ME/CFS. Some studies suggest the situation may be complicated by different subsets of patients.

The authors also don’t tell us why the stress response might get lodged on the “on” position long enough to get an immune response in the brain going, nor if people with FM are more susceptible to getting neuroinflammation started in the first place.

It’s interesting, though, that two things that came out of the Dubbo post-viral studies – that symptom severity during an initial infection, plus the presence of polymorphisms that could have pumped up cytokine production – suggested that an early over-active immune response to the infection could have paved the way for ME/CFS . One wonders if something similar will be found in people having trouble recovering from COVID-19.

  • On that note check out a really excellent article “COVID-19 Can Last for Several Months”. It’s the fourth one in the last month or so to focus on difficulty some people are having recovering from COVID-19 and it explicitly mentions ME/CFS.

FIrst and foremost the authors believe that brain inflammation in functional pain states like FM and ME/CFS must be addressed

Still, the study presents a pretty compelling picture of how an upregulated fight or flight system could lead to a chronic pain state maintained in the brain by immune activity. It suggests that pain state may be triggered by receptor activation in the body, not the central nervous system, and that a successful treatment needs to target both the neuroinflammation in the brain and the SNS activation in the body.

Dr. Klimas’s modeling work has come to a similar conclusion. She’s attempting to tamp down the neuroinflammation in the brain using etanercept (Enbrel) and then reset the HPA axis in Gulf War Illness and ME/CFS.

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