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Imagine a world where you could take one pill to treat both your mental pain and your physical pain? A pill that simultaneously eases your depression and your arthritis, or, erases anxious thoughts related to a past accident while also relieving the lingering back pain from your injuries? Visualize a world where you don’t have to take a handful of medications to treat fibromyalgia.

A protein previously connected to major depression, bipolar disorder, post-traumatic stress disorder and suicide may be a new target for future treatments of chronic pain.

Using a “state-of-the-art” drug and gene deletion that targeted this protein, researchers in the lab of Sandrine Géranton at UCL Institute of Neurology, London were able to halt the development of chronic pain, and, importantly, eliminate a pre-existing chronic pain condition in mice.

Chronic pain is relentless and difficult to live with. It is the most common form of long-term disability, being the number one reason for visits to the doctor. It is also expensive. The annual cost of chronic pain is about $635 billion in the US. This does not include the financial burden on the individual, such as inability to work. One in five adults suffer from chronic pain worldwide, and unfortunately for many, current medications often fall short of controlling the condition.

Chronic pain and mental health are intimately entwined. For example, depressed individuals feel more physical pain and chronic pain can lead to anxiety and depression. Pain is reported as more intense if it coincides with trauma. Given that the system I am going to tell you about has already been shown to be effective in treating models of depression and anxiety, perhaps a single pill for the combined treatment of chronic pain and mental health could be found in the future.

A stress protein conveys messages for chronic pain

Human genetic studies found that some forms (variants) of the FKBP51 gene influence pain symptom severity following stressful situations like car accidents, sexual assault or returning from war.

The Géranton lab looked at two models of chronic pain: arthritis-type inflammation in the ankle joint and neuropathic pain. They found that levels of FKB5P1 protein increased in the spinal cord following these chronic pain procedures (it also increases in the brain in response to stress, anxiety and suicide).

Symptoms of chronic pain include spontaneous pain or exaggerated responses to painful stimuli and non-painful stimuli. This hypersensitivity means that a light touch or simply putting a foot on the ground can result in the feeling of pain.

To look at this in regard to FKB5P1, the researchers compared normal mice and mice where they had deleted the gene that encodes FKB5P1. They found that even though the mice had similar responses to acute “painful” stimuli, after chronic pain procedures, the mice lacking FKB5P1 could withstand a higher level of force before they felt pain.

In other words: the mice without FKB5P1 had less hypersensitivity when they had arthritic-like or neuropathic-like pain. Encouragingly, the mice were also more able to move, suggesting that they were not feeling the debilitating effects of chronic pain as much. The researchers concluded that FKB5P1 is necessary for the symptom of hypersensitivity to painful stimuli in chronic pain conditions.

Curing chronic pain through spinal cord proteins

The scientists next targeted spinal cord FKB5P1. The experience of pain is subjective and being able to eliminate chronic pain symptoms through the spinal cord, independent of the brain, will be important for people who may have trouble convincing doctors of their condition.

The scientists were able (in mice) to block development of chronic pain and hypersensitivity to mildly painful stimuli by silencing spinal cord FKB5P1.

Obviously doing silencing FKB5P1 isn’t so easy in humans so, excitingly, the researchers were able to get a similar result by delivering a new compound that binds to FKB5P1 and prevents it from functioning, called SAFit2, to the spinal cord of the mice.

And even better, both techniques also reversed the symptoms in pre-existing chronic pain conditions when applied three days after the injury.

Importantly, the mice were still able to respond to necessary acute pain. Acute pain is protective, it directs us to stop doing something harmful or to seek treatment, and it disappears once the painful stimuli are removed or the wound has healed.

How does it work?

The researchers found that FKB5P1 is found in the same spinal cord nerve cells that contain sensors, called glucocorticoid receptors, for the stress hormone corticosterone (part of the adrenal stress system; cortisol in humans). FKBP51 prevents glucocorticoid receptors from responding to corticosterone.

Corticosterone increases in response to stress and is important for “fight-or-flight” responses. Normally, corticosterone acts on glucocorticoid receptors to reduce feelings of pain. This is probably advantageous when you need to run from an attacker despite an injury or lift a car off your baby. The researchers demonstrated that blocking glucocorticoid receptors made mice hypersensitive to pain, supporting that they normally function to reduce pain.

Yet in chronic pain models, when the researchers blocked glucocorticoid receptors, the opposite happened: it reduced pain. This switch did not happen in mice lacking FKBP51 – blocking glucocorticoid receptors continued to enhance pain. So, after chronic pain, the system that usually works to ease pain switches to a system that boosts pain (promoting hypersensitivity) because of elevated FKBP51.

In other words: when FKBP51 levels rise in chronic pain it prevents corticosterone-glucocorticoid receptor interactions that limit pain. FKBP51 is necessary for the expression of hypersensitivity to painful and non-painful stimuli through stress hormone pathways. It switches glucocorticoid receptors from anti-pain to pro-pain once chronic pain conditions have developed. With this knowledge, researchers and drug developers have a new target to develop medicines to prevent sufferers of chronic pain, like arthritis/ neuropathic pain, from responding too much to non-painful stimuli.

Stress pathways link chronic pain and mental health

By impacting both the peripheral and brain stress circuits, FKBP51 impacts both chronic pain and mental health.

Some people have FKBP51 gene variants that make them more likely to suffer from mental health issues like major depression, anxiety related disorders, bipolar disorder and post-traumatic stress disorder. FKBP51 protein is found in higher levels in brains examined from people who have committed suicide and in HIV patients.

The lab of Matthew Schmidt, Max Planck Institute of Psychiatry, Germany, has looked into FKBP51 and stress in the brain. It turns out that areas of the brain important for anxiety and stress, like one called the amygdala, acquire more FKBP51 following stress. They demonstrated that injecting FKBP51 into the amygdala of mice increases anxiety, whereas blocking it (with SAFit2) reduces anxiety. Mice that lack FKBP51 are also less affected by chronic stress.

A study from the Chad Dickey lab in University of South Florida also found that depressed-like behaviors in response to stress were less in mice without FKBP51 compared to mice with FKBP51. Interestingly, FKBP51 levels increase with age, contributing to depression and anxiety in the elderly. Perhaps FKBP51 levels also lead to development of chronic pain, e.g. arthritis, as we grow older?

Concluding remarks

Many mental health disorders, especially mood (depression/ anxiety) and sleep disorders, accompany chronic pain. It can be a vicious cycle when chronic pain impacts activities that are important for our health like ability to sleep or exercise, and our desire to socialize. All these factors contribute to our mental health and ability to handle pain and stress, and chronic pain management often involves treating sleep disturbances and anxiety on top of the pain itself.

In an overview of chronic pain and links with mental health disorders published in Pain Medicine, Drs Nicholson and Verma, said “a common cause of poor outcome is the failure to properly assess, and effectively treat, real and significant psychological cofactors and psychiatric comorbidities that make coping with chronic pain so difficult, such as poor sleep, depression, mood, and anxiety.”

The worst part about chronic pain is that it serves no purpose and it is hard to treat. The editor of Science Translational Medicine says “treatment tools are distressingly poor for alleviating long-lasting, debilitating pain”. Currently, many medications that are used to treat chronic pain are not completely effective and can have serious side-effects, including tolerance and addiction (especially opiates like morphine). Understanding the mechanisms behind chronic pain is key to better treatment options.

This new study suggests that the same system that controls how you respond to stress can affect how your body develops chronic pain and contributes to hypersensitivity to things that may not be painful or only mildly painful. A glimmer of hope for chronic pain sufferers of a future with novel treatment strategies, that presumably, by acting on the spinal cord, can bypass the “is it all in their mind” problems of seeking help for chronic pain.

For sufferers of persistent back pain, neuropathic pain, and conditions where chronic pain and mental health problems overlap, such as fibromyalgia, war heroes with both post-traumatic stress disorder and physical injuries, or survivors of sexual assault: could this single protein, FKBP51, be the key? Could a pill that inhibits this one protein be an anti-depressant, an anti-anxiety and an anti-pain treatment?

[Disclaimer: I am talking about the latest cutting edge neuroscience… it is not yet available for human consumption. Basic scientific research is the backbone for drug development. This is also not medical advice.]

To view the original paper discussed in this blog “The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling” in Science Translational Medicine click here.

Other papers mentioned: “Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties” in the Journal of Neuroscience click here.

“A New Anti-Depressive Strategy for the Elderly: Ablation of FKBP5/FKBP51” in PLOS One click here.

Further reading:

http://www.nature.com/ng/journal/v36/n12/full/ng1479.html

http://www.newswise.com/articles/nih-study-shows-prevalence-of-chronic-or-severe-pain-in-u-s-adults

http://www.hse.gov.uk/statistics/causdis/musculoskeletal/msd.pdf

https://www.sciencedaily.com/releases/2015/08/150819111112.htm

http://www.painmed.org/patientcenter/facts_on_pain.aspx

http://www.fmcpaware.org/aboutfibromyalgia.html

http://painmedicine.oxfordjournals.org/content/5/suppl_1/S9.long

http://www.nimh.nih.gov/health/publications/chronic-illness-mental-health-2015/index.shtml

http://www.asahq.org/resources/publications/newsletter-articles/2014/june-2014/the-global-burden-of-chronic-pain

http://www.nationalpainaudit.org/background

http://bmcpublichealth.biomedcentral.com/articles/10.1186/1471-2458-11-770

http://www.who.int/mediacentre/news/releases/2004/pr70/en/

http://www.iasp-pain.org/files/Content/ContentFolders/GlobalYearAgainstPain2/20042005RighttoPainRelief/whypaincontrolmatters.pdf

https://www.sciencedaily.com/releases/2012/09/120911091100.htm

The Blog was written by Carolyn Lacey, Scientific Outreach Manager at Neurexpert. To learn more about Carolyn and Neurexpert, please click here.