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When you think of the causes of pain in fibromyalgia and chronic fatigue syndrome (ME/CFS) and other painful disorders, you probably think of the nerves or the central nervous system. A recent study suggests that we should thinking much further afield.

The central nervous system is a powerful player but this laboratory study suggests that fibromyalgia and other chronic pain disorder might be better thought of as neuro- immune disorders which affect many processes in both the brain and body.

That seems to make sense. Our experience of pain, after all, can be an all-encompassing one; it can affect our mood, our relationships, our ability to think and our ability to function. It’s no wonder, then, that researchers are finding that other systems of the body are involved.

The Study

Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells, Renaud Massart, Sergiy Dymov, Magali Millecamps, Matthew Suderman, Stephanie Gregoire, Kevin Koenigs, Sebastian Alvarado, Maral Tajerian, Laura S. Stone, Moshe Szyf, Scientific Reports 6, Article number: 19615 (2016 doi:10.1038/srep19615

This study – done in rats – took a relatively new approach to pain.

As usual in animal studies, they first put the rats into a pain state. Nine months later – as the rats were nearing the ends of their normal lifespans – they looked at a part of their genetic makeup called methyl groups. These methyl groups – found at the ends of strands of DNA – turn genes off or on. This branch of genetics is called epigenetics.

epigenetics

Epigenetic processes can turn many genes on or off.

The relatively new field of epigenetics is transforming what researchers think about how our genes work. Before epigenetics, genes were thought of as a kind of blank slate, the expression of which was determined when we were conceived.

We know now that methyl groups which get attached to genes over time can radically change the expression of those genes. Furthermore we know that the longer you live the more likely that those changes will occur; i.e. the genetic template you were born with is not the one you will die with.

These changes can be invoked in a number of ways, but in general, stressful, biologically meaningful events produce the most changes in our gene expression. Since genes produce the proteins which do the basic work of the cell and our bodies, the potential of  epigenetic changes to contribute to illness and health is vast.

The Results

Our current study strongly argues for the critical involvement of DNA methylation in chronic pain. The authors

It stands to reason then that something like a major injury could significantly alter how our genes are functioning. Even these researchers were astonished, however, at the number of genes effected by one injury which occurred early in the rats lives.

They had every reason to be stunned. They found that about 25% of the gene methylation sites in the prefrontal cortex of the rat’s brains had been changed. That suggests that about 25% of the genes in this critical area of the brain – which has popped up in numerous FM and ME/CFS studies – functioned differently after the rats began experiencing pain.

prefrontal cortex

The expression of hundreds to thousands of genes in the prefrontal cortex of the brain were altered

The changes generally occurred in genes known to be involved in pain-producing pathways such as the dopaminergic, glutamatergic, opioid and serotoninergic systems and the inflammatory components of the brain. Many of the dysregulated genes and pathways identified in the brain have also been associated with three common outcomes of chronic pain – increased rates of anxiety, depression and cognitive problems.

The researchers highlighted one gene and two methylation enzymes. The GRINI gene plays a key role in producing neuroplastic changes throughout the central nervous system, and the Dnmt1 and dnmt3a enzymes  produced many of the changes in methylation status found. These genes or enzymes could be targeted by drug manufacturers seeking to reduce pain and the other problems produced by chronic pain.

Immune Involvement

“We were surprised by the sheer number of genes that were marked by the chronic pain—hundreds to thousands of different genes were changed…We can now consider the implications that chronic pain might have on other systems in the body that we don’t normally associate with pain.”

Changes to the DNA in the brain cells were expected but the numerous changes in T cells really caught the researchers eyes. This finding, the authors asserted, will have “broad implications” for the pain field.

t-cells

Similar epigenetic changes occurred in both the central nervous and immune systems

They noted that research has indicated that T cells, in particular, appear to play a role in producing hypersensitive pain states including allodynia. Indeed, this study follows a recent one suggesting that microglial changes in males, but T cell changes in females are causing the chronic pain states in the two sexes. The authors of this study also believe that the altered DNA methylation seen, probably plays a key role in the problems associated with peripheral neuropathy.

The fact that the same types of methylation changes occurred in both the brain and the immune genes suggested that chronic pain may be producing alterations to genes regulating pain and other conditions throughout the body.

Good News For Pain Patients

“The findings highlight the devastating impact of chronic pain on other important parts of the body such as the immune system.” The authors

Why is this finding such good news? Because the current therapeutic pain regimens – mostly opioid-based treatments focused on the central nervous system – simply aren’t, despite the decades spent refining and using them – very effective. We’re clearly missing vital parts of the pain production process and this study could fill in one of those missing pieces.

The other good news is that just as these epigenetic changes can occur over time the authors believe they can be reversed as well.

It should be pointed out that the study was done in rats not humans and that we may be quite a ways from identifying and producing an epigenetic drug targeting pain. This study, however, should stimulate more research which, hopefully, will produce new and better treatment options.

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