A new study from King's College London offers clues as to why
chronic pain can persist, even when the injury that caused it has
gone. Although still in its infancy, this research could explain
how small and seemingly innocuous injuries leave molecular
'footprints' which add up to more lasting damage, and ultimately
chronic pain.
All of us are likely to know someone who suffers from persistent
pain - it is a very common condition, which can be caused by sports
injuries, various diseases and the process of ageing. Treatment
options are limited and doctors are often unable to offer anything
more than partial relief with painkillers, leaving their patients
resigned to suffering.
While chronic pain can have many different causes, the outcome
is often the same: an overly sensitive nervous system which
responds much more than it normally would. However, a question
still remains as to why the nervous system should remain in this
sensitive state over long periods of time, especially in instances
where the underlying injury or disease has gone.
Researchers from King's sought to answer this question by
examining immune cells in the nervous system of mice, which are
known to be important for the generation of persistent pain.
In the study, they found that nerve damage changes epigenetic
marks on some of the genes in these immune cells. Epigenetics is
the process that determines which gene is expressed and where. Some
epigenetic signals have direct functional consequences, while
others are just primers: flags that indicate a potential to act or
be modified.
The cells examined in this King's study still behaved as normal,
but the existence of these novel epigenetic marks may mean that
they carry a 'memory' of the initial injury.
Dr Franziska Denk, from the Wolfson Centre for Age Related
Diseases at the Institute of Psychiatry, Psychology &
Neuroscience (IoPPN), King's College London, said: "We are
ultimately trying to reveal why pain can turn into a chronic
condition. We already knew that chronic pain patients have nerves
that are more active, and we think this is probably due to various
proteins and channels in those nerves having different
properties.
"However, it is unclear why these nerves should remain in this
overactive, highly sensitive state, even when the initial injury or
disease has gone: the back pain from two years ago that never quite
went away or the joints that are still painful despite your
rheumatoid arthritis being in remission."
Dr Denk added: "We want to know why these proteins and channels
should maintain their altered function over such a long period of
time. Cells have housekeeping systems by which the majority of
their content are replaced and renewed every few weeks and months -
so why do crucial proteins keep being replaced by malfunctioning
versions of themselves? Our study is the very first step towards
trying to answer this question by exploring the possibility that
changes in chronic pain may persist because of epigenetics. We hope
that future research in this area could help in the search for
novel therapeutic targets."
Professor Stephen McMahon from the IoPPN at King's College
London said: "This research raises many interesting questions: do
neurons also acquire epigenetic footprints as a result of nerve
injury? Do these molecular footprints affect the function of
proteins? And are they ultimately the reason that chronic pain
persists in patients over such long periods of time?
"The last question is particularly hard to answer, because to
study epigenetics we need access to pure cell populations.
Obviously, many of these are only accessible in postmortem tissue.
However, colleagues at King's are already doing this in psychiatry,
through studies such as the The PsychENCODE project, so it is
possible."
Dr Giovanna Lalli, Neuroscience & Mental Health Senior
Portfolio Developer at the Wellcome Trust, which part-funded the
study, said: "People develop chronic pain for a huge variety of
reasons. We therefore need an equally diverse range of treatments
to tackle the different root causes.
"The clues from this study, suggesting epigenetic changes may be
involved in pain persisting, will hopefully lead us to better
understand the mechanisms underlying chronic pain."
The paper, Persistent Alterations in Microglial Enhancers in a Model of
Chronic Pain, is published in Cell Reports.