Epigenetics: A Key to Controlling Acute and Chronic Pain

 Epigenetics, the study of changes in gene expression through mechanisms outside of the DNA structure, has been found to control a key pain receptor related to surgical incision pain, according to a study in the November issue of Anesthesiology. This study reveals new information about pain regulation in the spinal cord.

"Postoperative pain is an incompletely understood and only partially controllable condition that can result in suffering, medical complications, unplanned hospital admissions and disappointing surgery outcomes," said David J. Clark, M.D., Ph.D., Professor of Anesthesia at Stanford University and Director of Pain Management at the VA Palo Alto Health Care System. "We know that histone acetylation and deacetylation modifies many cellular processes and produces distinct outcomes. In this study we found that histones can epigenetically activate or silence gene expression to either increase or decrease incision pain."

Human DNA is wrapped around proteins called histones, much like thread is wrapped around a spool. When a histone undergoes deacetylation, the DNA wraps more tightly around the spool, effectively silencing genes. Conversely, when it undergoes acetylation, the DNA is loosened, allowing for transcription or modifications of genes to occur.

In this study, groups of mice had small surgical incisions made in their hind paws after being anesthetized. These mice were then regularly injected with suberoylanilide hydroxamic acid (SAHA), which prevents deacetylation (thus promoting gene transcription), or anacardic acid, which prevents acetylation (thus reducing gene transcription). The authors tested the animals daily for the degree of pain sensitivity in their hind paws.

The study found that regulation of histone acetylation can control pain sensitization after an incision. Specifically, maintaining histone in a relatively deacetylated state reduced hypersensitivity after incision. This is due, in part, to the epigenetic regulation of a specific gene known as CXCR2 and one of its chemokine ligands (KC). The authors also found that these epigenetic changes far outlasted the recovery of animals from their incisions, a property that might help explain why some patients suffer from chronic postoperative pain. Study authors suggest that looking into the roles of these epigenetic mechanisms may help scientists find new ways to treat or prevent acute and chronic postoperative pain in the future.

"Epigenetics is a relatively underappreciated area of science, but the discoveries yet to be made in this field will be many," said Dr. Clark. "While fascinating information has been found by studying specific genes, we need to bridge the gap in science and focus on groups or systems of many genes simultaneously, which could be give us clues to greater breakthroughs in pain control and other areas of medicine."

Tomado de: American Society of Anesthesiologists (ASA). "Epigenetics: A key to controlling acute and chronic pain." ScienceDaily, 25 Oct. 2013. Web. 22 Nov. 2013.

Researchers at the University of Leeds have found a previously unknown mechanism through which pain is signalled by nerve cells.

     A discovery that could explain the current failings in the drug development process for painkillers and which may offer opportunities for a new approach.

     The team, led by Dr Nikita Gamper of the University's Faculty of Biological Sciences, is investigating the difference between persistent pain, such as toothache, and pain that results from the increased sensitivity of nerves in injured or diseased tissue (for example when we touch inflamed skin), known as hyperalgesia.

    In research published online this week, (w/c 14 May) in Proceedings of the National Academy of Sciences (PNAS), Dr Gamper's team has discovered that these two types of pain are generated by the same nerves, but result from different underlying mechanisms.

    The project, funded jointly by the Wellcome Trust and the Medical Research Council, investigated the painful effects of two substances that cause local inflammation: bradykinin and substance P. Both substances bind to specific receptors on nerve cells, generating signals to the central nervous system. Because the receptors are from the same family, it has always been presumed they stimulate the same signalling pathway.

     However, the team found that each receptor produces different signals; the one associated with bradykinin causing both hyperalgesia and persistent pain, whereas the one associated with substance P only caused hyperalgesia.

    "Dr Gamper says: "Pain originates from a series of electrical signals sent by nerve cells in to the central nervous system and ultimately the brain. Despite much progress, we still don't know enough about the mechanisms by which these pain signals are generated. However, this research has shown that whilst the sensation of pain can be similar between various conditions, the underlying molecular mechanisms may in fact be very different."

    Existing painkillers are 'non-specific', designed to generally dull the reception of these signals in the central nervous system, and some stronger pain killers can provoke unwanted side effects such as disorientation, drowsiness or nausea. So while the search for new better drugs is pressing, the lack of progress in developing truly targeted analgesics has led to several pharmaceutical companies dropping this area of research altogether.

     "What's exciting about these findings is that substance P may actually suppress the activation of the pain sensing nerves themselves," says Dr Gamper.

     "It's increasingly evident that current strategies for testing and validating new painkillers often do not take into account a possible difference in how pain signals are generated. For instance, drugs for persistent pain are often tested solely for their ability to reduce hyperalgesia, and as a result, some of the drugs that are effective in the lab, fail in subsequent clinical trials. These findings challenge current approaches in drug development research and may offer new strategies," he says

University of Leeds. "Different mechanisms of pain revealed." ScienceDaily, 14 May 2012. Web. 18 May 2012.