To understand how chronic pain develops, researchers often examine changes in gene expression—which genes are turned on, and which ones are turned off—during different pain conditions. However, chronic pain is associated with alterations in thousands of genes, making it cumbersome to pinpoint the most relevant gene or set of genes that may contribute to it. As a result, pain investigators have begun to study the more limited number of “epigenetic” mechanisms that regulate gene expression and may play a role in chronic pain. A study from scientists at the University of Texas MD Anderson Cancer Center in Houston, US, shows the promise of this approach.
In this work, published November 9 in Nature Neuroscience, the researchers identified a protein—an epigenetic enzyme called G9a—that was essential for the development and persistence of chronic pain in a rodent model of pain caused by nerve injury. They also demonstrated that deleting G9a using genetic techniques could prevent chronic pain from developing. Further, inhibiting G9a with a drug could alleviate chronic pain that had already been established.
“These results are very clinically relevant,” said Hui-Lin Pan, who led the new study. For instance, since chronic pain often develops after surgery, “one of the potential clinical implications is that a G9a inhibitor given around the time of surgery may reduce the probability of developing chronic pain.”
G9a turns up the pain
Epigenetic regulators like G9a regulate gene expression without altering DNA base sequences. They do so by attaching chemical groups to DNA or removing them, or, in the case of G9a, by modifying histones, the proteins around which DNA wraps. These processes are critical for cell differentiation (for a cell to become a neuron, for instance, rather than another type of cell), and are one way in which environmental factors can have a long-lasting effect on genes. Epigenetic processes have been implicated in many diseases and disorders, including cancer and depression.
To test a role for epigenetics in pain caused by nerve injury (neuropathic pain), the authors examined the activity of a handful of epigenetic enzymes in dorsal root ganglia (DRG) neurons of rats with or without spinal nerve injury; DRG neurons are cells that relay pain signals coming from the body into the spinal cord. Shortly after nerve damage, the researchers found increased activity of G9a in DRG neurons from injured rats, compared to those from uninjured animals. G9A also chemically modified the histones of DRG neurons from injured rats. Meanwhile, inhibiting G9a with a drug reversed changes in the expression of many genes known to be altered during neuropathic pain, including potassium channel genes that control the electrical excitability of neurons.
After studying the DRG neurons, the researchers examined the behaviors of the animals to see if G9a contributed to the development of chronic pain. They found that nerve-injured mice who were genetically modified to lack G9a did not go on to develop pain hypersensitivity (measured by their responses to mechanical pressure). And, administration of the G9a inhibitor to rats with established chronic pain gradually restored normal levels of pain sensitivity, indicating that G9a also maintains chronic pain.
“The authors have undoubtedly shown that G9a is key to the development and maintenance of long term neuropathic pain states,” said Sandrine Geranton, a pain researcher at University College London, UK, who was not involved in the study. Still, she cautioned that it remains unclear which specific genes affected by inhibiting G9 were responsible for the pain-relieving effects.
Nonetheless, the findings suggest that G9a may be a good target for preventing pain or for ameliorating established pain. As for future research, Pan is now studying exactly how nerve injury increases G9a activity, and whether the current results apply to other models of chronic pain. —Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a neuroscientist-turned-science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman