A way to silence Neuropathic Pain

Laumet G, Garriga J, Chen SR, Zhang Y, Li DP, Smith TM, Dong Y, Jelinek J, Cesaroni M, Issa JP, Pan HL.G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition.Nat Neurosci. 2015;18(12):1746-55.

Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K+ channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. We found that nerve injury increased dimethylation (addition of two methyl groups- which is a carbon and three hydrogens) of Lys9 (The nineth amino acid in the protein which is a lysine amino acid) at postion on histone H3 (H3K9me2) at Kcna4, Kcnd2, Kcnq2 and Kcnma1 (potassium channels) promoters but did not affect levels of DNA methylation on these genes in DRGs. Nerve injury increased activity of euchromatic histone-lysine N-methyltransferase-2 (G9a), histone deacetylases and enhancer of zeste homolog-2 (EZH2), but only G9a inhibition consistently restored K+ channel expression. Selective knockout of the gene encoding G9a in DRG neurons completely blocked K+ channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced genes associated with K+ channels but also normalized 638 genes down- or upregulated by nerve injury. Thus G9a has a dominant function in transcriptional repression of K+ channels and in acute-to-chronic pain transition after nerve injury.

Neuropathic pain is caused by aberrant nerve signals generated within the nervous system, typically unrelated to any real pain causing sensation. Pain is often treated by using opiates but in neuropathic pain the opioid receptors are down regulated and this is why opioids , like morphine don't do the business when it comes to treating neuropathic pain.

In biochemistry, transferase is the general name for the class of enzymes that enact the transfer of specific functional groups(e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of different biochemical pathways throughout biology, and are integral to some of life’s most important processes. It is interesting that loss of activity of a methyl transferase (removes methyl group from the begining of the protein). The central point is that this effects way some genes are expressed in the dorsal root ganglia, which contain the nerve cell bodies of sensory nerves. In these nerves there is a excessive activity of methyl transferase function that result down regulation of some potassium channels such as the calcium activated potassium channel (Kcnma1) or voltage sensitive channels. These channels serve to limit rate the firing of nerves, so if the nerves are damaged and these channels are down regulated you get more firing of nerves and so things like pain and possibly spasticity can be aberrantly triggered. So this study indicates that therapy of pain may be achieved by upregulating the potassium channel activity and this may be achieved by blockade of of this transferase. So a new target for neuropathic pain