Sigma‐1 Receptor May Participate in the Regulation of Epigenetic Modifications Related to Neuropathic Pain

Abstract

Nerve injury causes abnormal hyperactivity of primary sensory nerves and causes changes in the expression of pro‐ and antinociceptive genes in the DRG. The ER chaperone sigma‐1 receptor (Sig‐1R) was demonstrated to play a role in neuropathic pain and is known to exist in the dorsal root ganglia (DRG), notably, at the nuclear envelope. According to the published data, in Spared Nerve Injury (SNI) model of neuropathic pain, Sig‐1R knockout mice did not develop cold allodynia and showed significantly less mechanical allodynia. However, the molecular mechanisms whereby Sig‐1Rs modulate neuropathic pain at the DRG are largely unknown. Recently, it was shown that the inhibition of histone methyltransferase at the DRG attenuates the neuropathic pain by correcting the dysfunctional potassium channels. Inasmuch as Sig‐1Rs exist at the nuclear envelope, we hypothesized that Sig‐1Rs may participate in the regulation of epigenetic modifications related to neuropathic pain. Immunoblotting of extracted histones from Sig‐1R knockout DRGs, when compared to wild type DRGs, showed a decrease in the level of H3K9me2, whereas total H3 methylation/acetylation, H3K9ac, H3K9me3, H3K27me3 and H3K4me3 histone marks were unchanged. However, the protein level or mRNA expression of euchromatic histone‐lysine N‐methyltransferase‐2 (G9a) which is an enzyme responsible for H3K9me2 modification was not altered in wild type and Sig‐1R knockout mice. Those results suggest that the Sig‐1R plays a role on the maintenance of the level of H3K9me2 downstream of the G9a. It is known that H3K9me2 preferentially marks chromatin at the nuclear periphery that interestingly is where Sig‐1Rs are located. Thus, we performed peptide pulldown experiments using unmodified and modified histone peptides to pull down Sig‐1Rs and found that indeed the H3K9me2 peptide can bind the Sig‐1R. When taken together, those results suggest that the Sig‐1R relates to the maintenance of the H3K9me2 level in the DRG and that the Sig‐1R may affect neuropathic pain by regulating the level of potassium channels by the epigenetic modification on histone 3. Support or Funding Information IRP/NIDA/NIH

Chaperone Sigma1R and Antidepressant Effect

“…The interaction of chaperones with histones in the processes of assembly, functioning, and degradation of nucleosomes has been demonstrated [ 257 ]. The effect of Sigma1R on gene expression, demonstrated in a number of studies [ 258 , 259 , 260 ], suggests the implication of Sigma1R to the control of epigenetic mechanisms of antidepressant action. Cocaine has been shown to act agonistically on Sigma1R and cause chaperone translocation towards the nuclear membrane and the formation of a chromatin remodeling complex (emerin/HDAC/BAF).…”