| First Author | Franco-Enzástiga Ú | Year | 2021 |
| Journal | J Neurochem | Volume | 156 |
| Issue | 6 | Pages | 897-916 |
| PubMed ID | 32750173 | Mgi Jnum | J:346478 |
| Mgi Id | MGI:6707734 | Doi | 10.1111/jnc.15140 |
| Citation | Franco-Enzastiga U, et al. (2021) Sex-dependent pronociceptive role of spinal alpha5 -GABAA receptor and its epigenetic regulation in neuropathic rodents. J Neurochem 156(6):897-916 |
| abstractText | Extrasynaptic alpha5 -subunit containing GABAA (alpha5 -GABAA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of alpha5 -GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by alpha5 -GABAA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in alpha5 -GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased alpha5 -GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over alpha5 -GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17beta-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased alpha5 -GABAA receptor and estrogen receptor alpha protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to alpha5 -GABAA receptor down-regulation in males, we examined CpG island DNA methylation of alpha5 -GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased alpha5 -GABAA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that alpha5 -GABAA receptor is a suitable target to treat chronic pain in females. |
