Loading…
Sex-dependent pronociceptive role of spinal α 5 -GABA A receptor and its epigenetic regulation in neuropathic rodents
Extrasynaptic α -subunit containing GABA (α -GABA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α -GABA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism...
Saved in:
Published in: | Journal of neurochemistry 2021-03, Vol.156 (6), p.897-916 |
---|---|
Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Extrasynaptic α
-subunit containing GABA
(α
-GABA
) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α
-GABA
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 α
-GABA
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 α
-GABA
receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α
-GABA
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 α
-GABA
receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17β-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α
-GABA
receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α
-GABA
receptor down-regulation in males, we examined CpG island DNA methylation of α
-GABA
receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α
-GABA
receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α
-GABA
receptor is a suitable target to treat chronic pain in females. |
---|---|
ISSN: | 0022-3042 1471-4159 |
DOI: | 10.1111/jnc.15140 |