Estradiol modulates the role of the spinal α 6 -subunit containing GABA A receptors in female rats with neuropathic pain.

The purpose of this study was to investigate the mechanisms underlying sex differences in the role of spinal α6 -subunit containing GABAA (α6 GABAA ) receptors in rats with neuropathic pain. Intrathecal 2,5-dihydro-7-methoxy-2-(4-methoxyphenyl)-3H-pyrazolo [4,3-c] quinoline-3-one (PZ-II-029, positive allosteric modulator of α6 GABAA receptors) reduced tactile allodynia in female but not in male rats with neuropathic pain. PZ-II-029 was also more effective in females than males in inflammatory and nociplastic pain. Ovariectomy abated the antiallodynic effect of PZ-II-029 in neuropathic rats, whereas 17β-estradiol or 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), estradiol receptor-α agonist, restored the effect of PZ-II-029 in ovariectomized rats. Blockade of estradiol receptor-α, using MPP (1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride), prevented the effect of 17β-estradiol on PZ-II-029-induced antiallodynia in ovariectomized neuropathic females. Nerve injury reduced α6 GABAA receptor protein expression at the dorsal root ganglia (DRG) and spinal cord of intact and ovariectomized female rats. In this last group, reconstitution with 17β-estradiol fully restored its expression in DRG and spinal cord. In male rats, nerve injury reduced α6 GABAA receptor protein expression only at the spinal cord. Nerve injury enhanced estradiol receptor-α protein expression at the DRG in intact non-ovariectomized rats. However, ovariectomy decreased estradiol receptor-α protein expression at the DRG. In the spinal cord there were no changes in estradiol receptor-α protein expression. 17β-estradiol restored estradiol receptor-α protein expression at the DRG and increased it at the spinal cord of neuropathic rats. These data suggest that 17β-estradiol modulates the expression and function of the α6 GABAA receptor through its interaction with estradiol receptor-α in female rats.