The actions of valproate and neurosteroids in a model of trigeminal pain

Gamma-aminobutyric acid (GABA) receptors are ubiquitous inhibitory receptors in the central and peripheral nervous systems. Valproic acid (2- propylpentanoic acid), which enhances GABA synthesis and blocks degradation, is useful in migraine treatment and may act through activation of GABA receptors to modulate trigeminal nociceptive neurons innervating the meninges. To investigate this possibility, we tested the effect of valproate and allopregnanolone, a metabolite of progesterone, which binds and modulates the GABA receptor in an animal model of cephalic pain. One hundred ten Hartley guinea pigs were pretreated with either valproate or allopregnanolone 30 minutes prior to activation of trigeminal afferent fibers via intracisternal injection of the irritant, capsaicin. The effects of valproic acid and allopregnanolone were examined on c-fos expression within the trigeminal nucleus caudalis (lamina I, II₀), the termination site for small unmyelinated C fibers projecting from the meninges. C-fos positive cells were counted at three representative levels (rostral, middle, and caudal) by an observer naive to the treatment group. We found that valproate (≤10 mg/kg, IP) reduced labeled cells by 52% (P<0.05) and allopregnanolone (≤100 mg/kg, IP) reduced labeled cells by 42% (P<0.01). Bicuculline (GABA(A) antagonist), but not phaclofen (GABA(B) antagonist), blocked the valproate effect, thereby documenting the importance of GABA(A) receptors. We conclude that the attenuation of c-fos-LI by valproate and allopregnanolone is mediated via GABA(A) receptors. These studies complement prior experiments showing that valproic acid and allopregnanolone block neurogenic inflammation within the meninges via GABA(A) receptor-mediated mechanisms. The findings suggest a potential strategy for discovering new antimigraine drugs with high affinity for the GABA(A) receptor and its modulatory sites.