Gamma-aminobutyric acid (GABA) receptors are ubiquitous inhibitory rec
eptors in the central and peripheral nervous systems. Valproic acid (2
-propylpentanoic acid), which enhances GABA synthesis and blocks degra
dation, is useful in migraine treatment and may act through activation
of GABA receptors to modulate trigeminal nociceptive neurons innervat
ing the meninges. To investigate this possibility, we tested the effec
t of valproate and allopregnanolone, a metabolite of progesterone, whi
ch binds and modulates the GABA receptor in an animal model of cephali
c pain. One hundred ten Hartley guinea pigs were pretreated with eithe
r valproate or allopregnanolone 30 minutes prior to activation of trig
eminal afferent fibers via intracisternal injection of the irritant, c
apsaicin. The effects of valproic acid and allopregnanolone were exami
ned on c-fos expression within the trigeminal nucleus caudalis (lamina
I, IIo), the termination site for small unmyelinated C fibers project
ing from the meninges. C-fos positive cells were counted at three repr
esentative levels (rostral, middle, and caudal) by an observer naive t
o the treatment group. We found that valproate (greater than or equal
to 10 mg/kg, IP) reduced labeled cells by 52% (P<0.05) and allopregnan
olone (greater than or equal to 100 mg/kg, IP) reduced labeled cells b
y 42% (P<0.01). Bicuculline (GABA(A) antagonist), but not phaclofen (G
ABA(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 val
proic acid and allopregnanolone block neurogenic inflammation within t
he meninges via GABA(A) receptor-mediated mechanisms. The findings sug
gest a potential strategy for discovering new antimigraine drugs with
high affinity for the GABA(A) receptor and its modulatory sites.