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, II), 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 (> or = 10 mg/kg, IP) reduced labeled cells by 52% (P < 0.05) and
allopregnanolone (> or = 100 mg/kg, IP) reduced labeled cells by 42% (P < 0.01).
Bicuculline (GABAA antagonist), but not
phaclofen (GABAB antagonist), blocked the
valproate effect, thereby documenting the importance of GABAA receptors. We conclude that the attenuation of c-fos-LI by
valproate and
allopregnanolone is mediated via GABAA receptors. These studies
complement prior experiments showing that
valproic acid and
allopregnanolone block
neurogenic inflammation within the meninges via GABAA receptor-mediated mechanisms. The findings suggest a potential strategy for discovering new antimigraine drugs with high affinity for the GABAA receptor and its modulatory sites.