THE ACTIONS OF VALPROATE AND NEUROSTEROIDS IN A MODEL OF TRIGEMINAL PAIN

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.