ATTENUATION BY VALPROATE OF C-FOS IMMUNOREACTIVITY IN TRIGEMINAL NUCLEUS CAUDALIS INDUCED BY INTRACISTERNAL CAPSAICIN

1 Valproic acid, useful in the treatment of migraine, is an inhibitor of gamma-aminobutyric acid (GABA) aminotransferase and activator of gl utamic acid decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2-propylpentanoic acid) were examined on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI) , a marker of neuronal activation, within the trigeminal nucleus cauda lis (lamina I, IIo; TNC) 2 h after intracisternal injection of the irr itant, capsaicin (0.1 ml; 15.25 mu g ml(-1)), in urethane-anaesthetize d Hartley guinea-pigs. Positive cells were counted in eighteen section s (50 mu m) at three representative levels (rostral, middle and caudal ) within lamina I, IIo of the TNC in 90 animals. 2 Numerous cells were labelled after capsaicin instillation (244+/-25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11+/-1). Positive cells were also found w ithin the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated pr eviously after application of intracisternal irritants such as autolog ous blood or carrageenin. 3 Valproate (greater than or equal to 10 mg kg(-1), i.p.) reduced labelled cells by 52% (P < 0.05) in lamina I, II o but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previo usly after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4 Pretreatment with bicuculline (30 mu g kg(-1); i.p.), a GABA(A) antagonist, but not phaclofen (1 mg kg(- 1)) a GABA(B) antagonist, reversed the effect of valproate and increas ed c-fos positive cells within lamina I, IIo. Somewhat paradoxically, bicuculline by itself (30 mu g kg(-1) i.p.) decreased the number of la belled cells suggesting that more than a single GABAergic mechanism ca n suppress c-fos expression. 5 We conclude that the mechanism of actio n of valproate is mediated via GABA(A) receptors. Since valproate decr eases both c-fos expression and as previously shown, neurogenic inflam mation within the meninges, the GABA(A) receptor complex might provide an important target for drug development in migraine and related head aches.