Attenuation by valproate of c‐fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin

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Abstract
1 Valproic acid, useful in the treatment of migraine, is an inhibitor of γ-aminobutyric acid (GABA) aminotransferase and activator of glutamic add 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 caudalis (lamina I, II0; TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 μ ml−1, in urethane-anaesthetized Hartley guinea-pigs. Positive cells were counted in eighteen sections (50 μm) at three representative levels (rostral, middle and caudal) within lamina I, II0 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 within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. 3 Valproate (≥ 10 mg kg−1, i.p.) reduced labelled cells by 52% (P0 but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4 Pretreatment with bicuculline (30 μg kg−1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg−1) a GABAB antagonist, reversed the effect of valproate and increased c-fos positive cells within lamina I, II0. Somewhat paradoxically, bicuculline by itself (30 μg kg−1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c-fos expression. 5 We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c-fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches.