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

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. 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. Valproate (≥ 10 mg kg⁻¹, i.p.) reduced labelled cells by 52% (P<0.05) in lamina I, II₀ 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. Pretreatment with bicuculline (30 μg 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 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. We conclude that the mechanism of action of valproate is mediated via GABA^A receptors. Since valproate decreases both c‐fos expression and as previously shown, neurogenic inflammation within the meninges, the GABA_A receptor complex might provide an important target for drug development in migraine and related headaches. 1995 British Pharmacological Society