Peripheral GABA_A receptor‐mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation

Abstract

1 The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([1251] 3 Valproate (6.6 mg kg-', i.p.) or muscimol (58 jig kg-', i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4 The GABAA-antagonist bicuculline (0.01 mg kg-', i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg', i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5 Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAAreceptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats. 6 We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAAmediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.

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

“…Valproate via GABAergic mechanisms probably inhibited neurotransmission rather than c-fos genomic expression inasmuch as the blockade was observed selectively within the TNC and not other brainstem nuclei. Changes in vascular haemodynamics probably did not mediate valproate's effect because rodents injected with valproate and monitored for 30 min show no alteration in heart rate or blood pressure (Lee et al, 1995). C-fos-LI within the TNC As in previous studies, (Strassman & Vos 1993;Cutrer et al, 1995a,b) blood injection (Nozaki et al, 1992a).…”

Homocysteine causes cerebrovascular leakage in mice

“…However, other mechanisms may also be involved. It has also been shown that γ-aminobutyric acid (GABA) (14,37) and N-methyl-D-aspartate (NMDA) (4,5) receptors have a role in increasing blood-brain barrier permeability. Because Hcy competitively inhibits GABA receptors (9) and activates NMDA receptors (8), it is likely that changes in their functional activity induced by Hcy may result in increased microvascular permeability, in conjunction with activation of MMP-9, seen in the present study.…”

Current and prospective pharmacological targets in relation to antimigraine action

“…GABA may be involved in the pathophysiology of migraine since (a) increased GABA concentrations in cerebrospinal fluid have been reported during a migraine attack (Welch et al 1975); (b) increased platelet levels of GABA have been observed in patients with tension-type headache (Kowa et al 1992), although it should be kept in mind that the pathophysiology of migraine and tension-type headache are obviously different; and (c) sodium valproate and muscimol dose dependently inhibit plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion, and these effects are blocked by the GABA A receptor antagonist bicuculline (Lee et al 1995). It thus appears that selective agonists of GABA A receptors could be clinically effective in the treatment of migraine.…”