PERIPHERAL GABA(A) RECEPTOR-MEDIATED EFFECTS OF SODIUM VALPROATE ON DURAL PLASMA-PROTEIN EXTRAVASATION TO SUBSTANCE-P AND TRIGEMINAL STIMULATION

1 The GABA transaminase inhibitor and activator of glutamic acid decar boxylase, valproic acid is being used for the treatment of migraine. I ts mechanism of action is unknown. We tested the effects of sodium val proate and GABA(A)-agonist muscimol on dural plasma protein ([I-125]-b ovine serum albumin) extravasation evoked by either unilateral trigemi nal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (S P) administration (1 nmol kg(-1),i.v.) in anaesthetized Sprague-Dawley rats. 2 Intraperitoneal (i.p.) injection of sodium valproate or musci mol, but not baclofen (less than or equal to 10 mg kg(-1), i.p.) dose- dependently reduced dural plasma protein extravasation caused either b y electrical trigeminal stimulation (ED(50): 6.6 +/- 1.4 mg kg(-1), i. p., and 58 +/- 28 mu g kg(-1), i.p. for valproate or muscimol, respect ively) or by intravenous substance P administration (ED(50): 3.2 +/- 1 .4 mg kg(-1), i.p. and 385 +/- 190 mu g kg(-1), i.p. for valproate or muscimol, respectively). 3 Valproate (6.6 mg kg(-1), i.p.) or muscimol (58 mu g kg(-1), i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4 Th e GABA(A)-antagonist bicuculline (0.01 mg kg(-1), i.p.) completely rev ersed the effect of valproate and muscimol on plasma extravasation fol lowing electrical stimulation or substance P administration, whereas t he GABA(B)-receptor antagonist, phaclofen (0.01-1 mg kg(-1), i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP admin istration. 5 Valproate decreased plasma extravasation following substa nce P administration in adult animals, neonatally treated with capsaic in by a bicuculline-reversible mechanism. This suggests that GABA(A)-r eceptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats. 6 We conc lude that sodium valproate blocks plasma extravasation in the meninges through GABA(A)-mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinicall y. Agonists and modulators at the GABA(A) receptor may become useful f or the development of selective therapeutic agents for migraine and cl uster headache.