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

摘要

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 GABA_A-agonist muscimol on dural plasma protein ([~(125)I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg~(-1),i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen ( ≤ 10 mg kg~(-1), i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED_(50): 6.6 ± 1.4 mg kg~(-1), i.p., and 58 ± 18 μg kg~(-1), i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED_(50): 3.2 ± 1.4 mg kg~(-1), i.p. and 385 ± 190 μg kg~(-1), i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg~(-1), i.p.) or muscimol (58 μg 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. The GABA_A-antagonist bicuculline (0.01 mg kg~(-1), i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the 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 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 GABA_A-receptors 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 GABA_A-mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABA_A receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.