GABA(A)-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges

1 The effects of progesterone, its A-ring-reduced metabolites, allopregnanolone, tetrahydroxydeoxycorticosterone and the synthetic neuroactive steroid alphaxalone were evaluated in a rat model of plasma extravasation within the meninges following unilateral electrical stimulation (ES) of the trigeminal ganglion (0.6 mA, 5 ms, 5 min) or substance P administration (1 nmol kg(-1), i.v.). 2 When administered 55 min prior to electrical stimulation, progesterone (greater than or equal to 500 mu g, s.c.) dose-dependently decreased plasma extravasation within the meninges (ED(50): 650 mu g) but not within conjunctiva and tongue. Promegestone (R5020), a non-metabolized progesterone agonist (1000 mu g, i.p.) was ineffective. The administration of progesterone (greater than or equal to 500 mu g s.c.) 55 min prior to substance P partially suppressed plasma extravasation within the meninges (ED(50): 550 mu g). 3 The GABA(A)-antagonist, bicuculline (ED(50): 8.2 mu g kg(-1), i.p) but not the GABA(B)-antagonist, phaclofen (100 mu g kg(-1) i.p.) attenuated the effects of progesterone after electrical stimulation and substance P administration. 4 The metabolites of progesterone, allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one (THP); ED(50): 0.58 mu g kg(-1), i.p.), tetrahydroxydeoxycorticosterone (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC); ED(50): 1.2 mu g kg(-1), i.p.) as well as the synthetic steroid alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione; ED(50): 1.8 mu g kg(-1), i.p.) suppressed plasma extravasation dose-dependently following ES, whereas the epimer of allopregnanolone, 3 beta-hydroxy-5 alpha-pregnan-20-one (100 mu g kg(-1), i.p.), did not. Extravasation caused by SP administration was partially suppressed by allopregnanolone (greater than or equal to 1 mu g kg(-1), i.p.) (ED(50):2.1 mu g kg(-1)). 5 The effect of progesterone (1000 mu g, s.c.) and allopregnanolone (100 mu g kg(-1), i.p.) on neurogenic plasma extravasation was reversed by bicuculline (10 mu g kg(-1), i.p.) or by a congener, bicuculline-methiodide (10 mu g kg(-1), i.p.) which does not cross the blood brain barrier. 6 Progesterone (1000 mu g, s.c.) had no effect on mean arterial blood pressure or heart rate when measured for 60 min after administration. 7 These results indicate that neurosteroid modulation of a GABA(A)-receptor located outside the blood brain barrier suppresses neurogenic and substance P-induced plasma extravasation within the meninges. The findings are consistent with previously reported data showing that valproic acid and muscimol inhibit meningeal oedema by bicuculline-sensitive mechanisms. Drugs which activate GABA(A)-receptors and its modulatory sites might be clinically effective in the treatment of migraine and cluster headache.