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GABA A ‐receptor‐mediated effects of progesterone, its ring‐A‐ reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges
Author(s) -
Limmroth Volker,
Lee Won Suk,
Moskowitz Michael A.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15160.x
Subject(s) - endocrinology , medicine , bicuculline , neuroactive steroid , allopregnanolone , extravasation , ed50 , chemistry , pharmacology , gabaa receptor , receptor , immunology
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 (≥500 μg, s.c.) dose‐dependently decreased plasma extravasation within the meninges (ED 50 : 650 μg) but not within conjunctiva and tongue. Promegestone (R5020), a non‐metabolized progesterone agonist (1000 μg, i.p.) was ineffective. The administration of progesterone (≥500 μg s.c.) 55 min prior to substance P partially suppressed plasma extravasation within the meninges (ED 50 : 550 μg). 3 The GABA A ‐antagonist, bicuculline (ED 50 : 8.2 μg kg −1 , i.p) but not the GABA B ‐antagonist, phaclofen (100 μg kg −1 , i.p.) attenuated the effects of progesterone after electrical stimulation and substance P administration. 4 The metabolites of progesterone, allopregnanolone (3α‐hydroxy‐5α‐pregnan‐20‐one (THP); ED 50 : 0.58 μg kg ‐1 , i.p.), tetrahydroxydeoxycorticosterone (3α,21‐dihydroxy‐5α‐pregnan‐20‐one (THDOC); ED 50 : 1.2 μg kg −1 , i.p.) as well as the synthetic steroid alphaxalone (3α‐hydroxy‐5α‐pregnane‐11,20‐dione; ED 50 : 1.8 μg kg −1 , i.p.) suppressed plasma extravasation dose‐dependently following ES, whereas the epimer of allopregnanolone, 3β‐hydroxy‐5α‐pregnan‐20‐one (100 μg kg −1 , i.p.), did not. Extravasation caused by SP administration was partially suppressed by allopregnanolone (≥ 1 μg kg −1 , i.p.) (ED 50 : 2.1 μg kg −1 ). 5 The effect of progesterone (1000 μg, s.c.) and allopregnanolone (100 μg kg −1 , i.p.) on neurogenic plasma extravasation was reversed by bicuculline (10 μg kg −1 , i.p.) or by a congener, bicucullinemethiodide (10 μg kg −1 , i.p.) which does not cross the blood brain barrier. 6 Progesterone (1000 μg, 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.