Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test

The present study investigated the effect of acute systemic administration of six progesterone metabolites oil formalin-induced pain ill the rat. The 3 alpha-hydroxylated metabolites allopregnanolone and pregnanolone are highly potent positive modulators at the GABA(A) receptor and produced a biphasic effect oil pain ill the formalin test. Dose-dependent antinociception was observed at lower doses (maximal antinociception at 0.16 mg/kg) and was reversed at higher closes. Bicuculline abolished the antinociceptive effect. The 3 beta-hydroxylated epipregnanolone and isopregnanolone are inactive or only weekly active at the GABA(A) receptor, and did not affect formalin-induced pain. 5 alpha- and 5 beta-dihydroprogesterone have also been shown to have low affinity for the GABA,x receptor, but call be rapidly metabolized to their 3 alpha-hydroxylated counterparts. In the formalin test, they produced a biphasic effect on pain similar to that of pregnanolone and allopregnanolone. but with lower potency. The effect was reversible by bicuculline, showing involvement of the GABA(A) receptor. and was blocked by indomethacin, implying, that the antinociceptive effect is dependent on their conversion to allopregnanolone or pregnanolone. The results indicate that GABA-ergic progesterone metabolites modulate nociception. A Change in levels of GABA-ergic progesterone metabolites. such as is observed ill depression. chronic fatigue and premenstrual dysphoric disorder could. therefore. contribute to the pain complaints associated with these disorders. (C) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.