The biological activity of 3α-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury

Identification of cellular targets pertinent for the development of effective therapies against pathological pain constitutes a difficult challenge. We combined several approaches to show that 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR), abundantly expressed in the spinal cord (SC), is a key target, the modulation of which markedly affects nociception. 3 alpha-HSOR catalyzes the biosynthesis and oxidation of 3 alpha,5 alpha-reduced neurosteroids as allopreguanolone (3 alpha,5 alpha-THP), which stimulates GABA(A) receptors. Intrathecal injection of Provera (pharmacological inhibitor of 3 alpha-HSOR activity) in naive rat SC decreased thermal and mechanical nociceptive thresholds assessed with behavioral methods. In contrast, pain thresholds were dose-dependently increased by 3 alpha,5 alpha-THP. In animals subjected to sciatic nerve injury-evoked neuropathic pain, molecular and biochemical experiments revealed an up-regulation of 3 alpha-HSOR reductive activity in the SC. Enhancement of 3 alpha,5 alpha-THP concentration in the SC induced analgesia in neuropathic rats while Provera exacerbated their pathological state. Possibilities are opened for chronic pain control with drugs modulating 3 alpha-HSOR activity in nerve cells. (C) 2007 Elsevier Inc. All rights reserved.