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

Abstract

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 3α-hydroxysteroid oxido-reductase (3α-HSOR), abundantly expressed in the spinal cord (SC), is a key target, the modulation of which markedly affects nociception. 3α-HSOR catalyzes the biosynthesis and oxidation of 3α,5α-reduced neurosteroids as allopregnanolone (3α,5α-THP), which stimulates GABAA receptors. Intrathecal injection of Provera (pharmacological inhibitor of 3α-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 3α,5α-THP. In animals subjected to sciatic nerve injury-evoked neuropathic pain, molecular and biochemical experiments revealed an up-regulation of 3α-HSOR reductive activity in the SC. Enhancement of 3α,5α-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 3α-HSOR activity in nerve cells.

Keywords

• Allodynia
• Neuropathy
• Neurobiology of pain
• Neurosteroid
• Sciatic nerve constriction
• Spinal cord