The biological activity of 3alpha-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 3alpha-hydroxysteroid oxido-reductase (3alpha-HSOR), abundantly expressed in the spinal cord (SC), is a key target, the modulation of which markedly affects nociception. 3alpha-HSOR catalyzes the biosynthesis and oxidation of 3alpha,5alpha-reduced neurosteroids as allopregnanolone (3alpha,5alpha-THP), which stimulates GABA(A) receptors. Intrathecal injection of Provera (pharmacological inhibitor of 3alpha-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 3alpha,5alpha-THP. In animals subjected to sciatic nerve injury-evoked neuropathic pain, molecular and biochemical experiments revealed an up-regulation of 3alpha-HSOR reductive activity in the SC. Enhancement of 3alpha,5alpha-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 3alpha-HSOR activity in nerve cells.
Meyer
Laurence
L
Equipe Stéroïdes et Système Nociceptif, Institut des Neurosciences Cellulaires et Intégratives, Unité Mixte de Recherche 7168/LC2-Centre National de la Recherche Scientifique, Université Louis Pasteur, 21 rue René Descartes, 67084 Strasbourg Cedex, France.
Venard
Christine
C
Schaeffer
Véronique
V
Patte-Mensah
Christine
C
Mensah-Nyagan
Ayikoe G
AG
D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors; D007839:Functional Laterality; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D017258:Medroxyprogesterone Acetate; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000503:physiopathology*; D013116:Spinal Cord / Q000201:enzymology*; D014110:Touch; D014316:Tritium / Q000378:metabolism
D004791:Enzyme Inhibitors; D014316:Tritium; D017258:Medroxyprogesterone Acetate; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D010751:Phosphopyruvate Hydratase