title: Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone.
abstract: A growing number of studies indicate that 3-alpha reduced neurosteroids are remarkable analgesics in various pain states. This is the case for allopregnanolone (AP), one of the most potent endogenous positive allosteric modulators of GABAA receptor function. From the pioneering work of Hans Selye, who described the sedative properties of steroids, synthetic compounds resembling the progesterone metabolite AP have been developed. If some of them have been used as anesthetics, it seems difficult to propose them as a therapeutic option for pain since they display several adverse side effects such as sedation, amnesia and functional tolerance. An alternative strategy, chosen by few laboratories around the world, is aimed at stimulating the local production of 3-alpha reduced neurosteroids in order to limit these well-known side effects. This pharmacological approach has the advantage of targeting specific structures, fully equipped with the necessary biosynthetic enzymatic machinery, where neurosteroids already act as endogenous pain modulators. The various pharmacological trials which attempted to treat pain symptoms by stimulating the production of 3-alpha reduced neurosteroids are reviewed here, as well as novel neurotransmitter systems possibly regulating their endogenous production.
authors.affiliation: Molecular Determinants of Pain, Institute for Cellular and Integrative Neurosciences (INCI), UPR Centre National de la Recherche Scientifique (CNRS) 3212 and University of Strasbourg Strasbourg, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Poisbeau
authors.affiliation: Molecular Determinants of Pain, Institute for Cellular and Integrative Neurosciences (INCI), UPR Centre National de la Recherche Scientifique (CNRS) 3212 and University of Strasbourg Strasbourg, France ; Rhenovia Pharma Mulhouse, France.
authors.forename: Anne Florence
authors.initials: AF
authors.lastname: Keller
authors.affiliation: Molecular Determinants of Pain, Institute for Cellular and Integrative Neurosciences (INCI), UPR Centre National de la Recherche Scientifique (CNRS) 3212 and University of Strasbourg Strasbourg, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Aouad
authors.affiliation: Molecular Determinants of Pain, Institute for Cellular and Integrative Neurosciences (INCI), UPR Centre National de la Recherche Scientifique (CNRS) 3212 and University of Strasbourg Strasbourg, France.
authors.forename: Nisrine
authors.initials: N
authors.lastname: Kamoun
authors.affiliation: UMR 788 Neuroprotection and Neuroregeneration: Neuroactive Small Molecules, Institut National de la Santé et de la Recherche Médicale (INSERM) and University Paris-Sud Kremlin-Bicêtre, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Groyer
authors.affiliation: UMR 788 Neuroprotection and Neuroregeneration: Neuroactive Small Molecules, Institut National de la Santé et de la Recherche Médicale (INSERM) and University Paris-Sud Kremlin-Bicêtre, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
keywords: allodynia; etifoxine; hyperalgesia; neurosteroids; nociception; pain