Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain

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• 作者：C. Patte-Mensah ; L. Meyer ; O. Taleb ; A.G. Mensah-Nyagan
• 关键词：AP ; 3伪 ; 5伪-tetrahydroprogesterone or allopregnanolone ; CNPase ; 2&prime ; 3&prime ; -cyclic nucleotide 3&prime ; -phosphodiesterase ; CV ; conduction velocity ; DHEA ; dehydroepiandrosterone ; DHEAS ; dehydroepiandrosterone sulfate ; DOC ; deoxycorticosterone ; DHDOC ; dihydrodeoxycorticosterone ; DHP ; dihydroprogesterone ; DHT ; dihydrotestosterone ; DH ; dorsal horn ; GABA ; gamma-aminobutyric acid ; 21-OHase ; 21-hydroxylase ; 3尾-HSD ; 3尾-hydroxysteroid dehydrogenase ; 17尾-HSD ; 17尾-hydroxysteroid dehydrogenase ; 3伪
• 刊名：Progress in Neurobiology
• 出版年：February, 2014
• 年：2014
• 卷：113
• 期：Complete
• 页码：70-78
• 全文大小：564 K

文摘

Because the treatment and management of neuropathic pain are extremely complicated, the characterization of novel analgesics and neuroprotectors with safe toxicological profiles is a crucial need to develop efficient therapies. Several investigations revealed that the natural neurosteroid allopregnanolone (AP) exerts analgesic, neuroprotective, antidepressant and anxiolytic effects. These effects result from AP ability to modulate GABA_A, glycine, L- and T-type calcium channels. It has been shown that AP treatment induced beneficial actions in humans and animal models with no toxic side effects. In particular, a multi-parametric analysis revealed that AP efficiently counteracted chemotherapy-evoked neuropathic pain in rats. It has also been demonstrated that the modulation of AP-producing enzyme, 3伪-hydroxysteroid oxido-reductase (3伪-HSOR), in the spinal cord regulates thermal and mechanical pain thresholds of peripheral nerve injured neuropathic rats. The painful symptoms were exacerbated by intrathecal injections of provera (pharmacological inhibitor of 3伪-HSOR) which decreased AP production in the spinal cord. By contrast, the enhancement of AP concentration in the intrathecal space induced analgesia and suppression of neuropathic symptoms. Moreover, in vivo siRNA-knockdown of 3伪-HSOR expression in healthy rat dorsal root ganglia increased thermal and mechanical pain perceptions while AP evoked a potent antinociceptive action. In humans, blood levels of AP were inversely associated with low back and chest pain. Furthermore, oral administration of AP analogs induced antinociception. Altogether, these data indicate that AP, which possesses a high therapeutic potential and a good toxicological profile, may be used to develop effective and safe strategies against chronic neuropathic pain.