• Pain · Sep 2010

    Selective regulation of 3 alpha-hydroxysteroid oxido-reductase expression in dorsal root ganglion neurons: a possible mechanism to cope with peripheral nerve injury-induced chronic pain.

    • Christine Patte-Mensah, Laurence Meyer, Véronique Schaeffer, and Ayikoe G Mensah-Nyagan.
    • Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, Unité de Physiopathologie et Médecine Translationnelle, EA-4438 Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67000 Strasbourg, France.
    • Pain. 2010 Sep 1;150(3):522-34.

    AbstractThe enzyme 3alpha-hydroxysteroid oxido-reductase (3alpha-HSOR) catalyzes the synthesis and bioavailability of 3alpha,5alpha-neurosteroids as allopregnanolone (3alpha,5alpha-THP) which activates GABA(A) receptors and blocks T-type calcium channels involved in pain mechanisms. Here, we used a multidisciplinary approach to demonstrate that 3alpha-HSOR is a cellular target the modulation of which in dorsal root ganglia (DRG) may contribute to suppress pain resulting from peripheral nerve injury. Immunohistochemistry and confocal microscope analyses showed 3alpha-HSOR-immunostaining in naive rat DRG sensory neurons and glial cells. Pulse-chase, high performance liquid chromatography and Flo/One characterization of neurosteroids demonstrated 3alpha,5alpha-THP production in DRG. Behavioral methods allowed identification of pain symptoms (thermal and mechanical hyperalgesia and/or allodynia) in rats subjected to sciatic nerve chronic constriction injury (CCI). Reverse transcription and real-time polymerase chain reaction revealed that 3alpha-HSOR mRNA concentration in CCI-rat ipsilateral DRG, 5-fold higher than in contralateral DRG, was also 4- to 6-fold elevated than that in sham-operated or naive rat DRG. Consistently, Western blotting confirmed increased 3alpha-HSOR protein levels in CCI-rat ipsilateral DRG and double immunolabeling showed that 3alpha-HSOR overexpression occurred in DRG neurons but not in glia. Functional plasticity of 3alpha-HSOR leading to increased 3alpha,5alpha-THP production was evidenced in CCI-rat DRG. Interestingly, behavioral and molecular time-course investigations revealed that 3alpha-HSOR gene upregulation was correlated to pain symptom development. Most importantly, in vivo knockdown of 3alpha-HSOR expression in healthy rat DRG using 6-carboxyfluorescein-3alpha-HSOR-siRNA exacerbated thermal and mechanical pain perceptions. This paper is the first to show that siRNA-induced knockdown of a key neurosteroid-synthesizing enzyme directly affects an important function as nociception. Hopefully, these results may be useful for the development of novel analgesics.Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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