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Biochemical and functional evidence for the control of pain mechanisms by dehydroepiandrosterone endogenously synthesized in the spinal cord
Author(s) -
Kibaly Cherkaouia,
Meyer Laurence,
PatteMensah Christine,
MensahNyagan Ayikoe G.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8930com
Subject(s) - dehydroepiandrosterone , neuropathic pain , pregnenolone , medicine , endocrinology , pharmacology , nociception , neuroactive steroid , chemistry , androgen , receptor , hormone , steroid , gabaa receptor
We investigated the role and mechanism of action of dehydroepiandrosterone (DHEA) produced by the spinal cord (SC) in pain modulation in sciatic‐neuropathic and control rats. Real‐time polymer‐ase chain reaction (PCR) after reverse transcription revealed cytochrome P450c17 (DHEA‐synthesizing enzyme) gene repression in neuropathic rat SC. A combination of pulse‐chase experiments, high performance liquid chromatography (HPLC), and flow‐scintillation detection showed decreased DHEA biosynthesis from pregnenolone in neuropathic SC slices. Radioimmuno‐assays demonstrated endogenous DHEA level drop in neuropathic SC. Behavioral analysis showed a rapid pronociceptive and a delayed antinociceptive action of acute DHEA treatment. Inhibition of DHEA biosynthesis in the SC by intrathecally administered ketoconazole (P450c17 inhibitor) induced analgesia in neuropathic rats. BD1047 (sigma‐1 receptor antagonist) blocked the transient pronociceptive effect evoked by acute DHEA administration. Chronic DHEA treatment increased and maintained elevated the basal nociceptive thresholds in neuropathic and control rats, suggesting that androgenic metabolites generated from daily administered DHEA exerted analgesic effects while DHEA itself (before being metabolized) induced a rapid pronociceptive action. Indeed, intrathecal administration of testosterone, an androgen deriving from DHEA, caused analgesia in neuropathic rats. Together, these molecular, biochemical, and functional results demonstrate that DHEA synthesized in the SC controls pain mechanisms. Possibilities are opened for pain modulation by drugs regulating P450c17 in nerve cells.— Kibaly C., Meyer, L., Patte‐Mensah, C., Mensah‐Nya‐gan A. G. Biochemical and functional evidence for the control of pain mechanisms by dehydroepiandros‐terone endogenously synthesized in the spinal cord. FASEB J. 22, 93–104 (2008)