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 polymerase 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. Radioimmunoassays 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.
Various studies have indicated that exogenous dehydroepiandrosterone (DHEA) modulates several mechanisms in the CNS of rodents. As adult rodent glands do not secrete significant amounts of DHEA, its role as endogenous modulator of the CNS remains possible only if DHEA is produced by nerve cells. Therefore, the last decade has been marked by diverse unsuccessful investigations aiming to demonstrate the activity of cytochrome P450c17 (P450c17), the key DHEA-synthesizing enzyme, in adult rodent CNS. Here, we combined molecular, anatomical, cellular and neurochemical approaches to provide the first demonstration of the existence of P450c17 and bioactivity in adult rat spinal cord (SC
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