Research indicates that
neurosteroids are locally synthesized in the central nervous system and play an important modulatory role in nociception. While the neurosteroidogenic
enzyme,
cytochrome P450 side-chain cleavage
enzyme (P450scc), is the initiating
enzyme of steroidogenesis, P450scc has not been examined under the pathophysiological conditions associated with
peripheral neuropathy. Thus, we investigated whether chronic constriction injury (CCI) of the sciatic nerve increases the expression of P450scc in the spinal cord and whether this increase modulates
serine racemase (Srr) expression and D-
serine production contributing to the development of
neuropathic pain. CCI increased the immunoreactivity of P450scc in astrocytes of the ipsilateral lumbar spinal cord dorsal horn. Intrathecal administration of the P450scc inhibitor,
aminoglutethimide, during the induction phase of
neuropathic pain (days 0 to 3 post-surgery) significantly suppressed the CCI-induced development of
mechanical allodynia and
thermal hyperalgesia, the increased expression of astrocyte Srr in both the total and cytosol levels, and the increases in D-
serine immunoreactivity at day 3 post-surgery. By contrast, intrathecal administration of
aminoglutethimide during the maintenance phase of
pain (days 14 to 17 post-surgery) had no effect on the developed
neuropathic pain nor the expression of spinal Srr and D-
serine immunoreactivity at day 17 post-surgery. Intrathecal administration of exogenous D-
serine during the induction phase of
neuropathic pain (days 0 to 3 post-surgery) restored the development of
mechanical allodynia, but not the
thermal hyperalgesia, that were suppressed by
aminoglutethimide administration. Collectively, these results demonstrate that spinal P450scc increases the expression of astrocyte Srr and D-
serine production, ultimately contributing to the development of
mechanical allodynia induced by
peripheral nerve injury.