We have recently demonstrated that the
neurosteroid-metabolizing
enzyme,
cytochrome P450c17 is increased in spinal astrocytes contributing to the development of
mechanical allodynia in chronic constriction injury (CCI)-induced neuropathic mice. However, the mechanisms by which spinal P450c17 modulates pathological changes in astrocytes remain unclear. In this study we investigated whether P450c17 modulates astrocyte activation and whether this process is mediated by spinal
p38 mitogen-activated protein kinase phosphorylation ultimately leading to the development of
mechanical allodynia in CCI mice. Sciatic nerve injury induced a significant increase in
glial fibrillary acidic protein (GFAP) expression in the superficial dorsal horn (SDH, laminae I-II) and nucleus proprius (NP, laminae III-IV) regions of the spinal cord dorsal horn. Repeated daily (from days 0-3 post-surgery) intrathecal administration of the P450c17 inhibitor,
ketoconazole (10 nmol) significantly inhibited the CCI-induced increase in GFAP-immunoreactivity, but had no effect on the CCI-induced increase in Iba-1-immunoreactivity. In addition, intrathecal administration of
ketoconazole significantly inhibited the CCI-induced increase in p38 phosphorylation, while the levels of ERK and JNK phosphorylation remained unchanged. The CCI-induced development of
mechanical allodynia was attenuated by administration of either
ketoconazole (10 nmol) or the
p38 MAPK inhibitor,
SB203580 (5 nmol). Administration of a sub-effective dose of
SB203580 (0.5 nmol) potentiated the pharmacological effect of
ketoconazole (1 nmol) on spinal GFAP-immunostaining, as well as, the development of
mechanical allodynia following CCI. Collectively these data suggest that spinal P450c17 activates astrocytes via p38 phosphorylation, ultimately leading to the development of
mechanical allodynia in a model of
peripheral neuropathy.