Exp Neurobiol.  2019 Aug;28(4):516-528. 10.5607/en.2019.28.4.516.

Spinal Nitric Oxide Synthase Type II Increases Neurosteroid-metabolizing Cytochrome P450c17 Expression in a Rodent Model of Neuropathic Pain

• Choi SR
• Beitz AJ
• Lee JH

• KMID: 2458549
• DOI: http://doi.org/10.5607/en.2019.28.4.516

Abstract

We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of N-methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKC- and PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.

Keyword

Nitric oxide synthase type II; Cytochrome P450c17; Dehydroepiandrosterone sulfate; Phosphorylation; Neuropathic pain

MeSH Terms

Animals
Central Nervous System Sensitization
Constriction
Cytochromes
Dehydroepiandrosterone
Dehydroepiandrosterone Sulfate
Hyperalgesia
N-Methylaspartate
Neuralgia*
Nitric Oxide Synthase Type II*
Nitric Oxide Synthase*
Nitric Oxide*
Oxidative Stress
Peripheral Nerve Injuries
Phosphorylation
Rats
RNA, Messenger
Rodentia*
Sciatic Nerve
Spinal Cord
Spinal Cord Dorsal Horn
Cytochromes
Dehydroepiandrosterone
Dehydroepiandrosterone Sulfate
N-Methylaspartate
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
RNA, Messenger