Choi, Sheu-Ran Roh, Dae-Hyun Yoon, Seo-Yeon Choi, Hoon-Seong Kang, Suk-Yun Han, Ho-Jae Beitz, Alvin J. Lee, Jang-Hern 2024-01-19T20:03:06Z 2024-01-19T20:03:06Z 2021-09-02 2019-05-01 0028-3908 https://pubs.kist.re.kr/handle/201004/120016 While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3 beta-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. Intrathecal administration of the P450c17 inhibitor, ketoconazole during the induction phase of neuropathic pain (day 0 to day 3 post-surgery) significantly reduced the development of mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw. However, administration of the 3 beta-HSD inhibitor, trilostane had no effect on the development of neuropathic pain. Sciatic nerve injury increased astrocyte Sig-1R expression as well as dissociation of Sig-1Rs from BiP in the spinal cord. These increases were suppressed by administration of ketoconazole, but not by administration of trilostane. Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by peripheral nerve injury. English PERGAMON-ELSEVIER SCIENCE LTD PAIN HYPERSENSITIVITY MOUSE MODEL DEHYDROEPIANDROSTERONE RAT PHOSPHORYLATION NEUROSTEROIDS BIOSYNTHESIS EXPRESSION INDUCTION STEROIDS Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors Article 10.1016/j.neuropharm.2019.02.013 1 NEUROPHARMACOLOGY, v.149, pp.169 - 180 NEUROPHARMACOLOGY 149 169 180 scie scopus 000462802900015 2-s2.0-85062699316 Neurosciences Pharmacology & Pharmacy Neurosciences & Neurology Pharmacology & Pharmacy Article PAIN HYPERSENSITIVITY MOUSE MODEL DEHYDROEPIANDROSTERONE RAT PHOSPHORYLATION NEUROSTEROIDS BIOSYNTHESIS EXPRESSION INDUCTION STEROIDS Cytochrome P450c17 3 beta-hydroxysteroid dehydrogenase Sigma-1 receptor Mechanical allodynia Neuropathic pain