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Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors.
Neuropharmacology. 2019 05 01; 149:169-180.N

Abstract

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 3β-hydroxysteroid dehydrogenase (3β-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 3β-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 3β-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.

Authors+Show Affiliations

Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.Department of Maxillofacial Tissue Regeneration and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, 02447, Republic of Korea.College of Korean Medicine, Dongshin University, Naju, 58245, Republic of Korea.Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, 34054, Republic of Korea.Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, 55108, USA.Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: jhl1101@snu.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30797030

Citation

Choi, Sheu-Ran, et al. "Spinal Cytochrome P450c17 Plays a Key Role in the Development of Neuropathic Mechanical Allodynia: Involvement of Astrocyte Sigma-1 Receptors." Neuropharmacology, vol. 149, 2019, pp. 169-180.
Choi SR, Roh DH, Yoon SY, et al. Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors. Neuropharmacology. 2019;149:169-180.
Choi, S. R., Roh, D. H., Yoon, S. Y., Choi, H. S., Kang, S. Y., Han, H. J., Beitz, A. J., & Lee, J. H. (2019). Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors. Neuropharmacology, 149, 169-180. https://doi.org/10.1016/j.neuropharm.2019.02.013
Choi SR, et al. Spinal Cytochrome P450c17 Plays a Key Role in the Development of Neuropathic Mechanical Allodynia: Involvement of Astrocyte Sigma-1 Receptors. Neuropharmacology. 2019 05 1;149:169-180. PubMed PMID: 30797030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors. AU - Choi,Sheu-Ran, AU - Roh,Dae-Hyun, AU - Yoon,Seo-Yeon, AU - Choi,Hoon-Seong, AU - Kang,Suk-Yun, AU - Han,Ho-Jae, AU - Beitz,Alvin J, AU - Lee,Jang-Hern, Y1 - 2019/02/20/ PY - 2018/08/27/received PY - 2019/01/13/revised PY - 2019/02/10/accepted PY - 2019/2/24/pubmed PY - 2020/1/28/medline PY - 2019/2/24/entrez KW - 3β-hydroxysteroid dehydrogenase KW - Cytochrome P450c17 KW - Ketoconazole (PubChem CID: 456201) KW - Mechanical allodynia KW - Neuropathic pain KW - PRE084 (PubChem CID: 126402) KW - Sigma-1 receptor KW - Trilostane (PubChem CID: 656583) SP - 169 EP - 180 JF - Neuropharmacology JO - Neuropharmacology VL - 149 N2 - 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 3β-hydroxysteroid dehydrogenase (3β-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 3β-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 3β-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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/30797030/Spinal_cytochrome_P450c17_plays_a_key_role_in_the_development_of_neuropathic_mechanical_allodynia:_Involvement_of_astrocyte_sigma_1_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(18)30569-0 DB - PRIME DP - Unbound Medicine ER -