title: Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.
abstract: The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine's role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated significantly. In sum, methytransferase G9a/Glp complex partially controls dopaminergic transmission by methylating Th in peripheral nerve injury-induced neuropathic pain.
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Nan
authors: N
authors: Wang
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Xiaofeng
authors: X
authors: Shen
authors: Department of Stomatology, Affiliated Hospital of Qinghai University, China.
authors: Senzhu
authors: S
authors: Bao
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Shan-Wu
authors: SW
authors: Feng
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Wei
authors: W
authors: Wang
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Yusheng
authors: Y
authors: Liu
authors: Internal Medicine, Shanghai Municipal Hospital of TCM, Shanghai TCM University, China.
authors: Yiquan
authors: Y
authors: Wang
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Xian
authors: X
authors: Wang
authors: Institute of Pediatrics, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Xirong
authors: X
authors: Guo
authors: Institute of Pediatrics, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Rong
authors: R
authors: Shen
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Haibo
authors: H
authors: Wu
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China.
authors: Liming
authors: L
authors: Lei
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China xusq@njmu.edu.cn fred.wang@basehq.org.
authors: Shiqin
authors: S
authors: Xu
authors: Department of Anesthesiology, Affiliated Hospital of Obstetrics and Gynecology, Nanjing Medical University, China Division of Neuroscience, The Bonoi Academy of Science & Education, USA.
authors: Fuzhou
authors: F
authors: Wang
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006967:Hypersensitivity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D020426:Sciatic Neuropathy / Q000150:complications; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001381:Azepines; C518299:BIX 01294; D011799:Quinazolines; D014446:Tyrosine 3-Monooxygenase; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D004298:Dopamine
keywords: G9a/Glp; Nerve injury; desensitization; dopamine; tyrosine hydroxylase