Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats
Abstract. Introduction:. Neuropathic pain (NP) affects countless people worldwide; however, few effective treatments are currently available. Histone deacetylases (HDACs) participate in epigenetic modifications in neuropathy-induced nociceptive sensitization. Gamma-aminobutyric acid (GABA) is a majo...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer
2024-12-01
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| Series: | PAIN Reports |
| Online Access: | http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001209 |
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| author | Zhi-Hong Wen Nan-Fu Chen Hao-Jung Cheng Hsiao-Mei Kuo Pei-Yu Chen Chien-Wei Feng Zhi-Kang Yao Wu-Fu Chen Chun-Sung Sung |
| author_facet | Zhi-Hong Wen Nan-Fu Chen Hao-Jung Cheng Hsiao-Mei Kuo Pei-Yu Chen Chien-Wei Feng Zhi-Kang Yao Wu-Fu Chen Chun-Sung Sung |
| author_sort | Zhi-Hong Wen |
| collection | DOAJ |
| description | Abstract. Introduction:. Neuropathic pain (NP) affects countless people worldwide; however, few effective treatments are currently available. Histone deacetylases (HDACs) participate in epigenetic modifications in neuropathy-induced nociceptive sensitization. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter that can inhibit NP. The present study aimed to examine the role of spinal HDAC and its isoforms in neuropathy.
Methods:. Male Wistar Rat with chronic constriction injury (CCI)-induced peripheral neuropathy and HDAC inhibitor, panobinostat, was administrated intrathecally. We performed quantitative real-time polymerase chain reaction (RT-qPCR), western blot, and immunohistochemical analysis of lumbar spinal cord dorsal horn and nociceptive behaviors (thermal hyperalgesia and mechanical allodynia) measurements.
Results:. Herein, RT-qPCR analysis revealed that spinal hdac3, hdac4, and hdac6 were upregulated in CCI rats. Western blotting and immunofluorescence staining further confirmed that HDAC3, HDAC4, and HDAC6 were significantly upregulated, whereas GABA and its synthesis key enzyme glutamic acid decarboxylase (GAD) 65 were dramatically downregulated. Intrathecal panobinostat attenuated nociceptive behavior and restored the downregulated spinal GAD65 and GABA expression in CCI rats.
Conclusions:. HDAC upregulation might induce nociception through GAD65 and GABA inhibition in CCI-induced neuropathy. These findings strongly suggest that HDACs negatively regulate inhibitory neurotransmitters, constituting a potential therapeutic strategy for an epigenetic approach to manage NP. |
| format | Article |
| id | doaj-art-12cb326a078d418e99313cf80c56fe60 |
| institution | OA Journals |
| issn | 2471-2531 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wolters Kluwer |
| record_format | Article |
| series | PAIN Reports |
| spelling | doaj-art-12cb326a078d418e99313cf80c56fe602025-08-20T01:53:26ZengWolters KluwerPAIN Reports2471-25312024-12-0196e120910.1097/PR9.0000000000001209PR90000000000001209Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in ratsZhi-Hong Wen0Nan-Fu Chen1Hao-Jung Cheng2Hsiao-Mei Kuo3Pei-Yu Chen4Chien-Wei Feng5Zhi-Kang Yao6Wu-Fu Chen7Chun-Sung Sung8a Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwanc Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwanb Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwane Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwana Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwanf Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwana Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwana Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwanh Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, TaiwanAbstract. Introduction:. Neuropathic pain (NP) affects countless people worldwide; however, few effective treatments are currently available. Histone deacetylases (HDACs) participate in epigenetic modifications in neuropathy-induced nociceptive sensitization. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter that can inhibit NP. The present study aimed to examine the role of spinal HDAC and its isoforms in neuropathy. Methods:. Male Wistar Rat with chronic constriction injury (CCI)-induced peripheral neuropathy and HDAC inhibitor, panobinostat, was administrated intrathecally. We performed quantitative real-time polymerase chain reaction (RT-qPCR), western blot, and immunohistochemical analysis of lumbar spinal cord dorsal horn and nociceptive behaviors (thermal hyperalgesia and mechanical allodynia) measurements. Results:. Herein, RT-qPCR analysis revealed that spinal hdac3, hdac4, and hdac6 were upregulated in CCI rats. Western blotting and immunofluorescence staining further confirmed that HDAC3, HDAC4, and HDAC6 were significantly upregulated, whereas GABA and its synthesis key enzyme glutamic acid decarboxylase (GAD) 65 were dramatically downregulated. Intrathecal panobinostat attenuated nociceptive behavior and restored the downregulated spinal GAD65 and GABA expression in CCI rats. Conclusions:. HDAC upregulation might induce nociception through GAD65 and GABA inhibition in CCI-induced neuropathy. These findings strongly suggest that HDACs negatively regulate inhibitory neurotransmitters, constituting a potential therapeutic strategy for an epigenetic approach to manage NP.http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001209 |
| spellingShingle | Zhi-Hong Wen Nan-Fu Chen Hao-Jung Cheng Hsiao-Mei Kuo Pei-Yu Chen Chien-Wei Feng Zhi-Kang Yao Wu-Fu Chen Chun-Sung Sung Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats PAIN Reports |
| title | Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats |
| title_full | Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats |
| title_fullStr | Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats |
| title_full_unstemmed | Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats |
| title_short | Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats |
| title_sort | upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the gaba system in chronic constriction injury induced neuropathy in rats |
| url | http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001209 |
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