Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons
The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current,...
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| Format: | Article |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1144614/full |
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| author | Lamei Li Lamei Li Yuanying Liu Yuanying Liu Wenchao Hu Jing Yang Suibin Ma Zhicheng Tian Zixuan Cao Kunqing Pan Ming Jiang Xia Liu Shengxi Wu Ceng Luo Rou-Gang Xie |
| author_facet | Lamei Li Lamei Li Yuanying Liu Yuanying Liu Wenchao Hu Jing Yang Suibin Ma Zhicheng Tian Zixuan Cao Kunqing Pan Ming Jiang Xia Liu Shengxi Wu Ceng Luo Rou-Gang Xie |
| author_sort | Lamei Li |
| collection | DOAJ |
| description | The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected Ih currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2+/HCN2+ expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently Ih, which in turn leads to neuronal hyperexcitability. |
| first_indexed | 2024-03-11T20:00:41Z |
| format | Article |
| id | doaj.art-b35b650aa1a74e45b0612e42e3995b11 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-11T20:00:41Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b35b650aa1a74e45b0612e42e3995b112023-10-04T09:03:47ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-10-011610.3389/fnmol.2023.11446141144614Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neuronsLamei Li0Lamei Li1Yuanying Liu2Yuanying Liu3Wenchao Hu4Jing Yang5Suibin Ma6Zhicheng Tian7Zixuan Cao8Kunqing Pan9Ming Jiang10Xia Liu11Shengxi Wu12Ceng Luo13Rou-Gang Xie14Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaSchool of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan’an University, Yan’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaSchool of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan’an University, Yan’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaHeart Hospital, Xi’an International Medical Center Hospital, Xi’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaNo.6 Cadet Regiment, School of Basic Medical Sciences, Fourth Military Medical University, Xi’an, ChinaNo.19 Cadet Regiment, School of Basic Medical Sciences, Fourth Military Medical University, Xi’an, ChinaSchool of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan’an University, Yan’an, ChinaSchool of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan’an University, Yan’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaDepartment of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ChinaThe C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected Ih currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2+/HCN2+ expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently Ih, which in turn leads to neuronal hyperexcitability.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1144614/fullthe C-C motif chemokine ligand 2 (CCL2)the C-C motif chemokine receptor 2 (CCR2)dorsal root ganglion (DRG)hyperpolarization-activated current (IH)nociceptorPain |
| spellingShingle | Lamei Li Lamei Li Yuanying Liu Yuanying Liu Wenchao Hu Jing Yang Suibin Ma Zhicheng Tian Zixuan Cao Kunqing Pan Ming Jiang Xia Liu Shengxi Wu Ceng Luo Rou-Gang Xie Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons Frontiers in Molecular Neuroscience the C-C motif chemokine ligand 2 (CCL2) the C-C motif chemokine receptor 2 (CCR2) dorsal root ganglion (DRG) hyperpolarization-activated current (IH) nociceptor Pain |
| title | Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons |
| title_full | Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons |
| title_fullStr | Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons |
| title_full_unstemmed | Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons |
| title_short | Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons |
| title_sort | peripheral ccl2 induces inflammatory pain via regulation of ih currents in small diameter drg neurons |
| topic | the C-C motif chemokine ligand 2 (CCL2) the C-C motif chemokine receptor 2 (CCR2) dorsal root ganglion (DRG) hyperpolarization-activated current (IH) nociceptor Pain |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1144614/full |
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