Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models
Background The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory...
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| Format: | Article |
| Language: | English |
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Korean Society of Anesthesiologists
2019-02-01
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| Series: | Korean Journal of Anesthesiology |
| Subjects: | |
| Online Access: | http://ekja.org/upload/pdf/kja-d-18-00022.pdf |
| _version_ | 1819277471613190144 |
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| author | Yumi Kim So Young Kwon Hong Soo Jung Yoo Jung Park Yong Shin Kim Jang Hyeok In Jin Woo Choi Jin A Kim Jin Deok Joo |
| author_facet | Yumi Kim So Young Kwon Hong Soo Jung Yoo Jung Park Yong Shin Kim Jang Hyeok In Jin Woo Choi Jin A Kim Jin Deok Joo |
| author_sort | Yumi Kim |
| collection | DOAJ |
| description | Background The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. Methods Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. Results Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. Conclusions The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response. |
| first_indexed | 2024-12-23T23:56:39Z |
| format | Article |
| id | doaj.art-07c2f39868f043bba69bf052aff766c1 |
| institution | Directory Open Access Journal |
| issn | 2005-6419 2005-7563 |
| language | English |
| last_indexed | 2024-12-23T23:56:39Z |
| publishDate | 2019-02-01 |
| publisher | Korean Society of Anesthesiologists |
| record_format | Article |
| series | Korean Journal of Anesthesiology |
| spelling | doaj.art-07c2f39868f043bba69bf052aff766c12022-12-21T17:25:14ZengKorean Society of AnesthesiologistsKorean Journal of Anesthesiology2005-64192005-75632019-02-01721606710.4097/kja.d.18.000228457Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain modelsYumi KimSo Young KwonHong Soo JungYoo Jung ParkYong Shin KimJang Hyeok InJin Woo ChoiJin A KimJin Deok JooBackground The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. Methods Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. Results Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. Conclusions The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.http://ekja.org/upload/pdf/kja-d-18-00022.pdfadenosine a3amitriptylinecyclic amp response element-binding proteincytokinemitogen-activated protein kinase |
| spellingShingle | Yumi Kim So Young Kwon Hong Soo Jung Yoo Jung Park Yong Shin Kim Jang Hyeok In Jin Woo Choi Jin A Kim Jin Deok Joo Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models Korean Journal of Anesthesiology adenosine a3 amitriptyline cyclic amp response element-binding protein cytokine mitogen-activated protein kinase |
| title | Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models |
| title_full | Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models |
| title_fullStr | Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models |
| title_full_unstemmed | Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models |
| title_short | Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models |
| title_sort | amitriptyline inhibits the mapk erk and creb pathways and proinflammatory cytokines through a3ar activation in rat neuropathic pain models |
| topic | adenosine a3 amitriptyline cyclic amp response element-binding protein cytokine mitogen-activated protein kinase |
| url | http://ekja.org/upload/pdf/kja-d-18-00022.pdf |
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