Cannabinoid Receptor Type 2 Agonist Reduces Morphine Tolerance via Mitogen Activated Protein Kinase Phosphatase Induction and Mitogen Activated Protein Kinase Dephosphorylation
•Repeated morphine treatment reduced MKP-1/3 expression in the spinal cord.•AM1241 increased the expression of spinal MKP-1/3 in morphine tolerant mice.•AM1241 reduced MAPK phosphorylation by increasing MKP-1/3 expression.•The effect of AM1241 on morphine tolerance was blocked by MKP-1/3 antagonist....
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Veröffentlicht in: | Neuroscience 2022-01, Vol.480, p.56-64 |
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description | •Repeated morphine treatment reduced MKP-1/3 expression in the spinal cord.•AM1241 increased the expression of spinal MKP-1/3 in morphine tolerant mice.•AM1241 reduced MAPK phosphorylation by increasing MKP-1/3 expression.•The effect of AM1241 on morphine tolerance was blocked by MKP-1/3 antagonist.
Morphine is an opioid drug often used in treating moderate to severe pain. However, morphine tolerance in patients limits its used in clinical settings. Our previous study showed that a cannabinoid type 2 (CB2) receptor agonist attenuated morphine tolerance. However, the exact mechanism by which CB2 agonists reduce morphine tolerance remains unclear. In this study, we investigated the effect of mitogen activated protein kinase (MAPK) and mitogen activated protein kinase phosphatases 1 and 3 (MKP-1 and MKP-3) on the regulation of morphine tolerance by CB2 receptor agonist. Chronic morphine treatments for 7 days reduced the protein expression of MKP-1 and MKP-3 in the spinal cord and increased the phosphorylation of p38, ERK1/2 and the level of proinflammatory mediator, such as IL-1β, IL-6 and TNF-α. Coadministration of CB2 receptor agonist AM1241 alleviated the inhibition of MKP-1 and MKP-3 by chronic morphine administration and reduced the expression of phosphorylated MAPK and proinflammatory factors. The effect of the CB2 receptor agonist on morphine-induced downregulation of MKP-1 and MKP-3 was reversed by the MKP-1 and MKP-3 antagonist triptolide. Our findings suggested that CB2 receptor agonist may induce the expression of MKP-1 and MKP-3 to promote MAPK dephosphorylation and reduce the production of downstream cytokine, thereby reducing morphine tolerance. This finding suggested that MKPs may serve as a new target for alleviating morphine tolerance. |
doi_str_mv | 10.1016/j.neuroscience.2021.11.007 |
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Morphine is an opioid drug often used in treating moderate to severe pain. However, morphine tolerance in patients limits its used in clinical settings. Our previous study showed that a cannabinoid type 2 (CB2) receptor agonist attenuated morphine tolerance. However, the exact mechanism by which CB2 agonists reduce morphine tolerance remains unclear. In this study, we investigated the effect of mitogen activated protein kinase (MAPK) and mitogen activated protein kinase phosphatases 1 and 3 (MKP-1 and MKP-3) on the regulation of morphine tolerance by CB2 receptor agonist. Chronic morphine treatments for 7 days reduced the protein expression of MKP-1 and MKP-3 in the spinal cord and increased the phosphorylation of p38, ERK1/2 and the level of proinflammatory mediator, such as IL-1β, IL-6 and TNF-α. Coadministration of CB2 receptor agonist AM1241 alleviated the inhibition of MKP-1 and MKP-3 by chronic morphine administration and reduced the expression of phosphorylated MAPK and proinflammatory factors. The effect of the CB2 receptor agonist on morphine-induced downregulation of MKP-1 and MKP-3 was reversed by the MKP-1 and MKP-3 antagonist triptolide. Our findings suggested that CB2 receptor agonist may induce the expression of MKP-1 and MKP-3 to promote MAPK dephosphorylation and reduce the production of downstream cytokine, thereby reducing morphine tolerance. This finding suggested that MKPs may serve as a new target for alleviating morphine tolerance.</description><identifier>ISSN: 0306-4522</identifier><identifier>EISSN: 1873-7544</identifier><identifier>DOI: 10.1016/j.neuroscience.2021.11.007</identifier><identifier>PMID: 34774714</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Cannabinoid Receptor Agonists ; cannabinoid type 2 receptor ; Drug Tolerance ; Dual Specificity Phosphatase 1 ; Humans ; Mitogen-Activated Protein Kinases ; MKP1/3 ; Morphine - pharmacology ; morphine tolerance ; p38 Mitogen-Activated Protein Kinases ; proinflammatory cytokine ; Protein Phosphatase 1 ; Receptors, Cannabinoid</subject><ispartof>Neuroscience, 2022-01, Vol.480, p.56-64</ispartof><rights>2021 IBRO</rights><rights>Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-74b636ffaf0eb549403f803a42f7a5241ebc948c4fb300c53bac8c09e09cd05c3</citedby><cites>FETCH-LOGICAL-c380t-74b636ffaf0eb549403f803a42f7a5241ebc948c4fb300c53bac8c09e09cd05c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuroscience.2021.11.007$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34774714$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kong, Qingling</creatorcontrib><creatorcontrib>Tian, Songyu</creatorcontrib><creatorcontrib>Ma, Chao</creatorcontrib><creatorcontrib>Wang, Guonian</creatorcontrib><creatorcontrib>Zhang, Mingyue</creatorcontrib><title>Cannabinoid Receptor Type 2 Agonist Reduces Morphine Tolerance via Mitogen Activated Protein Kinase Phosphatase Induction and Mitogen Activated Protein Kinase Dephosphorylation</title><title>Neuroscience</title><addtitle>Neuroscience</addtitle><description>•Repeated morphine treatment reduced MKP-1/3 expression in the spinal cord.•AM1241 increased the expression of spinal MKP-1/3 in morphine tolerant mice.•AM1241 reduced MAPK phosphorylation by increasing MKP-1/3 expression.•The effect of AM1241 on morphine tolerance was blocked by MKP-1/3 antagonist.
Morphine is an opioid drug often used in treating moderate to severe pain. However, morphine tolerance in patients limits its used in clinical settings. Our previous study showed that a cannabinoid type 2 (CB2) receptor agonist attenuated morphine tolerance. However, the exact mechanism by which CB2 agonists reduce morphine tolerance remains unclear. In this study, we investigated the effect of mitogen activated protein kinase (MAPK) and mitogen activated protein kinase phosphatases 1 and 3 (MKP-1 and MKP-3) on the regulation of morphine tolerance by CB2 receptor agonist. Chronic morphine treatments for 7 days reduced the protein expression of MKP-1 and MKP-3 in the spinal cord and increased the phosphorylation of p38, ERK1/2 and the level of proinflammatory mediator, such as IL-1β, IL-6 and TNF-α. Coadministration of CB2 receptor agonist AM1241 alleviated the inhibition of MKP-1 and MKP-3 by chronic morphine administration and reduced the expression of phosphorylated MAPK and proinflammatory factors. The effect of the CB2 receptor agonist on morphine-induced downregulation of MKP-1 and MKP-3 was reversed by the MKP-1 and MKP-3 antagonist triptolide. Our findings suggested that CB2 receptor agonist may induce the expression of MKP-1 and MKP-3 to promote MAPK dephosphorylation and reduce the production of downstream cytokine, thereby reducing morphine tolerance. This finding suggested that MKPs may serve as a new target for alleviating morphine tolerance.</description><subject>Cannabinoid Receptor Agonists</subject><subject>cannabinoid type 2 receptor</subject><subject>Drug Tolerance</subject><subject>Dual Specificity Phosphatase 1</subject><subject>Humans</subject><subject>Mitogen-Activated Protein Kinases</subject><subject>MKP1/3</subject><subject>Morphine - pharmacology</subject><subject>morphine tolerance</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>proinflammatory cytokine</subject><subject>Protein Phosphatase 1</subject><subject>Receptors, Cannabinoid</subject><issn>0306-4522</issn><issn>1873-7544</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkd1u0zAUxy3ExMrgFZDFFTcJ_kqdcFd1Y0xs2oTKteU4J6ur1A62U6lvxSPOXQvijp0bH1n_Dx39EPpISUkJnX_elA6m4KOx4AyUjDBaUloSIl-hGa0lL2QlxGs0I5zMC1Exdo7exrgheSrB36BzLqQUkooZ-r3UzunWOm87_AMMjMkHvNqPgBlePHpnY8r_3WQg4jsfxrV1gFd-gKBzOd5Zje9s8o_g8MIku9MJOvwQfALr8HfrdAT8sPZxXOt02G9czkrWO6xd93_rJYzPZh_2gz7Y3qGzXg8R3p_eC_Tz69Vq-a24vb--WS5uC8Nrkgop2jmf973uCbSVaAThfU24FqyXumKCQmsaURvRt5wQU_FWm9qQBkhjOlIZfoE-HXPH4H9NEJPa2mhgGLQDP0XFqkbKpq6ZyNIvR6nJUGKAXo3BbnXYK0rUgZjaqH-JqQMxRanKxLL5w6lnarfQ_bX-QZQFl0cB5Gt3FoI6xXQ2gEmq8_YlPU9C_LL1</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>Kong, Qingling</creator><creator>Tian, Songyu</creator><creator>Ma, Chao</creator><creator>Wang, Guonian</creator><creator>Zhang, Mingyue</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20220101</creationdate><title>Cannabinoid Receptor Type 2 Agonist Reduces Morphine Tolerance via Mitogen Activated Protein Kinase Phosphatase Induction and Mitogen Activated Protein Kinase Dephosphorylation</title><author>Kong, Qingling ; Tian, Songyu ; Ma, Chao ; Wang, Guonian ; Zhang, Mingyue</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-74b636ffaf0eb549403f803a42f7a5241ebc948c4fb300c53bac8c09e09cd05c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Cannabinoid Receptor Agonists</topic><topic>cannabinoid type 2 receptor</topic><topic>Drug Tolerance</topic><topic>Dual Specificity Phosphatase 1</topic><topic>Humans</topic><topic>Mitogen-Activated Protein Kinases</topic><topic>MKP1/3</topic><topic>Morphine - pharmacology</topic><topic>morphine tolerance</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>proinflammatory cytokine</topic><topic>Protein Phosphatase 1</topic><topic>Receptors, Cannabinoid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kong, Qingling</creatorcontrib><creatorcontrib>Tian, Songyu</creatorcontrib><creatorcontrib>Ma, Chao</creatorcontrib><creatorcontrib>Wang, Guonian</creatorcontrib><creatorcontrib>Zhang, Mingyue</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kong, Qingling</au><au>Tian, Songyu</au><au>Ma, Chao</au><au>Wang, Guonian</au><au>Zhang, Mingyue</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cannabinoid Receptor Type 2 Agonist Reduces Morphine Tolerance via Mitogen Activated Protein Kinase Phosphatase Induction and Mitogen Activated Protein Kinase Dephosphorylation</atitle><jtitle>Neuroscience</jtitle><addtitle>Neuroscience</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>480</volume><spage>56</spage><epage>64</epage><pages>56-64</pages><issn>0306-4522</issn><eissn>1873-7544</eissn><abstract>•Repeated morphine treatment reduced MKP-1/3 expression in the spinal cord.•AM1241 increased the expression of spinal MKP-1/3 in morphine tolerant mice.•AM1241 reduced MAPK phosphorylation by increasing MKP-1/3 expression.•The effect of AM1241 on morphine tolerance was blocked by MKP-1/3 antagonist.
Morphine is an opioid drug often used in treating moderate to severe pain. However, morphine tolerance in patients limits its used in clinical settings. Our previous study showed that a cannabinoid type 2 (CB2) receptor agonist attenuated morphine tolerance. However, the exact mechanism by which CB2 agonists reduce morphine tolerance remains unclear. In this study, we investigated the effect of mitogen activated protein kinase (MAPK) and mitogen activated protein kinase phosphatases 1 and 3 (MKP-1 and MKP-3) on the regulation of morphine tolerance by CB2 receptor agonist. Chronic morphine treatments for 7 days reduced the protein expression of MKP-1 and MKP-3 in the spinal cord and increased the phosphorylation of p38, ERK1/2 and the level of proinflammatory mediator, such as IL-1β, IL-6 and TNF-α. Coadministration of CB2 receptor agonist AM1241 alleviated the inhibition of MKP-1 and MKP-3 by chronic morphine administration and reduced the expression of phosphorylated MAPK and proinflammatory factors. The effect of the CB2 receptor agonist on morphine-induced downregulation of MKP-1 and MKP-3 was reversed by the MKP-1 and MKP-3 antagonist triptolide. Our findings suggested that CB2 receptor agonist may induce the expression of MKP-1 and MKP-3 to promote MAPK dephosphorylation and reduce the production of downstream cytokine, thereby reducing morphine tolerance. This finding suggested that MKPs may serve as a new target for alleviating morphine tolerance.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>34774714</pmid><doi>10.1016/j.neuroscience.2021.11.007</doi><tpages>9</tpages></addata></record> |
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subjects | Cannabinoid Receptor Agonists cannabinoid type 2 receptor Drug Tolerance Dual Specificity Phosphatase 1 Humans Mitogen-Activated Protein Kinases MKP1/3 Morphine - pharmacology morphine tolerance p38 Mitogen-Activated Protein Kinases proinflammatory cytokine Protein Phosphatase 1 Receptors, Cannabinoid |
title | Cannabinoid Receptor Type 2 Agonist Reduces Morphine Tolerance via Mitogen Activated Protein Kinase Phosphatase Induction and Mitogen Activated Protein Kinase Dephosphorylation |
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