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Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain
Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/k...
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Published in: | Molecular pain 2021, Vol.17, p.17448069211003375-17448069211003375 |
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description | Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies. |
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Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.</description><identifier>ISSN: 1744-8069</identifier><identifier>EISSN: 1744-8069</identifier><identifier>DOI: 10.1177/17448069211003375</identifier><identifier>PMID: 33745380</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; AKT1 protein ; Analgesics ; Analgesics - pharmacology ; Animals ; c-Jun protein ; Cyclic GMP ; Cyclic GMP - metabolism ; Disease Models, Animal ; Dorsal root ganglia ; Drug tolerance ; Drug Tolerance - physiology ; Gene expression ; Intracellular ; Intracellular signalling ; JNK Mitogen-Activated Protein Kinases - metabolism ; JNK protein ; Kinases ; Micro Report ; Morphine ; Morphine - pharmacology ; Nervous system ; Neuralgia - metabolism ; Opioids ; Peripheral neuropathy ; Phosphatidylinositol 3-Kinases - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; PTEN protein ; Quercetin ; Sciatic nerve ; Signal transduction ; Spinal cord ; Spinal nerves ; Spinal Nerves - metabolism ; Thalidomide ; Transcription factors</subject><ispartof>Molecular pain, 2021, Vol.17, p.17448069211003375-17448069211003375</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. 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Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>AKT1 protein</subject><subject>Analgesics</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>c-Jun protein</subject><subject>Cyclic GMP</subject><subject>Cyclic GMP - metabolism</subject><subject>Disease Models, Animal</subject><subject>Dorsal root ganglia</subject><subject>Drug tolerance</subject><subject>Drug Tolerance - physiology</subject><subject>Gene expression</subject><subject>Intracellular</subject><subject>Intracellular signalling</subject><subject>JNK Mitogen-Activated Protein Kinases - metabolism</subject><subject>JNK protein</subject><subject>Kinases</subject><subject>Micro Report</subject><subject>Morphine</subject><subject>Morphine - pharmacology</subject><subject>Nervous system</subject><subject>Neuralgia - metabolism</subject><subject>Opioids</subject><subject>Peripheral neuropathy</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>PTEN protein</subject><subject>Quercetin</subject><subject>Sciatic nerve</subject><subject>Signal transduction</subject><subject>Spinal cord</subject><subject>Spinal nerves</subject><subject>Spinal Nerves - metabolism</subject><subject>Thalidomide</subject><subject>Transcription factors</subject><issn>1744-8069</issn><issn>1744-8069</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>AFRWT</sourceid><sourceid>PIMPY</sourceid><recordid>eNp1ks9uFSEUxifGxv7RB3BjSNy4oYVhgJmNSdNorVbroq4nDHPuHSoDU2Bq7qv16WS8tVZNFwQ4_M53vkNOUbyk5JBSKY-orKqaiKaklBDGJH9S7C0xvASfPjjvFvsxXmVGEkGfFbuZrTiryV5xe-YG05lkvEN-hdIAaBp8zMs4H3O8B8Twd-NUBHz86RLrjbZGo9PPX7HGH2eHvuAEYcyARVsMRbPON-PWaFJp-KE2SKUEblYJ4q8KPdyA9dMILi1FRx-mwThAyVsIymlAxiGV43NWG30PdsEczMEvirn8pIx7XuyslI3w4m4_KL69f3d58gGfX5yenRyfY10JkTAnq66noq6rqu9qLquu1IoD71hf1oISKEmlZF2WDfRC0oY3HRGs1FJqykASdlC83epOczdCr7ProGw7BTOqsGm9Mu3fL84M7drftLKpWUVFFnhzJxD89QwxtaOJGqxVDnKLbckJEzKb4Rl9_Q965eeQfzNTgrJSEEkXR3RL6eBjDLC6N0NJu0xG-99k5JxXD7u4z_g9Chk43AJRreFP2ccVfwJmqsPK</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Okerman, Travis</creator><creator>Jurgenson, Taylor</creator><creator>Moore, Madelyn</creator><creator>Klein, Amanda H</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><scope>AFRWT</scope><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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3433-2180</orcidid></search><sort><creationdate>2021</creationdate><title>Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain</title><author>Okerman, Travis ; Jurgenson, Taylor ; Moore, Madelyn ; Klein, Amanda H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-50fbd168844db8574b2ca5e5b3d28610e204a78229ed671959b0632c77c13e703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>AKT1 protein</topic><topic>Analgesics</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>c-Jun protein</topic><topic>Cyclic GMP</topic><topic>Cyclic GMP - metabolism</topic><topic>Disease Models, Animal</topic><topic>Dorsal root ganglia</topic><topic>Drug tolerance</topic><topic>Drug Tolerance - physiology</topic><topic>Gene expression</topic><topic>Intracellular</topic><topic>Intracellular signalling</topic><topic>JNK Mitogen-Activated Protein Kinases - metabolism</topic><topic>JNK protein</topic><topic>Kinases</topic><topic>Micro Report</topic><topic>Morphine</topic><topic>Morphine - pharmacology</topic><topic>Nervous system</topic><topic>Neuralgia - metabolism</topic><topic>Opioids</topic><topic>Peripheral neuropathy</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>PTEN protein</topic><topic>Quercetin</topic><topic>Sciatic nerve</topic><topic>Signal transduction</topic><topic>Spinal cord</topic><topic>Spinal nerves</topic><topic>Spinal Nerves - metabolism</topic><topic>Thalidomide</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Okerman, Travis</creatorcontrib><creatorcontrib>Jurgenson, Taylor</creatorcontrib><creatorcontrib>Moore, Madelyn</creatorcontrib><creatorcontrib>Klein, Amanda H</creatorcontrib><collection>Sage Journals GOLD Open Access 2024</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular pain</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Okerman, Travis</au><au>Jurgenson, Taylor</au><au>Moore, Madelyn</au><au>Klein, Amanda H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain</atitle><jtitle>Molecular pain</jtitle><addtitle>Mol Pain</addtitle><date>2021</date><risdate>2021</risdate><volume>17</volume><spage>17448069211003375</spage><epage>17448069211003375</epage><pages>17448069211003375-17448069211003375</pages><issn>1744-8069</issn><eissn>1744-8069</eissn><abstract>Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>33745380</pmid><doi>10.1177/17448069211003375</doi><orcidid>https://orcid.org/0000-0002-3433-2180</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 1-Phosphatidylinositol 3-kinase AKT protein AKT1 protein Analgesics Analgesics - pharmacology Animals c-Jun protein Cyclic GMP Cyclic GMP - metabolism Disease Models, Animal Dorsal root ganglia Drug tolerance Drug Tolerance - physiology Gene expression Intracellular Intracellular signalling JNK Mitogen-Activated Protein Kinases - metabolism JNK protein Kinases Micro Report Morphine Morphine - pharmacology Nervous system Neuralgia - metabolism Opioids Peripheral neuropathy Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism PTEN protein Quercetin Sciatic nerve Signal transduction Spinal cord Spinal nerves Spinal Nerves - metabolism Thalidomide Transcription factors |
title | Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain |
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