The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia
A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midb...
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Veröffentlicht in: | Pain (Amsterdam) 2019-11, Vol.160 (11), p.2524-2534 |
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creator | Taylor, Norman E. Long, Hu Pei, JunZhu Kukutla, Phanidhar Phero, Anthony Hadaegh, Farnaz Abdelnabi, Ahmed Solt, Ken Brenner, Gary J. |
description | A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia. |
doi_str_mv | 10.1097/j.pain.0000000000001647 |
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This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.</description><identifier>ISSN: 0304-3959</identifier><identifier>EISSN: 1872-6623</identifier><identifier>DOI: 10.1097/j.pain.0000000000001647</identifier><identifier>PMID: 31246732</identifier><language>eng</language><publisher>United States: Wolters Kluwer</publisher><subject>Analgesics, Opioid - pharmacology ; Animals ; Dopaminergic Neurons - drug effects ; GABAergic Neurons - drug effects ; gamma-Aminobutyric Acid - pharmacology ; Mice, Transgenic ; Morphine - pharmacology ; Neural Pathways - drug effects ; Nucleus Accumbens - drug effects ; Receptors, Opioid - drug effects ; Tegmentum Mesencephali - cytology ; Tegmentum Mesencephali - drug effects ; Ventral Tegmental Area - drug effects</subject><ispartof>Pain (Amsterdam), 2019-11, Vol.160 (11), p.2524-2534</ispartof><rights>Wolters Kluwer</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5282-f3224fd627c772e3a4f25a8b7c8eeb8c7a683c12289153ff7d78aa204a8002063</citedby><cites>FETCH-LOGICAL-c5282-f3224fd627c772e3a4f25a8b7c8eeb8c7a683c12289153ff7d78aa204a8002063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31246732$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Taylor, Norman E.</creatorcontrib><creatorcontrib>Long, Hu</creatorcontrib><creatorcontrib>Pei, JunZhu</creatorcontrib><creatorcontrib>Kukutla, Phanidhar</creatorcontrib><creatorcontrib>Phero, Anthony</creatorcontrib><creatorcontrib>Hadaegh, Farnaz</creatorcontrib><creatorcontrib>Abdelnabi, Ahmed</creatorcontrib><creatorcontrib>Solt, Ken</creatorcontrib><creatorcontrib>Brenner, Gary J.</creatorcontrib><title>The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia</title><title>Pain (Amsterdam)</title><addtitle>Pain</addtitle><description>A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.</description><subject>Analgesics, Opioid - pharmacology</subject><subject>Animals</subject><subject>Dopaminergic Neurons - drug effects</subject><subject>GABAergic Neurons - drug effects</subject><subject>gamma-Aminobutyric Acid - pharmacology</subject><subject>Mice, Transgenic</subject><subject>Morphine - pharmacology</subject><subject>Neural Pathways - drug effects</subject><subject>Nucleus Accumbens - drug effects</subject><subject>Receptors, Opioid - drug effects</subject><subject>Tegmentum Mesencephali - cytology</subject><subject>Tegmentum Mesencephali - drug effects</subject><subject>Ventral Tegmental Area - drug effects</subject><issn>0304-3959</issn><issn>1872-6623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUU2PFCEQJUbjjqt_QTl66REKGmgPJmbjV7KJHtYzqaHpGWbpZoRuN_vvZXbWzSoXqsKr9x71CHnD2ZqzTr_brw8YpjV7dLiS-glZcaOhUQrEU7JigslGdG13Rl6Usq8gAOiekzPBQSotYEV-XO08zanMOY2-Dxjp7Lejn-ZaTYuLfinvKdJrf0vH1C8R55RpGuhRnuLU03QIKfS1xLj1JeBL8mzAWPyr-_uc_Pz86eria3P5_cu3i4-XjWvBQDMIADn0CrTTGrxAOUCLZqOd8X5jnEZlhOMApuOtGAbda4MITKKpv2BKnJMPJ97DsqnOXbWcMdpDDiPmW5sw2H9fprCz2_TbaiGFEqwSvL0nyOnX4stsx1CcjxEnn5ZiAVqmpJR3WvoEdXVTJfvhQYYze8zD7u1xIfb_POrk68cuH-b-BlAB8gS4SXH2uVzH5cZnu_MY590dnxKdaoDxjvPaNUdmEH8AR06YAg</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Taylor, Norman E.</creator><creator>Long, Hu</creator><creator>Pei, JunZhu</creator><creator>Kukutla, Phanidhar</creator><creator>Phero, Anthony</creator><creator>Hadaegh, Farnaz</creator><creator>Abdelnabi, Ahmed</creator><creator>Solt, Ken</creator><creator>Brenner, Gary J.</creator><general>Wolters Kluwer</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><scope>5PM</scope></search><sort><creationdate>20191101</creationdate><title>The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia</title><author>Taylor, Norman E. ; Long, Hu ; Pei, JunZhu ; Kukutla, Phanidhar ; Phero, Anthony ; Hadaegh, Farnaz ; Abdelnabi, Ahmed ; Solt, Ken ; Brenner, Gary J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5282-f3224fd627c772e3a4f25a8b7c8eeb8c7a683c12289153ff7d78aa204a8002063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Analgesics, Opioid - pharmacology</topic><topic>Animals</topic><topic>Dopaminergic Neurons - drug effects</topic><topic>GABAergic Neurons - drug effects</topic><topic>gamma-Aminobutyric Acid - pharmacology</topic><topic>Mice, Transgenic</topic><topic>Morphine - pharmacology</topic><topic>Neural Pathways - drug effects</topic><topic>Nucleus Accumbens - drug effects</topic><topic>Receptors, Opioid - drug effects</topic><topic>Tegmentum Mesencephali - cytology</topic><topic>Tegmentum Mesencephali - drug effects</topic><topic>Ventral Tegmental Area - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Taylor, Norman E.</creatorcontrib><creatorcontrib>Long, Hu</creatorcontrib><creatorcontrib>Pei, JunZhu</creatorcontrib><creatorcontrib>Kukutla, Phanidhar</creatorcontrib><creatorcontrib>Phero, Anthony</creatorcontrib><creatorcontrib>Hadaegh, Farnaz</creatorcontrib><creatorcontrib>Abdelnabi, Ahmed</creatorcontrib><creatorcontrib>Solt, Ken</creatorcontrib><creatorcontrib>Brenner, Gary J.</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Pain (Amsterdam)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Taylor, Norman E.</au><au>Long, Hu</au><au>Pei, JunZhu</au><au>Kukutla, Phanidhar</au><au>Phero, Anthony</au><au>Hadaegh, Farnaz</au><au>Abdelnabi, Ahmed</au><au>Solt, Ken</au><au>Brenner, Gary J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia</atitle><jtitle>Pain (Amsterdam)</jtitle><addtitle>Pain</addtitle><date>2019-11-01</date><risdate>2019</risdate><volume>160</volume><issue>11</issue><spage>2524</spage><epage>2534</epage><pages>2524-2534</pages><issn>0304-3959</issn><eissn>1872-6623</eissn><abstract>A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.</abstract><cop>United States</cop><pub>Wolters Kluwer</pub><pmid>31246732</pmid><doi>10.1097/j.pain.0000000000001647</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Analgesics, Opioid - pharmacology Animals Dopaminergic Neurons - drug effects GABAergic Neurons - drug effects gamma-Aminobutyric Acid - pharmacology Mice, Transgenic Morphine - pharmacology Neural Pathways - drug effects Nucleus Accumbens - drug effects Receptors, Opioid - drug effects Tegmentum Mesencephali - cytology Tegmentum Mesencephali - drug effects Ventral Tegmental Area - drug effects |
title | The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia |
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