Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward

Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of...

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Veröffentlicht in:The Journal of pharmacology and experimental therapeutics 2022-08, Vol.382 (2), p.167-180
Hauptverfasser: Beierle, Jacob A., Yao, Emily J., Goldstein, Stanley I., Lynch, William B., Scotellaro, Julia L., Shah, Anyaa A., Sena, Katherine D., Wong, Alyssa L., Linnertz, Colton L., Averin, Olga, Moody, David E., Reilly, Christopher A., Peltz, Gary, Emili, Andrew, Ferris, Martin T., Bryant, Camron D.
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container_issue 2
container_start_page 167
container_title The Journal of pharmacology and experimental therapeutics
container_volume 382
creator Beierle, Jacob A.
Yao, Emily J.
Goldstein, Stanley I.
Lynch, William B.
Scotellaro, Julia L.
Shah, Anyaa A.
Sena, Katherine D.
Wong, Alyssa L.
Linnertz, Colton L.
Averin, Olga
Moody, David E.
Reilly, Christopher A.
Peltz, Gary
Emili, Andrew
Ferris, Martin T.
Bryant, Camron D.
description Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.
doi_str_mv 10.1124/jpet.122.001217
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We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.</description><identifier>ISSN: 0022-3565</identifier><identifier>ISSN: 1521-0103</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.122.001217</identifier><identifier>PMID: 35688478</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Analgesics, Opioid - pharmacology ; Animals ; Brain - drug effects ; Female ; Homeodomain Proteins - genetics ; Male ; Metabolism, Transport, and Pharmacogenetics ; Mice ; Mice, Inbred BALB C ; Oxycodone - pharmacology ; Oxymorphone - pharmacology ; Reward</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2022-08, Vol.382 (2), p.167-180</ispartof><rights>2022 American Society for Pharmacology and Experimental Therapeutics</rights><rights>Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.</rights><rights>Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-ef03f684e090dee20557b81af9e3eaf2576890d9763af158ab629c0bc79f0a003</citedby><cites>FETCH-LOGICAL-c443t-ef03f684e090dee20557b81af9e3eaf2576890d9763af158ab629c0bc79f0a003</cites><orcidid>0000-0001-6517-7614 ; 0000-0002-5006-1982</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35688478$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Beierle, Jacob A.</creatorcontrib><creatorcontrib>Yao, Emily J.</creatorcontrib><creatorcontrib>Goldstein, Stanley I.</creatorcontrib><creatorcontrib>Lynch, William B.</creatorcontrib><creatorcontrib>Scotellaro, Julia L.</creatorcontrib><creatorcontrib>Shah, Anyaa A.</creatorcontrib><creatorcontrib>Sena, Katherine D.</creatorcontrib><creatorcontrib>Wong, Alyssa L.</creatorcontrib><creatorcontrib>Linnertz, Colton L.</creatorcontrib><creatorcontrib>Averin, Olga</creatorcontrib><creatorcontrib>Moody, David E.</creatorcontrib><creatorcontrib>Reilly, Christopher A.</creatorcontrib><creatorcontrib>Peltz, Gary</creatorcontrib><creatorcontrib>Emili, Andrew</creatorcontrib><creatorcontrib>Ferris, Martin T.</creatorcontrib><creatorcontrib>Bryant, Camron D.</creatorcontrib><title>Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. 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The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.</description><subject>Analgesics, Opioid - pharmacology</subject><subject>Animals</subject><subject>Brain - drug effects</subject><subject>Female</subject><subject>Homeodomain Proteins - genetics</subject><subject>Male</subject><subject>Metabolism, Transport, and Pharmacogenetics</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Oxycodone - pharmacology</subject><subject>Oxymorphone - pharmacology</subject><subject>Reward</subject><issn>0022-3565</issn><issn>1521-0103</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kT1vFDEQhi0EIpdATYdc0uzFH2vvboMUDhIiBUUKpKGxvPZsztGevdi-JFfx1_FpQwRFKlszjx-P5kXoHSVLSll9fDtBXlLGloRQRpsXaEEFoxWhhL9EC0IYq7iQ4gAdpnRbmLqW_DU6KLW2rZt2gX7_XD8wfJ6wxivtrbM6Az4DD_jaW4jjzvkbfPmw24Q4rUMpf4Os-zC6gn2K2nm8Ct6Az1FnFzw-SSkYVyQW37u8xt9zuVefYYKi83mvMsHuRVdwr6N9g14Nekzw9vE8QtenX36svlYXl2fnq5OLytQ1zxUMhA-yrYF0xAIwIkTTt1QPHXDQAxONbEunayTXAxWt7iXrDOlN0w1EE8KP0MfZO237Ddh54lFN0W103Kmgnfq_491a3YQ71fG6LLorgg-Pghh-bSFltXHJwDhqD2GbFJONkKSRRBT0eEZNDClFGJ6-oUTtY1P72FSJTc2xlRfv_53uif-bUwG6GYCyozsHUSXjoCzeuggmKxvcs_I_T_KqJg</recordid><startdate>202208</startdate><enddate>202208</enddate><creator>Beierle, Jacob A.</creator><creator>Yao, Emily J.</creator><creator>Goldstein, Stanley I.</creator><creator>Lynch, William B.</creator><creator>Scotellaro, Julia L.</creator><creator>Shah, Anyaa A.</creator><creator>Sena, Katherine D.</creator><creator>Wong, Alyssa L.</creator><creator>Linnertz, Colton L.</creator><creator>Averin, Olga</creator><creator>Moody, David E.</creator><creator>Reilly, Christopher A.</creator><creator>Peltz, Gary</creator><creator>Emili, Andrew</creator><creator>Ferris, Martin T.</creator><creator>Bryant, Camron D.</creator><general>Elsevier Inc</general><general>The American Society for Pharmacology and Experimental Therapeutics</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><orcidid>https://orcid.org/0000-0001-6517-7614</orcidid><orcidid>https://orcid.org/0000-0002-5006-1982</orcidid></search><sort><creationdate>202208</creationdate><title>Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward</title><author>Beierle, Jacob A. ; 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BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. 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subjects Analgesics, Opioid - pharmacology
Animals
Brain - drug effects
Female
Homeodomain Proteins - genetics
Male
Metabolism, Transport, and Pharmacogenetics
Mice
Mice, Inbred BALB C
Oxycodone - pharmacology
Oxymorphone - pharmacology
Reward
title Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward
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