{"doi":"10.1124/jpet.122.001217","title":"Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward","abstract":"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 <i>Zhx2</i>, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces <i>Zhx2</i> expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the <i>Zhx2</i> eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, <i>Zhx2</i> is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate <i>Zhx2</i> and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. <h3>SIGNIFICANCE STATEMENT</h3> 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.","journal":"Journal of Pharmacology and Experimental Therapeutics","year":2022,"id":280428,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":410327,"name":"Emily J. Yao","orcid":null,"position":1,"is_corresponding":false},{"id":817256,"name":"Stanley I. Goldstein","orcid":"0000-0003-2271-7267","position":2,"is_corresponding":false},{"id":955353,"name":"William B. Lynch","orcid":null,"position":3,"is_corresponding":false},{"id":624516,"name":"Julia L. Scotellaro","orcid":null,"position":4,"is_corresponding":false},{"id":410329,"name":"Anyaa A. Shah","orcid":null,"position":5,"is_corresponding":false},{"id":955354,"name":"Katherine D. Sena","orcid":null,"position":6,"is_corresponding":false},{"id":955355,"name":"Alyssa L. Wong","orcid":null,"position":7,"is_corresponding":false},{"id":275065,"name":"Colton L. Linnertz","orcid":"0000-0003-2969-8193","position":8,"is_corresponding":false},{"id":955356,"name":"Olga Averin","orcid":null,"position":9,"is_corresponding":false},{"id":160322,"name":"David E. Moody","orcid":null,"position":10,"is_corresponding":false},{"id":407036,"name":"Christopher A. Reilly","orcid":"0000-0002-5006-1982","position":11,"is_corresponding":false},{"id":555735,"name":"Gary Peltz","orcid":"0000-0001-6191-7697","position":12,"is_corresponding":false},{"id":253656,"name":"Andrew Emili","orcid":"0000-0001-8995-246X","position":13,"is_corresponding":false},{"id":275086,"name":"Martin T. Ferris","orcid":"0000-0003-1241-6268","position":14,"is_corresponding":false},{"id":291791,"name":"Camron D. Bryant","orcid":"0000-0003-4505-5809","position":15,"is_corresponding":false},{"id":375681,"name":"Jacob A. Beierle","orcid":"0000-0001-6517-7614","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:29:03.247347Z","pmid":"35688478","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}