{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:02:06Z","timestamp":1791910926649,"version":"4.3.4"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2020,3,1]],"date-time":"2020-03-01T00:00:00Z","timestamp":1583020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Endogenous opioid peptides are released at sites of injury, and their cognate G protein\u2013coupled opioid receptors (ORs) are expressed on immune cells. Although drugs of misuse appropriate ORs, conflicting reports indicate immunostimulatory and immunosuppressive activity, in that opioid users have elevated infection risk, opioids activate innate immune cells, and opioids attenuate inflammation in murine T cell\u2013mediated autoimmunity models. The i.v. use of drugs transmits bloodborne pathogens, particularly viruses, making the study of CD8+ T cells timely. From a cohort of nonuser controls and methadone users, we demonstrate, via t-Stochastic Neighbor Embedding and k-means cluster analysis of surface marker expression, that chronic opioid use alters human CD8+ T cell subset balance, with notable decreases in T effector memory RA+ cells. Studying global CD8+ T cell populations, there were no differences in expression of OR and several markers of functionality, demonstrating the need for finer analysis. Purified CD8+ T cells from controls respond to opioids ex vivo by increasing cytoplasmic calcium, a novel finding for OR signal transduction, likely because of cell lineage. CD8+ T cells from controls exposed to \u03bc-OR agonists ex vivo decrease expression of activation markers CD69 and CD25, although the same markers are elevated in \u03bc-OR\u2013treated cells from methadone users. In contrast to control cells, T cell subsets from methadone users show decreased expression of CD69 and CD25 in response to TCR stimulus. Overall, these results indicate a direct, selective role for opioids in CD8+ T cell immune regulation via their ability to modulate cell responses through the opioid receptors and TCRs.<\/jats:p>","DOI":"10.4049\/jimmunol.1900862","type":"journal-article","created":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T21:35:13Z","timestamp":1579728913000},"page":"1188-1200","source":"Crossref","is-referenced-by-count":16,"title":["Chronic Methadone Use Alters the CD8+ T Cell Phenotype In Vivo and Modulates Its Responsiveness Ex Vivo to Opioid Receptor and TCR Stimuli"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9950-5433","authenticated-orcid":false,"given":"Claire","family":"Mazahery","sequence":"first","affiliation":[{"name":"Department of Pathology, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4318-5693","authenticated-orcid":false,"given":"Bryan L","family":"Benson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7419-7382","authenticated-orcid":false,"given":"Ang\u00e9lica","family":"Cruz-Lebr\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5706-0667","authenticated-orcid":false,"given":"Alan D","family":"Levine","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University , Cleveland, OH 44106"},{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University , Cleveland, OH 44106"},{"name":"Department of Pharmacology, Case Western Reserve University , Cleveland, OH 44106"},{"name":"Department of Medicine, Case Western Reserve University , Cleveland, OH 44106"},{"name":"Department of Pediatrics, Case Western Reserve University , Cleveland, OH 44106"},{"name":"Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,3,1]]},"reference":[{"key":"2025030417510901000_r1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.drugalcdep.2018.04.036","article-title":"Association between injection in public places and HIV\/HCV risk behavior among people who use drugs in Ukraine","volume":"189","author":"Mazhnaya","year":"2018","journal-title":"Drug Alcohol Depend."},{"key":"2025030417510901000_r2","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ebiom.2018.10.007","article-title":"A large HCV transmission network enabled a fast-growing HIV outbreak in rural Indiana, 2015","volume":"37","author":"Ramachandran","year":"2018","journal-title":"EBioMedicine"},{"key":"2025030417510901000_r3","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.drugalcdep.2018.07.034","article-title":"Hepatitis C virus prevalence and estimated incidence among new injectors during the opioid epidemic in New York City, 2000-2017: protective effects of non-injecting drug use","volume":"192","author":"Des Jarlais","year":"2018","journal-title":"Drug Alcohol Depend."},{"key":"2025030417510901000_r4","doi-asserted-by":"crossref","first-page":"S305","DOI":"10.2105\/AJPH.2018.304788","article-title":"Gaps in preexposure prophylaxis uptake for HIV prevention in the veterans health administration","volume":"108","author":"Garner","year":"2018","journal-title":"Am. J. Public Health"},{"key":"2025030417510901000_r5","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1093\/infdis\/jiz133","article-title":"Opioids and infectious diseases: a converging public health crisis","volume":"220","author":"Schwetz","year":"2019","journal-title":"J. Infect. Dis."},{"key":"2025030417510901000_r6","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.10657","article-title":"Opioid injection in rural areas of the United States: a potential obstacle to ending the HIV epidemic","author":"Lerner","year":"2019","journal-title":"JAMA"},{"key":"2025030417510901000_r7","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.1182\/blood-2008-10-182709","article-title":"Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control","volume":"113","author":"Ferre","year":"2009","journal-title":"Blood"},{"key":"2025030417510901000_r8","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fimmu.2016.00134","article-title":"Suppression of HIV replication by CD8(+) regulatory T-cells in elite controllers","volume":"7","author":"Lu","year":"2016","journal-title":"Front. Immunol."},{"key":"2025030417510901000_r9","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nature11443","article-title":"Vaccine-induced CD8+ T cells control AIDS virus replication","volume":"491","author":"Mudd","year":"2012","journal-title":"Nature"},{"key":"2025030417510901000_r10","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1111\/bph.13750","article-title":"Opioids and the immune system - friend or foe","volume":"175","author":"Plein","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"2025030417510901000_r11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12865-015-0093-0","article-title":"Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis","volume":"16","author":"McLaughlin","year":"2015","journal-title":"BMC Immunol."},{"key":"2025030417510901000_r12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/sji.12538","article-title":"Fentanyl suppresses the survival of CD4+ T cells isolated from human umbilical cord blood through inhibition of IKKs-mediated NF-\u03baB activation","volume":"85","author":"Ma","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"2025030417510901000_r13","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.4049\/jimmunol.1300320","article-title":"Inhibition of NF-\u03baB by opioids in T cells","volume":"191","author":"B\u00f6rner","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417510901000_r14","doi-asserted-by":"crossref","first-page":"882","DOI":"10.4049\/jimmunol.0802763","article-title":"Mechanisms of opioid-mediated inhibition of human T cell receptor signaling","volume":"183","author":"B\u00f6rner","year":"2009","journal-title":"J. Immunol."},{"key":"2025030417510901000_r15","first-page":"427","article-title":"Hepatic Methionine-enkephalin may interfere with response to antiviral therapy in chronic hepatitis C","volume":"24","author":"Floreani","year":"2012","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"2025030417510901000_r16","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S0002-9440(10)63476-1","article-title":"Morphine enhances hepatitis C virus (HCV) replicon expression","volume":"163","author":"Li","year":"2003","journal-title":"Am. J. Pathol."},{"key":"2025030417510901000_r17","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1086\/340816","article-title":"Morphine promotes simian acquired immunodeficiency syndrome virus replication in monkey peripheral mononuclear cells: induction of CC chemokine receptor 5 expression for virus entry","volume":"185","author":"Suzuki","year":"2002","journal-title":"J. Infect. Dis."},{"key":"2025030417510901000_r18","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S0022-3565(25)11336-0","article-title":"Chronic morphine administration impairs cell-mediated immune responses in swine","volume":"260","author":"Molitor","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2025030417510901000_r19","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1111\/j.1572-0241.2007.01045.x","article-title":"Low-dose naltrexone therapy improves active Crohn\u2019s disease","volume":"102","author":"Smith","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"2025030417510901000_r20","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1007\/s10620-011-1653-7","article-title":"Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn\u2019s disease: a randomized placebo-controlled trial","volume":"56","author":"Smith","year":"2011","journal-title":"Dig. Dis. Sci."},{"key":"2025030417510901000_r21","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1177\/1352458510366857","article-title":"The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial","volume":"16","author":"Sharafaddinzadeh","year":"2010","journal-title":"Mult. Scler."},{"key":"2025030417510901000_r22","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1001\/archneur.57.8.1178","article-title":"\u03b2-endorphin concentrations in peripheral blood mononuclear cells of patients with multiple sclerosis: effects of treatment with interferon \u03b2","volume":"57","author":"Gironi","year":"2000","journal-title":"Arch. Neurol."},{"key":"2025030417510901000_r23","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1177\/1352458508095828","article-title":"A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis","volume":"14","author":"Gironi","year":"2008","journal-title":"Mult. Scler."},{"key":"2025030417510901000_r24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/ana.22006","article-title":"Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis","volume":"68","author":"Cree","year":"2010","journal-title":"Ann. Neurol."},{"key":"2025030417510901000_r25","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1093\/cid\/ciy809","article-title":"Long-acting opioid use and the risk of serious infections: a retrospective cohort study","volume":"68","author":"Wiese","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"2025030417510901000_r26","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/art.39462","article-title":"Opioid analgesics and the risk of serious infections among patients with rheumatoid arthritis: a self-controlled case series study","volume":"68","author":"Wiese","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"2025030417510901000_r27","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1111\/j.1532-5415.2011.03586.x","article-title":"Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study","volume":"59","author":"Dublin","year":"2011","journal-title":"J. Am. Geriatr. Soc."},{"key":"2025030417510901000_r28","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.canlet.2013.10.029","article-title":"Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK)","volume":"344","author":"Li","year":"2014","journal-title":"Cancer Lett."},{"key":"2025030417510901000_r29","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.intimp.2018.09.040","article-title":"Rules to activate CD8+T cells through regulating subunits of opioid receptors by methionine enkephalin (MENK)","volume":"65","author":"Jiao","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"2025030417510901000_r30","doi-asserted-by":"crossref","first-page":"e15375","DOI":"10.1097\/MD.0000000000015375","article-title":"Effects of systemic and neuraxial morphine on the immune system","volume":"98","author":"Chen","year":"2019","journal-title":"Medicine (Baltimore)"},{"key":"2025030417510901000_r31","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1053\/j.gastro.2013.09.020","article-title":"Endogenous regulation of visceral pain via production of opioids by colitogenic CD4(+) T cells in mice","volume":"146","author":"Bou\u00e9","year":"2014","journal-title":"Gastroenterology"},{"key":"2025030417510901000_r32","first-page":"278","article-title":"Immune cell-derived opioids protect against neuropathic pain in mice. [Published erratum appears in 2009 J. Clin. Invest. 119: 1051.]","volume":"119","author":"Labuz","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2025030417510901000_r33","doi-asserted-by":"crossref","first-page":"4350","DOI":"10.1523\/JNEUROSCI.4349-05.2006","article-title":"Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain","volume":"26","author":"Labuz","year":"2006","journal-title":"J. Neurosci."},{"key":"2025030417510901000_r34","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev.ne.07.030184.001255","article-title":"Endogenous opioids: biology and function","volume":"7","author":"Akil","year":"1984","journal-title":"Annu. Rev. Neurosci."},{"key":"2025030417510901000_r35","first-page":"132","article-title":"Opioid peptides","volume":"21","author":"Froehlich","year":"1997","journal-title":"Alcohol Health Res. World"},{"key":"2025030417510901000_r36","doi-asserted-by":"crossref","first-page":"249","DOI":"10.36076\/ppj.2011\/14\/249","article-title":"Peripherally acting opioids and clinical implications for pain control","volume":"14","author":"Sehgal","year":"2011","journal-title":"Pain Physician"},{"key":"2025030417510901000_r37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1743-3150.2004.00554.x","article-title":"Function of opioids in the enteric nervous system","volume":"16","author":"Wood","year":"2004","journal-title":"Neurogastroenterol. Motil."},{"key":"2025030417510901000_r38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.coph.2008.12.009","article-title":"Peripheral mechanisms of opioid analgesia","volume":"9","author":"Stein","year":"2009","journal-title":"Curr. Opin. Pharmacol."},{"key":"2025030417510901000_r39","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/nm908","article-title":"Attacking pain at its source: new perspectives on opioids","volume":"9","author":"Stein","year":"2003","journal-title":"Nat. Med."},{"key":"2025030417510901000_r40","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1128\/CDLI.7.5.719-723.2000","article-title":"Detection and function of opioid receptors on cells from the immune system","volume":"7","author":"Bidlack","year":"2000","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"2025030417510901000_r41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0165-5728(97)00221-X","article-title":"Opiate binding sites in the cellular immune system: expression and regulation","volume":"83","author":"Madden","year":"1998","journal-title":"J. Neuroimmunol."},{"key":"2025030417510901000_r42","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ejphar.2003.10.033","article-title":"Heterodimerization and cross-desensitization between the \u03bc-opioid receptor and the chemokine CCR5 receptor","volume":"483","author":"Chen","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"2025030417510901000_r43","doi-asserted-by":"crossref","first-page":"970","DOI":"10.3389\/fmicb.2016.00970","article-title":"Opioids and viral infections: a double-edged sword","volume":"7","author":"Tahamtan","year":"2016","journal-title":"Front. Microbiol."},{"key":"2025030417510901000_r44","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1186\/s12879-018-3408-y","article-title":"Rising rates of injection drug use associated infective endocarditis in Virginia with missed opportunities for addiction treatment referral: a retrospective cohort study","volume":"18","author":"Gray","year":"2018","journal-title":"BMC Infect. Dis."},{"key":"2025030417510901000_r45","doi-asserted-by":"crossref","first-page":"e0208410","DOI":"10.1371\/journal.pone.0208410","article-title":"Establishing trust in HIV\/HCV research among people who inject drugs (PWID): insights from empirical research","volume":"13","author":"Abadie","year":"2018","journal-title":"PLoS One"},{"key":"2025030417510901000_r46","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.drugalcdep.2017.09.030","article-title":"Rural and urban comparisons of polysubstance use profiles and associated injection behaviors among people who inject drugs in Puerto Rico","volume":"181","author":"Hautala","year":"2017","journal-title":"Drug Alcohol Depend."},{"key":"2025030417510901000_r47","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1747-597X-10-3","article-title":"The SALOME study: recruitment experiences in a clinical trial offering injectable diacetylmorphine and hydromorphone for opioid dependency","volume":"10","author":"Oviedo-Joekes","year":"2015","journal-title":"Subst. Abuse Treat. Prev. Policy"},{"key":"2025030417510901000_r48","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1176\/appi.ps.201300235","article-title":"Medication-assisted treatment with methadone: assessing the evidence","volume":"65","author":"Fullerton","year":"2014","journal-title":"Psychiatr. Serv."},{"key":"2025030417510901000_r49","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/HRP.0000000000000075","article-title":"Medication-assisted treatment of opioid use disorder: review of the evidence and future directions","volume":"23","author":"Connery","year":"2015","journal-title":"Harv. Rev. Psychiatry"},{"key":"2025030417510901000_r50","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0025-6196(11)60750-7","article-title":"Opioid metabolism","volume":"84","author":"Smith","year":"2009","journal-title":"Mayo Clin. Proc."},{"key":"2025030417510901000_r51","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S0026-895X(25)09932-8","article-title":"Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors","volume":"45","author":"Raynor","year":"1994","journal-title":"Mol. Pharmacol."},{"key":"2025030417510901000_r52","first-page":"83","article-title":"Molecular biology of opioid receptors","volume":"161","author":"Raynor","year":"1996","journal-title":"NIDA Res. Monogr."},{"key":"2025030417510901000_r53","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1161\/01.STR.0000072512.30658.E7","article-title":"Neuroprotective \u03ba-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats","volume":"34","author":"Goyagi","year":"2003","journal-title":"Stroke"},{"key":"2025030417510901000_r54","doi-asserted-by":"crossref","first-page":"e71024","DOI":"10.1371\/journal.pone.0071024","article-title":"The N-terminally truncated \u03bc3 and \u03bc3-like opioid receptors are transcribed from a novel promoter upstream of exon 2 in the human OPRM1 gene","volume":"8","author":"Andersen","year":"2013","journal-title":"PLoS One"},{"key":"2025030417510901000_r55","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-\u0394 \u0394 C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2025030417510901000_r56","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction","volume":"13","author":"Ye","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"2025030417510901000_r57","doi-asserted-by":"crossref","first-page":"D1144","DOI":"10.1093\/nar\/gkr1013","article-title":"PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update","volume":"40","author":"Wang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2025030417510901000_r58","first-page":"1","volume-title":"Federal Guidelines for Opioid Treatment Programs.","author":"Substance Abuse and Mental Health Services Administration","year":"2015"},{"key":"2025030417510901000_r59","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1073\/pnas.1321405111","article-title":"Automatic Classification of Cellular Expression by Nonlinear Stochastic Embedding (ACCENSE)","volume":"111","author":"Shekhar","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417510901000_r60","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1084\/jem.186.9.1407","article-title":"Phenotypic and functional separation of memory and effector human CD8+ T cells","volume":"186","author":"Hamann","year":"1997","journal-title":"J. Exp. Med."},{"key":"2025030417510901000_r61","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/cyto.a.22351","article-title":"From \u201ctruly na\u00efve\u201d to \u201cexhausted senescent\u201d T cells: when markers predict functionality","volume":"85","author":"Larbi","year":"2014","journal-title":"Cytometry A"},{"key":"2025030417510901000_r62","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.3389\/fimmu.2018.02692","article-title":"Defining memory CD8 T cell","volume":"9","author":"Martin","year":"2018","journal-title":"Front. Immunol."},{"key":"2025030417510901000_r63","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1097\/ALN.0b013e318238bba6","article-title":"Molecular mechanisms of opioid receptor-dependent signaling and behavior","volume":"115","author":"Al-Hasani","year":"2011","journal-title":"Anesthesiology"},{"key":"2025030417510901000_r64","doi-asserted-by":"crossref","first-page":"8294","DOI":"10.1073\/pnas.93.16.8294","article-title":"Dual signal transduction through delta opioid receptors in a transfected human T-cell line","volume":"93","author":"Sharp","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417510901000_r65","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S0026-895X(25)09249-1","article-title":"Dual excitatory and inhibitory effects of opioids on intracellular calcium in neuroblastoma x glioma hybrid NG108-15 cells","volume":"42","author":"Jin","year":"1992","journal-title":"Mol. Pharmacol."},{"key":"2025030417510901000_r66","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/00031305.2018.1529624","article-title":"The p value requires context, not a threshold","volume":"73","author":"Betensky","year":"2019","journal-title":"Am. Stat."},{"key":"2025030417510901000_r67","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1080\/00031305.2018.1537889","article-title":"Assessing statistical results: magnitude, precision, and model uncertainty","volume":"73","author":"Anderson","year":"2019","journal-title":"Am. Stat."},{"key":"2025030417510901000_r68","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/d41586-019-00874-8","article-title":"It\u2019s time to talk about ditching statistical significance","volume":"567","year":"2019","journal-title":"Nature"},{"key":"2025030417510901000_r69","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.4049\/jimmunol.175.9.5895","article-title":"Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets","volume":"175","author":"Willinger","year":"2005","journal-title":"J. Immunol."},{"key":"2025030417510901000_r70","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1146\/annurev.immunol.22.012703.104702","article-title":"Central memory and effector memory T cell subsets: function, generation, and maintenance","volume":"22","author":"Sallusto","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"2025030417510901000_r71","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1186\/1743-422X-7-310","article-title":"PD-1 expression on peripheral CD8+ TEM\/TEMRA subsets closely correlated with HCV viral load in chronic hepatitis C patients","volume":"7","author":"Shen","year":"2010","journal-title":"Virol. J."},{"key":"2025030417510901000_r72","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1182\/blood-2008-02-135715","article-title":"PI3Kgamma (PI3Kgamma) is essential for efficient induction of CXCR3 on activated T cells","volume":"112","author":"Barbi","year":"2008","journal-title":"Blood"},{"key":"2025030417510901000_r73","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1189\/jlb.0305167","article-title":"Morphine inhibits CD8+ T cell-mediated, noncytolytic, anti-HIV activity in latently infected immune cells","volume":"78","author":"Wang","year":"2005","journal-title":"J. Leukoc. Biol."},{"key":"2025030417510901000_r74","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nn.4571","article-title":"PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1. [Published erratum appears in 2019 Nat. Neurosci. 22: 503.]","volume":"20","author":"Chen","year":"2017","journal-title":"Nat. Neurosci."},{"key":"2025030417510901000_r75","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1111\/j.1476-5381.2011.01335.x","article-title":"Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human","volume":"164","author":"Morgan","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"2025030417510901000_r76","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1124\/jpet.117.240622","article-title":"Arresting the development of addiction: the role of \u03b2-arrestin 2 in drug Abuse","volume":"361","author":"Porter-Stransky","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2025030417510901000_r77","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1038\/nchembio.2490","article-title":"Discovery of new GPCR ligands to illuminate new biology","volume":"13","author":"Roth","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"2025030417510901000_r78","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/nchembio.2527","article-title":"Structure-inspired design of \u03b2-arrestin-biased ligands for aminergic GPCRs","volume":"14","author":"McCorvy","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"2025030417510901000_r79","doi-asserted-by":"crossref","first-page":"8969","DOI":"10.1074\/jbc.R115.713313","article-title":"The \u03b2-arrestins: multifunctional regulators of G protein-coupled receptors","volume":"291","author":"Smith","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2025030417510901000_r80","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41594-017-0011-7","article-title":"Structure and dynamics of GPCR signaling complexes","volume":"25","author":"Hilger","year":"2018","journal-title":"Nat. Struct. Mol. Biol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/204\/5\/1188\/61882104\/ji1900862.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/204\/5\/1188\/61882104\/ji1900862.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T18:05:40Z","timestamp":1741111540000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/204\/5\/1188\/7943854"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,1]]},"references-count":80,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1900862","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,3]]},"published":{"date-parts":[[2020,3,1]]}}}