The observation of the immunomodulatory effects of opioid drugs opened the discussion about possible mechanisms of action and led researchers to consider the presence of opioid receptors (OR) in cells of the immune system. To date, numerous studies analyzing the expression of OR subtypes in animal and human immune cells have been performed. Some of them confirmed the expression of OR at both the mRNA and protein level, while others did not detect the receptor mRNA either. Although this topic remains controversial, further studies are constantly being published. The most recent articles suggested that the expression level of OR in human peripheral blood lymphocytes could help to evaluate the success of methadone maintenance therapy in former opioid addicts, or could serve as a biomarker for chronic pain diagnosis. However, the applicability of these findings to clinical practice needs to be verified by further investigations.

Department of Cell Biology Faculty of Science Charles University 12843 Prague Czech Republic

Department of Nanotoxicology and Molecular Epidemiology Institute of Experimental Medicine of the Czech Academy of Sciences 14220 Prague Czech Republic

Laboratory of Biomathematics Institute of Physiology of the Czech Academy of Sciences 14220 Prague Czech Republic

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Preston K.L. Drug abstinence effects: Opioids. Br. J. Addict. 1991;86:1641–1646. doi: 10.1111/j.1360-0443.1991.tb01759.x. PubMed DOI

Darcq E., Kieffer B.L. Opioid receptors: Drivers to addiction? Nat. Rev. Neurosci. 2018;19:499–514. doi: 10.1038/s41583-018-0028-x. PubMed DOI

Listos J., Lupina M., Talarek S., Mazur A., Orzelska-Gorka J., Kotlinska J. The mechanisms involved in morphine addiction: An overview. Int. J. Mol. Sci. 2019;20:4302. doi: 10.3390/ijms20174302. PubMed DOI PMC

Kreek M.J. Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann. N. Y. Acad. Sci. 2000;909:186–216. doi: 10.1111/j.1749-6632.2000.tb06683.x. PubMed DOI

Ball J.C., Ross A. The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome. 1st ed. Springer; New York, NY, USA: 1991.

Connock M., Juarez-Garcia A., Jowett S., Frew E., Liu Z., Taylor R.J., Fry-Smith A., Day E., Lintzeris N., Roberts T., et al. Methadone and buprenorphine for the management of opioid dependence: A systematic review and economic evaluation. Health Technol. Assess. 2007;11:1–171. doi: 10.3310/hta11090. PubMed DOI

Whelan P.J., Remski K. Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds. J. Neurosci. Rural Pract. 2012;3:45–50. doi: 10.4103/0976-3147.91934. PubMed DOI PMC

Vadivelu N., Kai A.M., Kodumudi V., Sramcik J., Kaye A.D. The opioid crisis: A comprehensive overview. Curr. Pain Headache Rep. 2018;22:16. doi: 10.1007/s11916-018-0670-z. PubMed DOI

Waldhoer M., Bartlett S.E., Whistler J.L. Opioid receptors. Annu. Rev. Biochem. 2004;73:953–990. doi: 10.1146/annurev.biochem.73.011303.073940. PubMed DOI

Shang Y., Filizola M. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling. Eur. J. Pharmacol. 2015;763:206–213. doi: 10.1016/j.ejphar.2015.05.012. PubMed DOI PMC

Erbs E., Faget L., Scherrer G., Matifas A., Filliol D., Vonesch J.L., Koch M., Kessler P., Hentsch D., Birling M.C., et al. A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct Funct. 2015;220:677–702. doi: 10.1007/s00429-014-0717-9. PubMed DOI PMC

Ozawa A., Brunori G., Mercatelli D., Wu J., Cippitelli A., Zou B., Xie X.S., Williams M., Zaveri N.T., Low S., et al. Knock-in mice with NOP-eGFP receptors identify receptor cellular and regional localization. J. Neurosci. 2015;35:11682–11693. doi: 10.1523/JNEUROSCI.5122-14.2015. PubMed DOI PMC

Stein C., Zöllner C. Opioids and sensory nerves. Handb. Exp. Pharmacol. 2009;194:495–518. PubMed

Galligan J.J., Sternini C. Insights into the role of opioid receptors in the GI tract: Experimental evidence and therapeutic relevance. Handb. Exp. Pharmacol. 2017;239:363–378. PubMed PMC

Peng J., Sarkar S., Chang S.L. Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Depend. 2012;124:223–228. doi: 10.1016/j.drugalcdep.2012.01.013. PubMed DOI PMC

Connor M., Christie M.D. Opioid receptor signalling mechanisms. Clin. Exp. Pharmacol. Physiol. 1999;26:493–499. doi: 10.1046/j.1440-1681.1999.03049.x. PubMed DOI

Law P.Y., Wong Y.H., Loh H.H. Molecular mechanisms and regulation of opioid receptor signaling. Annu. Rev. Pharmacol. Toxicol. 2000;40:389–430. doi: 10.1146/annurev.pharmtox.40.1.389. PubMed DOI

Law P.Y., Loh H.H., Wei L.N. Insights into the receptor transcription and signaling: Implications in opioid tolerance and dependence. Neuropharmacology. 2004;47(Suppl. S1):300–311. doi: 10.1016/j.neuropharm.2004.07.013. PubMed DOI

Stein C. Opioid Receptors. Annu. Rev. Med. 2016;67:433–451. doi: 10.1146/annurev-med-062613-093100. PubMed DOI

Feng Y., He X., Yang Y., Chao D., Lazarus L.H., Xia Y. Current research on opioid receptor function. Curr. Drug Targets. 2012;13:230–246. doi: 10.2174/138945012799201612. PubMed DOI PMC

Le Merrer J., Becker J.A., Befort K., Kieffer B.L. Reward processing by the opioid system in the brain. Physiol. Rev. 2009;89:1379–1412. doi: 10.1152/physrev.00005.2009. PubMed DOI PMC

Khan M.S., Boileau I., Kolla N., Mizrahi R. A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: Relevance to schizophrenia. Transl. Psychiatry. 2018;8:38. doi: 10.1038/s41398-017-0080-8. PubMed DOI PMC

Pellissier L.P., Pujol C.N., Becker J.A.J., Le Merrer J. Delta opioid receptors: Learning and motivation. Handb. Exp. Pharmacol. 2018;247:227–260. PubMed

Van Steenbergen H., Eikemo M., Leknes S. The role of the opioid system in decision making and cognitive control: A review. Cogn. Affect. Behav. Neurosci. 2019;19:435–458. doi: 10.3758/s13415-019-00710-6. PubMed DOI PMC

Raehal K.M., Bohn L.M. The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics. Neuropharmacology. 2011;60:58–65. doi: 10.1016/j.neuropharm.2010.08.003. PubMed DOI PMC

Lutz P.E., Kieffer B.L. Opioid receptors: Distinct roles in mood disorders. Trends Neurosci. 2012;36:195–206. doi: 10.1016/j.tins.2012.11.002. PubMed DOI PMC

Lutz P.E., Kieffer B.L. The multiple facets of opioid receptor function: Implications for addiction. Curr. Opin. Neurobiol. 2013;23:473–479. doi: 10.1016/j.conb.2013.02.005. PubMed DOI PMC

Nadal X., La Porta C., Andreea Bura S., Maldonado R. Involvement of the opioid and cannabinoid systems in pain control: New insights from knockout studies. Eur. J. Pharmacol. 2013;716:142–157. doi: 10.1016/j.ejphar.2013.01.077. PubMed DOI

Williams J.T., Ingram S.L., Henderson G., Chavkin C., von Zastrow M., Schulz S., Koch T., Evans C.J., Christie M.J. Regulation of μ-opioid receptors: Desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 2013;65:223–254. doi: 10.1124/pr.112.005942. PubMed DOI PMC

Varastehmoradi B., Wegener G., Sanchez C., Smith K.L. Opioid system modulation of cognitive affective bias: Implications for the treatment of mood disorders. Behav. Pharmacol. 2020;31:122–135. doi: 10.1097/FBP.0000000000000559. PubMed DOI

Avidor-Reiss T., Bayewitch M., Levy R., Matus-Leibovitch N., Nevo I., Vogel Z. Adenylylcyclase supersensitization in mu-opioid receptor-transfected Chinese hamster ovary cells following chronic opioid treatment. J. Biol. Chem. 1995;270:29732–29738. PubMed

Avidor-Reiss T., Nevo I., Levy R., Pfeuffer T., Vogel Z. Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gbetagamma. J. Biol. Chem. 1996;271:21309–21315. doi: 10.1074/jbc.271.35.21309. PubMed DOI

Ammer H., Christ T.E. Identitity of adenylyl cyclase isoform determines the G protein mediating chronic opioid-induced adenylyl cyclase supersensitivity. J. Neurochem. 2002;83:818–827. doi: 10.1046/j.1471-4159.2002.01188.x. PubMed DOI

Varga E.V., Rubenzik M.K., Stropova D., Sugiyama M., Grife V., Hruby V.J., Rice K.C., Roeske W.R., Yamamura H.I. Converging protein kinase pathways mediate adenylyl cyclase superactivation upon chronic delta-opioid agonist treatment. J. Pharmacol. Exp. Ther. 2003;306:109–115. doi: 10.1124/jpet.103.049643. PubMed DOI

Schallmach E., Steiner D., Vogel Z. Adenylyl cyclase type II activity is regulated by two different mechanisms: Implications for acute and chronic opioid exposure. Neuropharmacology. 2006;50:998–1005. doi: 10.1016/j.neuropharm.2006.01.004. PubMed DOI

Chan P., Lutfy K. Molecular changes in opioid addiction: The role of adenylyl cyclase and cAMP/PKA system. Prog. Mol. Biol. Transl. Sci. 2016;137:203–227. PubMed

Bourova L., Vosahlikova M., Kagan D., Dlouha K., Novotny J., Svoboda P. Long-term adaptation to high doses of morphine causes desensitization of μ-OR and δ-OR-stimulated G protein response in forebrain cortex but does not decrease the amount of G-protein alpha subunits. Med. Sci. Monit. 2010;16:BR260–BR270. PubMed

Ujcikova H., Dlouha K., Roubalova L., Vosahlikova M., Kagan D., Svoboda P. Up-regulation of adenylylcyclases I and II induced by long-term adaptation of rats to morphine fades away 20 days after morphine withdrawal. Biochim. Biophys. Acta. 2011;1810:1220–1229. doi: 10.1016/j.bbagen.2011.09.017. PubMed DOI

Ujcikova H., Eckhardt A., Kagan D., Roubalova L., Svoboda P. Proteomic analysis of post-nuclear supernatant fraction and percoll-purified membranes prepared from brain cortex of rats exposed to increasing doses of morphine. Proteome Sci. 2014;12:11. doi: 10.1186/1477-5956-12-11. PubMed DOI PMC

Ujcikova H., Vosahlikova M., Roubalova L., Svoboda P. Proteomic analysis of protein composition of rat forebrain cortex exposed to morphine for 10 days; comparison with animals exposed to morphine and subsequently nurtured for 20 days in the absence of this drug. J. Proteomics. 2016;145:11–23. doi: 10.1016/j.jprot.2016.02.019. PubMed DOI

Wybran J., Appelboom T., Famaey J.P., Govaerts A. Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J. Immunol. 1979;123:1068–1070. PubMed

Bryant H.U., Roudebush R.E. Suppressive effects of morphine pellet implants on in vivo parameters of immune function. J. Pharmacol. Exp. Ther. 1990;255:410–414. PubMed

Pacifici R., Minetti M., Zuccaro P., Pietraforte D. Morphine affects cytostatic activity of macrophages by the modulation of nitric oxide release. Int. J. Immunopharmacol. 1995;17:771–777. doi: 10.1016/0192-0561(95)00046-5. PubMed DOI

Sacerdote P., Manfredi B., Mantegazza P., Panerai A.E. Antinociceptive and immunosuppressive effects of opiate drugs: A structure-related activity study. Br. J. Pharmacol. 1997;121:834–840. doi: 10.1038/sj.bjp.0701138. PubMed DOI PMC

Gaveriaux-Ruff C., Matthes H.W., Peluso J., Kieffer B.L. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proc. Natl. Acad. Sci. USA. 1998;95:6326–6330. doi: 10.1073/pnas.95.11.6326. PubMed DOI PMC

Casellas A.M., Guardiola H., Renaud F.L. Inhibition by opioids of phagocytosis in peritoneal macrophages. Neuropeptides. 1991;18:35–40. doi: 10.1016/0143-4179(91)90161-B. PubMed DOI

Bussiere J.L., Adler M.W., Rogers T.J., Eisenstein T.K. Cytokine reversal of morphine-induced suppression of the antibody response. J. Pharmacol. Exp. Ther. 1993;264:591–597. PubMed

Eisenstein T.K., Meissler J.J., Jr., Rogers T.J., Geller E.B., Adler M.W. Mouse strain differences in immunosuppression by opioids in vitro. J. Pharmacol. Exp. Ther. 1995;275:1484–1489. PubMed

Lysle D.T., Coussons M.E., Watts V.J., Bennett E.H., Dykstra L.A. Morphine-induced alterations of immune status: Dose dependency, compartment specificity and antagonism by naltrexone. J. Pharmacol. Exp. Ther. 1993;265:1071–1078. PubMed

Roy S., Balasubramanian S., Sumandeep S., Charboneau R., Wang J., Melnyk D., Beilman G.J., Vatassery R., Barke R.A. Morphine directs T cells toward T(H2) differentiation. Surgery. 2001;130:304–309. doi: 10.1067/msy.2001.116033. PubMed DOI

Al-Hashimi M., Scott S.W.M., Thompson J.P., Lambert D.G. Opioids and immune modulation: More questions than answers. Br. J. Anaesth. 2013;111:80–88. doi: 10.1093/bja/aet153. PubMed DOI

Holan V., Zajicova A., Krulova M., Blahoutova V., Wilczek H. Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clin. Exp. Immunol. 2003;132:40–45. doi: 10.1046/j.1365-2249.2003.02103.x. PubMed DOI PMC

Zajicova A., Wilczek H., Holan V. The alterations of immunological reactivity in heroin addicts and their normalization in patients maintained on methadone. Folia Biol. (Praha) 2004;50:24–28. PubMed

Chan Y.Y., Yang S.N., Lin J.C., Chang J.L., Lin J.G., Lo W.Y. Inflammatory response in heroin addicts undergoing methadone replacement therapy. Psychiatry Res. 2015;226:230–234. doi: 10.1016/j.psychres.2014.12.053. PubMed DOI

Borner C., Lanciotti S., Koch T., Hollt V., Kraus J. μ opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J. Neuroimmunol. 2013;263:35–42. doi: 10.1016/j.jneuroim.2013.07.012. PubMed DOI

Kraus J. Expression and functions of μ-opioid receptors and cannabinoid receptors type 1 in T lymphocytes. Ann. N. Y. Acad. Sci. 2012;1261:1–6. doi: 10.1111/j.1749-6632.2012.06524.x. PubMed DOI

Liang X., Liu R., Chen C., Ji F., Li T. Opioid system modulates the immune function: A review. Transl. Perioper. Pain Med. 2016;1:5–13. PubMed PMC

Eisenstein T.K. The role of opioid receptors in immune system function. Front. Immunol. 2019;10:2904. doi: 10.3389/fimmu.2019.02904. PubMed DOI PMC

Carr D.J., Bost K.L., Blalock J.E. The production of antibodies which recognize opiate receptors on murine leukocytes. Life Sci. 1988;42:2615–2624. doi: 10.1016/0024-3205(88)90331-1. PubMed DOI

Miller B. Delta opioid receptor expression is induced by concanavalin A in CD4+ T cells. J. Immunol. 1996;157:5324–5328. PubMed

Bidlack J.M., Abraham M.K. Mitogen-induced activation of mouse T cells increases kappa opioid receptor expression. Adv. Exp. Med. Biol. 2001;493:103–110. PubMed

Cechova K., Hlouskova M., Javorkova E., Roubalova L., Ujcikova H., Holan V., Svoboda P. Up-regulation of μ-, δ- and κ-opioid receptors in concanavalin A-stimulated rat spleen lymphocytes. J. Neuroimmunol. 2018;321:12–23. doi: 10.1016/j.jneuroim.2018.05.008. PubMed DOI

Sibinga N.E., Goldstein A. Opioid peptides and opioid receptors in cells of the immune system. Annu. Rev. Immunol. 1988;6:219–249. doi: 10.1146/annurev.iy.06.040188.001251. PubMed DOI

Bidlack J.M., Khimich M., Parkhill A.L., Sumagin S., Sun B., Tipton C.M. Opioid receptors and signaling on cells from the immune system. J. Neuroimmune Pharmacol. 2006;1:260–269. doi: 10.1007/s11481-006-9026-2. PubMed DOI

Sharp B.M. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behav. Immun. 2006;20:9–14. doi: 10.1016/j.bbi.2005.02.002. PubMed DOI

Nguyen K., Miller B.C. CD28 costimulation induces delta opioid receptor expression during anti-CD3 activation of T cells. J. Immunol. 2002;168:4440–4445. doi: 10.4049/jimmunol.168.9.4440. PubMed DOI

Zhang L., Belkowski J.S., Briscoe T., Rogers T.J. Regulation of mu opioid receptor expression in developing T cells. J. Neuroimmune Pharmacol. 2012;7:835–842. doi: 10.1007/s11481-012-9396-6. PubMed DOI PMC

Williams J.P., Thompson J.P., McDonald J., Barnes T.A., Cote T., Rowbotham D.J., Lambert D.G. Human peripheral blood mononuclear cells express nociceptin/orphanin FQ, but not mu, delta, or kappa opioid receptors. Anesth. Analg. 2007;105:998–1005. doi: 10.1213/01.ane.0000278865.11991.9d. PubMed DOI

Borner C., Stumm R., Hollt V., Kraus J. Comparative analysis of mu-opioid receptor expression in immune and neuronal cells. J. Neuroimmunol. 2007;188:56–63. doi: 10.1016/j.jneuroim.2007.05.007. PubMed DOI

Borner C., Kraus J., Bedini A., Schraven B., Hollt V. T-cell receptor/CD28-mediated activation of human T lymphocytes induces expression of functional mu-opioid receptors. Mol. Pharmacol. 2008;74:496–504. doi: 10.1124/mol.108.046029. PubMed DOI

Peluso J., LaForge K.S., Matthes H.W., Kreek M.J., Kieffer B.L., Gavériaux-Ruff C. Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells. J. Neuroimmunol. 1998;81:184–192. doi: 10.1016/S0165-5728(97)00178-1. PubMed DOI

Suzuki S., Miyagi T., Chuang T.K., Chuang L.F., Doi R.H., Chuang R.Y. Morphine upregulates mu opioid receptors of human and monkey lymphocytes. Biochem. Biophys. Res. Commun. 2000;279:621–628. doi: 10.1006/bbrc.2000.4006. PubMed DOI

Suzuki S., Chuang L.F., Doi R.H., Bidlack J.M., Chuang R.Y. Kappa-opioid receptors on lymphocytes of a human lymphocytic cell line: Morphine-induced up-regulation as evidenced by competitive RT-PCR and indirect immunofluorescence. Int. Immunopharmacol. 2001;1:1733–1742. doi: 10.1016/S1567-5769(01)00083-2. PubMed DOI

Sedqi M., Roy S., Ramakrishnan S., Elde R., Loh H.H. Complementary DNA cloning of a mu-opioid receptor from rat peritoneal macrophages. Biochem. Biophys. Res. Commun. 1995;209:563–574. doi: 10.1006/bbrc.1995.1538. PubMed DOI

Chuang T.K., Killam Jr K.F., Chuang L.F., Kung H.F., Sheng W.S., Chao C.C., Yu L., Chuang R.Y. Mu opioid receptor gene expression in immune cells. Biochem. Biophys. Res. Commun. 1995;216:922–930. doi: 10.1006/bbrc.1995.2709. PubMed DOI

Toskulkao T., Pornchai R., Akkarapatumwong V., Vatanatunyakum S., Govitrapong P. Alteration of lymphocyte opioid receptors in methadone maintenance subjects. Neurochem. Int. 2010;56:285–290. doi: 10.1016/j.neuint.2009.10.013. PubMed DOI

Campana G., Sarti D., Spampinato S., Raffaeli W. Long-term intrathecal morphine and bupivacaine upregulate MOR gene expression in lymphocytes. Int. Immunopharmacol. 2010;10:1149–1152. doi: 10.1016/j.intimp.2010.06.016. PubMed DOI

Raffaeli W., Malafoglia V., Bonci A., Tenti M., Ilari S., Gremigni P., Iannuccelli C., Gioia C., Di Franco M., Mollace V., et al. Identification of MOR-positive B cell as possible innovative biomarker (Mu lympho-marker) for chronic pain diagnosis in patients with fibromyalgia and osteoarthritis diseases. Int. J. Mol. Sci. 2020;21:1499. doi: 10.3390/ijms21041499. PubMed DOI PMC

Maher D.P., Walia D., Heller N.M. Suppression of human natural killer cells by different classes of opioids. Anesth. Analg. 2019;128:1013–1021. doi: 10.1213/ANE.0000000000004058. PubMed DOI PMC

Gaveriaux C., Peluso J., Simonin F., Laforet J., Kieffer B. Identification of kappa- and delta-opioid receptor transcripts in immune cells. FEBS Lett. 1995;369:272–276. doi: 10.1016/0014-5793(95)00766-3. PubMed DOI

Sharp B.M., Shahabi N., McKean D., Li M.D., McAllen K. Detection of basal levels and induction of delta opioid receptor mRNA in murine splenocytes. J. Neuroimmunol. 1997;78:198–202. doi: 10.1016/S0165-5728(97)00101-X. PubMed DOI

Li M.D., McAllen K., Sharp B.M. Regulation of delta opioid receptor expression by anti-CD3-epsilon, PMA, and ionomycin in murine splenocytes and T cells. J. Leukoc. Biol. 1999;65:707–714. doi: 10.1002/jlb.65.5.707. PubMed DOI

Chuang L.F., Chuang T.K., Killam Jr K.F., Chuang A.J., Kung H.F., Yu L., Chuang R.Y. Delta opioid receptor gene expression in lymphocytes. Biochem. Biophys. Res. Commun. 1994;202:1291–1299. doi: 10.1006/bbrc.1994.2071. PubMed DOI

Wick M.J., Minnerath S.R., Roy S., Ramakrishnan S., Loh H.H. Differential expression of opioid receptor genes in human lymphoid cell lines and peripheral blood lymphocytes. J. Neuroimmunol. 1996;64:29–36. doi: 10.1016/0165-5728(95)00144-1. PubMed DOI

Belkowski S.M., Zhu J., Liu-Chen L.Y., Eisenstein T.K., Adler M.W., Rogers T.J. Sequence of kappa-opioid receptor cDNA in the R1.1 thymoma cell line. J. Neuroimmunol. 1995;62:113–117. doi: 10.1016/0165-5728(95)00116-J. PubMed DOI

Alicea C., Belkowski S.M., Sliker J.K., Zhu J., Liu-Chen L.Y., Eisenstein T.K., Adler M.W., Rogers T.J. Characterization of kappa-opioid receptor transcripts expressed by T cells and macrophages. J. Neuroimmunol. 1998;91:55–62. doi: 10.1016/S0165-5728(98)00151-9. PubMed DOI

Ignatowski T.A., Bidlack J.M. Differential kappa-opioid receptor expression on mouse lymphocytes at varying stages of maturation and on mouse macrophages after selective elicitation. J. Pharmacol. Exp. Ther. 1999;290:863–870. PubMed

Karaji A.G., Khansari N., Ansary B., Dehpour A.R. Detection of opioid receptors on murine lymphocytes by indirect immunofluorescence: Mature normal and tumor bearing mice lymphocytes. Int. Immunopharmacol. 2005;5:1019–1027. doi: 10.1016/j.intimp.2005.01.012. PubMed DOI

Belkowski S.M., Zhu J., Liu-Chen L.Y., Eisenstein T.K., Adler M.W., Rogers T.J. Detection of kappa-opioid receptor mRNA in immature T cells. Adv. Exp. Med. Biol. 1995;373:11–16. PubMed

Ignatowski T.A., Bidlack J.M. Detection of kappa opioid receptors on mouse thymocyte phenotypic subpopulations as assessed by flow cytometry. J. Pharmacol. Exp. Ther. 1998;284:298–306. PubMed

Chuang L.F., Chuang T.K., Killam Jr K.F., Qiu Q., Wang X.R., Lin J.J., Kung H.F., Sheng W., Chao C., Yu L., et al. Expression of kappa opioid receptors in human and monkey lymphocytes. Biochem. Biophys. Res. Commun. 1995;209:1003–1010. doi: 10.1006/bbrc.1995.1597. PubMed DOI

Shahkarami K., Vousooghi N., Golab F., Mohsenzadeh A., Baharvand P., Sadat-Shirazi M.S., Babhadi-Ashar N., Shakeri A., Zarrindast M.R. Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: Possible role as a biomarker in severe opioid use disorder. Drug Alcohol Depend. 2019;205:107638. doi: 10.1016/j.drugalcdep.2019.107638. PubMed DOI

Gunji N., Nagashima M., Asano G., Yoshino S. Expression of kappa-opioid receptor mRNA in human peripheral blood lymphocytes and the relationship between its expression and the inflammatory changes in rheumatoid arthritis. Rheumatol. Int. 2000;19:95–100. doi: 10.1007/s002960050110. PubMed DOI

Zhang L., Stüber F., Lippuner C., Schiff M., Stamer U.M. ERK and p38 contribute to the regulation of nociceptin and the nociceptin receptor in human peripheral blood leukocytes. Mol. Pain. 2019;15:1744806919828921. doi: 10.1177/1744806919828921. PubMed DOI PMC

Serhan C.N., Fierro I.M., Chiang N., Pouliot M. Cutting edge: Nociceptin stimulates neutrophil chemotaxis and recruitment: Inhibition by aspirin-triggered-15-epi-lipoxin A4. J. Immunol. 2001;166:3650–3654. doi: 10.4049/jimmunol.166.6.3650. PubMed DOI

Mazzone A., Mazzucchelli I., Fossati G., Gritti D., Fea M., Ricevuti G. Granulocyte defects and opioid receptors in chronic exposure to heroin or methadone in humans. Int. J. Immunopharmacol. 1994;16:959–967. doi: 10.1016/0192-0561(94)90049-3. PubMed DOI

Caldiroli E., Leoni O., Cattaneo S., Rasini E., Marino V., Tosetto C., Mazzone A., Fietta A.M., Lecchini S., Frigo G.M. Neutrophil function and opioid receptor expression on leucocytes during chronic naltrexone treatment in humans. Pharmacol. Res. 1999;40:153–158. doi: 10.1006/phrs.1999.0488. PubMed DOI

Beck M., Mirmohammadsadegh A., Franz B., Blanke J., Hengge U.R. Opioid receptors on white blood cells: Effect of HIV infection and methadone treatment. Pain. 2002;98:187–194. doi: 10.1016/S0304-3959(02)00044-1. PubMed DOI

Vousooghi N., Goodarzi A., Roushanzamir F., Sedaghati T., Zarrindast M.R., Noori-Daloii M.R. Expression of mu opioid receptor splice variants mRNA in human blood lymphocytes: A peripheral marker for opioid addiction studies. Int. Immunopharmacol. 2009;9:1016–1020. doi: 10.1016/j.intimp.2009.02.010. PubMed DOI

Shen H., Sprott H., Aeschlimann A., Gay R.E., Michel B.A., Gay S., Sprott H. Analgesic action of acetaminophen in symptomatic osteoarthritis of the knee. Rheumatology. 2006;45:765–770. doi: 10.1093/rheumatology/kei253. PubMed DOI

Malafoglia V., Celi M., Muscoli C., Ilari S., Lauro F., Giancotti L.A., Morabito C., Feola M., Tarantino U., Raffaeli W. Lymphocyte opioid receptors as innovative biomarkers of osteoarthritic pain, for the assessment and risk management of opioid tailored therapy, before hip surgery, to prevent chronic pain and opioid tolerance/addiction development: OpMarkArt (Opioids-Markers-Arthroprosthesis) study protocol for a randomized controlled trial. Trials. 2017;18:605. PubMed PMC

Dothel G., Chang L., Shih W., Barbaro M.R., Cremon C., Stanghellini V., De Ponti F., Mayer E.A., Barbara G., Sternini C. µ-opioid receptor, β-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients. Neurogastroenterol. Motil. 2019;31:e13688. doi: 10.1111/nmo.13688. PubMed DOI PMC

Stamer U.M., Book M., Comos C., Zhang L., Nauck F., Stuber F. Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients. Br. J. Anaesth. 2011;106:566–572. doi: 10.1093/bja/aer007. PubMed DOI

Gavioli E.C., de Medeiros I.U., Monteiro M.C., Calo G., Romao P.R. Nociceptin/orphanin FQ-NOP receptor system in inflammatory and immune-mediated diseases. Vitam. Horm. 2015;97:241–266. PubMed

Steidl U., Bork S., Schaub S., Selbach O., Seres J., Aivado M., Schroeder T., Rohr U.P., Fenk R., Kliszewski S., et al. Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators. Blood. 2004;104:81–88. doi: 10.1182/blood-2004-01-0373. PubMed DOI

Liu J., Chen W., Meng J., Lu C., Wang E., Shan F. Induction on differentiation and modulation of bone marrow progenitor of dendritic cell by methionine enkephalin (MENK) Cancer Immunol. Immunother. 2012;61:1699–1711. doi: 10.1007/s00262-012-1221-9. PubMed DOI PMC

Abdyazdani N., Nourazarian A., Nozad Charoudeh H., Kazemi M., Feizy N., Akbarzade M., Mehdizadeh A., Rezaie J., Rahbarghazi R. The role of morphine on rat neural stem cells viability, neuro-angiogenesis and neuro-steroidgenesis properties. Neurosci. Lett. 2017;636:205–212. doi: 10.1016/j.neulet.2016.11.025. PubMed DOI

Willner D., Cohen-Yeshurun A., Avidan A., Ozersky V., Shohami E., Leker R.R. Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via mu receptors. PLoS ONE. 2014;9:e103043. doi: 10.1371/journal.pone.0103043. PubMed DOI PMC

Dholakiya S.L., Aliberti A., Barile F.A. Morphine sulfate concomitantly decreases neuronal differentiation and opioid receptor expression in mouse embryonic stem cells. Toxicol. Lett. 2016;247:45–55. doi: 10.1016/j.toxlet.2016.01.010. PubMed DOI

Sasaki M., Abe R., Fujita Y., Ando S., Inokuma D., Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J. Immunol. 2008;180:2581–2587. doi: 10.4049/jimmunol.180.4.2581. PubMed DOI

Holan V., Hermankova B., Bohacova P., Kossl J., Chudickova M., Hajkova M., Krulova M., Zajicova A., Javorkova E. Distinct immunoregulatory mechanisms in mesenchymal stem cells: Role of the cytokine environment. Stem Cell Rev. Rep. 2016;12:654–663. doi: 10.1007/s12015-016-9688-y. PubMed DOI

Holan V., Cechova K., Zajicova A., Kossl J., Hermankova B., Bohacova P., Hajkova M., Krulova M., Svoboda P., Javorkova E. The impact of morphine on the characteristics and function properties of human mesenchymal stem cells. Stem Cell Rev. Rep. 2018;14:801–811. doi: 10.1007/s12015-018-9843-8. PubMed DOI

Holan V., Echalar B., Palacka K., Kossl J., Bohacova P., Krulova M., Brejchova J., Svoboda P., Zajicova A. The altered migration and distribution of systemically administered mesenchymal stem cells in morphine-treated recipients. Unpublished. PubMed

Rook J.M., McCarson K.E. Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochem. Pharmacol. 2007;74:752–757. doi: 10.1016/j.bcp.2007.06.005. PubMed DOI PMC

Chrastil J., Sampson C., Jones K.B., Higgins T.F. Postoperative opioid administration inhibits bone healing in an animal model. Clin. Orthop. Relat. Res. 2013;471:4076–4081. doi: 10.1007/s11999-013-3232-z. PubMed DOI PMC

Barlass U., Dutta R., Cheema H., George J., Sareen A., Dixit A., Yuan Z., Giri B., Meng J., Banerjee S., et al. Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. Gut. 2018;67:600–602. doi: 10.1136/gutjnl-2017-313717. PubMed DOI

The Dose-Dependent Effects of Multifunctional Enkephalin Analogs on the Protein Composition of Rat Spleen Lymphocytes, Cortex, and Hippocampus; Comparison with Changes Induced by Morphine