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The Opioidergic System in the Combined Regulation of Pain and Immunity

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Abstract

Opioidergic mechanisms are involved in responses to nociceptive and antigenic stimuli at all levels and stages (from peripheral nociceptors to the cerebral cortex and from the precursors of immunocompetent cells to mature effector cells). In most experimental and clinical studies, opioid-mediated analgesia proved to be accompanied by immunosuppression. Opioid receptors of μ, δ, and κ types are involved in the mechanisms of combined regulation of pain and immunity, with μ and δ receptors suppressing the immune response and κ receptors enhancing it. By modifying the chemical structure of opioid ligands, it is possible to preserve the analgesic effect and avoid the development of immunosuppression. The opioidergic mechanisms are coupled with nonopioid peptidergic and nonpeptide systems of pain and immunity regulation.

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REFERENCES

  • Antonijevic, I.,Mousa, S.A.,Schaefer, M., and Stein, C., Perineural Defect and Peripheral Opioid Analgesia in Inflammation, J. Neurosci., 1995, vol. 15, pp. 165–172.

    PubMed  Google Scholar 

  • Apte, R.N.,Durum, S.K., and Oppenheim, J.J., Opioids Modulate Interleukin-1 Production and Secretion by Bone Marrow Macrophages, Immunol. Lett., 1990, vol. 24, pp. 141–148.

    PubMed  Google Scholar 

  • Ardon, M.E. andHelme, R.R., Conditioning with Transcutaneous Nerve Stimulation Reduces C Fiber Mediated Axon Reflex Flare in Human Skin, J. Physiol., 1990, vol. 429, pp. 49–57.

    Google Scholar 

  • Basbaum, A.I. andLevine, J.D., Opiate Analgesia: How Central Is a Peripheral Target?, N. Engl. J. Med., 1991, vol. 325, pp. 1168–1169.

    PubMed  Google Scholar 

  • Ben-Eliyahu, S.,Shavit, Y.,Yirimiya, R., and Lebeskind, J.C., Stress-Induced Suppression of natural Killer Cell Cytotoxicity in the Rat: A Naltrexone-Insensitive Paradigm, Behav. Neurosci., 1990, vol. 104, no. 1, pp. 235–238.

    PubMed  Google Scholar 

  • Benus, R.F.,Bohus, B.,Koolhaas, J.M., and van Oortmerssen, G.A., Behavioral Differences between Artificially Selected Aggressive and Nonaggressive Mice: Response to Apomorphine, Behav. Brain Res., 1991, vol. 43, pp. 203–208.

    PubMed  Google Scholar 

  • Bessler, H.,Sztein, M.B., and Serrate, A., β-Endorph in Modulation of IL-1-Induced IL-2 Production, Immunopharmacology, 1990, vol. 19, pp. 5–14.

    PubMed  Google Scholar 

  • Borszcz, G.S.,Johnson, C.P., and Williams, D.H., Increases in Vocalization and Motor Reflex Thresholds Generated by the Intrathecal Administration of Serotonin or Norepinephrine, Behav. Neurosci., 1996a, vol. 110, pp. 809–822.

    PubMed  Google Scholar 

  • Borszcz, G.S.,Johnson, C.P., and Thorp, M.V., The Differential Contribution of Spinopetal Projections to Increases in Vocalization and Motor Reflex Thresholds Generated by the Microinjection of Morphine into the Periaqueductal Gray, Behav. Neurosci., 1996b, vol. 110, pp. 368–388.

    PubMed  Google Scholar 

  • Bouix, O.,Elmezouini, M., and Orsetti, A., Effects of Naloxone Opiate Blockade on the Immunomodulation Induced by Exercise in Rats, Int. J. Sports Med., 1995, vol. 16, no. 1, pp. 29–33.

    PubMed  Google Scholar 

  • Brown, S.L. andvan Epps, D.E., Opioid Peptides Modulate Production of Interferon-γ by Human Mononuclear Cells, Cell Immunol., 1986, vol. 103, pp. 19–26.

    PubMed  Google Scholar 

  • Bussiere, J.L.,Taub, D.D.,Meissler, J.J., et al., Effects of Opioids on Murine Antibody responses, in Alcohol, Drugs of Abuse, and Immunomodulation, Watson, R.R., Ed., New York: Pergamon, 1993, pp. 563–572.

    Google Scholar 

  • Cabot, P.J.,Carter, L.,Gaiddon, C., et al., Immune Cell-Derived beta-Endorphin: Production, Release, and Control of Inflammatory Pain in Rats, J. Clin. Invest., 1997, vol. 100, no. 1, pp. 142–148.

    PubMed  Google Scholar 

  • Carr, D.J.,Gerak, L.R., and France, C.P., Naltrexone Antagonizes the Analgesic and Immunosuppressive Effects of Morphine in Mice, J. Pharmacol. Exp. Ther., 1994, vol. 269, no. 2, pp. 693–698.

    PubMed  Google Scholar 

  • Cheido, M.A. andIdova, G.V., Effects of Opioid Peptides on Immunomodulatory Processes, Ross. Fiziol. Zh., 1998, vol. 84, no. 4, pp. 385–390.

    Google Scholar 

  • Codd, E.E.,Shank, R.P.,Schupsky, J.J., and Raffa, R.B., Serotonin and Norepinephrine Uptake Inhibiting Activity of Centrally Acting Analgesics: Structural Determinants and Role in Antinociception, J. Pharmacol. Exp. Ther., 1995, vol. 274, pp. 1263–1270.

    PubMed  Google Scholar 

  • Daffny, N.,Lee, J.R., and Dougherty, P., Immune Response Products Alter CNS Activity: Interferon Modulates Central Opioid Functions, J. Neurosci. Res., 1988, vol. 19, pp. 130–139.

    PubMed  Google Scholar 

  • Devor, M. andRaber, P., Heritability of Symptoms in an Experimental Model of Neuropathic Pain, Pain, 1990, vol. 42, pp. 51–67.

    PubMed  Google Scholar 

  • Dickenson, A.H., Central Acute Pain Mechanisms, Ann. Med., 1995, vol. 27, no. 2, pp. 223–227.

    PubMed  Google Scholar 

  • Dubinin, K.V.,Zakharova, L.A.,Alekseev, T.A., et al., The Involvement of μ-, γ-, and κ-Opioid Receptors in Regulation of the Humoral Immune Response, Biokhimiya, 1994a, vol. 59, no. 8, pp. 1230–1236.

    Google Scholar 

  • Dubinin, K.,Zakharova, L.A.,Khegai, L., and Saitsev, S.V., Immunomodulating Effect of Met-Enkephal in on Different Stages of Lymphocyte Proliferation Induced by Concanavalin A in vitro, Immunopharmacol. Immunotoxicol., 1994b, vol. 16, pp. 463–472.

    PubMed  Google Scholar 

  • Duvaux-Viret, A.,Stefano, G.B.,Smith, A.M.,Dissous, C., and Capron, A., Immunosuppression in the Definitive Hosts of the Human Parasite, Schistosoma mansoni, by Release of Immunoreactive Neuropeptides, Proc. Natl. Acad. Sci. USA, 1992, vol. 98, pp. 778–781.

    Google Scholar 

  • Efuni, S.S.,Rossels, A.N.,Agranat, V.Z., et al., The Influence of New Immunostimulator Myelopid on Active Peptide Level, Abstr. 1st Int. Congress ISNIM, Florence, 1990, p. 564.

  • Eisenstein, T.K.,Meissler, J.J.,Rogers, T.J., et al., Mouse Strain Differences in Immunosuppression by Opioids in vitro, J. Pharmacol. Exp. Ther., 1995, vol. 275, no. 3, pp. 1484–1489.

    PubMed  Google Scholar 

  • Fagarasan, M.O.,Arora, P.K., and Axelrod, J., Interleukin-1 Potentiation of β-Endorphin Secretion and the Dynamics of Interleukin-1 Internalization in Pituitary Cells, Prog. Neuropsychopharmacol. Biol. Psychiat., 1991, vol. 15, pp. 551–560.

    Google Scholar 

  • Fonina, L.A.,Gurianov, S.A.,Nazimov, I.V., et al., Structures of Two Myelopeptides Affecting Pain, Biomed. Sci., 1992, vol. 2, pp. 665–668.

    Google Scholar 

  • Freier, D.O. andFuchs, B.A., A Mechanism of Action for Morphine-Induced Immunosuppression: Corticosterone Mediates Morphine-Induced Suppression of Natural Killer Cell Activity, J. Pharmacol. Exp. Ther., 1994, vol. 270, no. 3, pp. 1127–1133.

    PubMed  Google Scholar 

  • Gebhart, G.F., Visceral Nociception: Consequences, Modulation, and Future, Eur. J. Anesth., 1995, vol. 12, Suppl. 10, pp. 24–27.

    Google Scholar 

  • Glamsta, E.-L.,Marklund, A.,Hellman, U., et al., Isolation and Characterization of a Hemoglobin-Derived Opioid Peptide from the Human Pituitary Gland, Reg. Pept., 1991, vol. 34, pp. 169–179.

    Google Scholar 

  • Guan, L.,Townsend, R.,Eisenstein, T.K., et al., Both T Cells and Macrophages Are Targets of Opioid-Induced Immunosuppression, Brain Behav. Immun., 1994, vol. 8, pp. 229–240.

    PubMed  Google Scholar 

  • Hassan, A.H.S.,Przewlocki, R.,Herz, A., and Stein, C., Dynorphin, a Preferential Ligand for κ-Opioid Receptors Is Present in Nerve Fibers and Immune Cells within Inflamed Tissue of the Rat, Neurosci. Lett., 1992, vol. 140, pp. 85–88.

    PubMed  Google Scholar 

  • Heagy, W.,Shipp, M.A., and Finberg, R.W., Opioid Receptor Agonist and Ca2+ Modulation in Human B Cell Lines, J. Immunol., 1992, vol. 149, pp. 4074–4081.

    PubMed  Google Scholar 

  • Hernandez, M.C.,Flores, L.R., and Bayer, B.M., Immunosuppression by Morphine Is Mediated by Central Pathways, J. Pharmacol. Exp. Ther., 1993, vol. 267, no. 3, pp. 1336–1341.

    PubMed  Google Scholar 

  • Herzberg, U.,Murtaugh, M.P.,Mullet, M.A., and Beitz, A.J., Electrical Stimulation of the Sciatic Nerve Alters Neuropeptide Content and Lymphocyte Migration in the Subcutaneous Tissue of the Rat Hindpaw, Neuroreports, 1995, vol. 6, no. 13, pp. 1773–1777.

    Google Scholar 

  • Ichinose, M.,Asai, M., and Sawada, M., Enhancement of Phagocytosis by Dynorphin A in Mouse Peritoneal Macrophages, J. Neuroimmunol., 1995, vol. 60, pp. 37–43.

    PubMed  Google Scholar 

  • Jessop, D.S.,Lightman, S.L., and Chowdrey, H.S., Effects of a Chronic Inflammatory Stress on Levels of Pro-Opiomelanocortin-Derived Peptides in Rat Spleen and Thymus, J. Neuroimmunol., 1994, vol. 49, pp. 197–203.

    PubMed  Google Scholar 

  • Kalyuzhnyi, L.V., Physiological Mechanisms of Pain and Analgesia, Ross. Fiziol. Zh., 1991, vol. 77, no. 4, pp. 123–133.

    Google Scholar 

  • Kar, S. andQuirion, R., Neuropeptide Receptors in Developing and Adult Rat Spinal Cord: An in Vitro Quantitative Autoradiography Study of Calcitonin Gene-Related Peptide, Neurokinins, mu-Opioid, Galanin, Somatostatin, Neurotensin, and Vasoactive Intestinal Polypeptide Receptors, J. Comp. Neurol., 1995, vol. 354, no. 2, pp. 253–281.

    PubMed  Google Scholar 

  • Kaufman, D.L.,Keith, D.E.,Anton, B., et al., Characterization of the Murine mu-Opioid Receptor Gene, J. Biol. Chem., 1995, vol. 270, pp. 15877–15883.

    PubMed  Google Scholar 

  • Kavaliers, M. andColwell, D.D., Multiple Opioid System Involvement in the Mediation of Parasitic Infection-Induced Analgesia, Brain Res., 1993, vol. 623, pp. 316–320.

    PubMed  Google Scholar 

  • Kavelaars, A.,Berkenbosch, F.,Croiset, G., et al., Induction of β-Endorphin Secretion by Lymphocytes after Subcutaneous Administration of Corticotropin Releasing Factor, Endocrinology, 1990a, vol. 126, no. 2, pp. 759–764.

    PubMed  Google Scholar 

  • Kavelaars, A.,Ballieux, R.E., and Heijnen, C.J., Differential Effects of β-Endorphin on cAMP Levels in Human Peripheral Blood Mononuclear Cells, Brain Behav. Immun., 1990b, vol. 4, pp. 171–179.

    PubMed  Google Scholar 

  • Kay, N.E.,Morley, J.E., and Allen, J.I., Interaction between Endogenous Opioids and IL-2 on PHA-Stimulated Human Lymphocytes, Immunology, 1990, vol. 70, pp. 485–491.

    PubMed  Google Scholar 

  • Kharchenko, E.P.,Kalikhevich, V.N.,Sokolova, T.V., et al., Opiate-Like Peptides Principally Differing from Enkephalins in Their Structure, Biokhimiya, 1988, vol. 53, no. 7, pp. 1128–1135.

    Google Scholar 

  • Kimball, E.S. andRaffa, R.B., Obligatory Role of B Cells and Adherent Accessory Cells in the Transfer of a Defect in Morphine-Mediated Antinociception in C57BL/6J/bg (Beige-J) Mice, J. Neuroimmunol., 1989, vol. 22, pp. 185–192.

    PubMed  Google Scholar 

  • Koch, G.,Wiedemann, K., and Teschemacher, H., Opioid Activities of Human β-Casomorphins, Naunyn-Schmiedeberg's Arch. Pharmacol., 1985, vol. 331, pp. 351–354.

    Google Scholar 

  • Konkoy, C.S. andChilders, S.R., Relationship between κ1 Opioid Receptor Binding and Inhibition of Adenylyl Cyclase in Guinea Pig Brain Membranes, Biochem. Pharmacol., 1993, vol. 36, pp. 627–633.

    Google Scholar 

  • Kozlov, A.Yu., Studies on the Role of Enkephalinase in Mechanisms of Morphine and Acupunctural Analgesia, Cand. Sci. (Biol.) Dissertation, Moscow, 1995.

  • Kryzhanovskii, G.N., Obshchaya patofiziologiya nervnoi sistemy (General Pathophysiology of the Nervous System), Moscow: Meditsina, 1997.

    Google Scholar 

  • Kusnecov, A.W.,Husband, A.J.,King, M.G., and Smith, R., Modulation of Mitogen-Induced Spleen Cell Proliferation and the Antibody-Forming Cell Response by β-Endorphin in vivo, Peptides, 1989, vol. 10, pp. 473–479.

    PubMed  Google Scholar 

  • Lawrence, D.M.P. andBidlack, J.M., The kappa Opioid Receptor Expressed on the Mouse R1.1 Thymoma Cell Line Is Coupled to Adenylyl Cyclase through a Pertussis Toxin-Sensitive Guanine Nucleotide-Binding regulatory Protein, J. Pharmacol. Exp. Ther., 1993, vol. 266, pp. 1678–1683.

    PubMed  Google Scholar 

  • Lefkowitz, R.J.,Inglese, J.,Koch, W.J., et al., G-Protein-Coupled Receptors: Regulatory Role of Receptor Kinases and Arrestin Proteins, Cold Spring Harbor Symp. Quant. Biol., 1992, vol. 57, pp. 127–133.

    PubMed  Google Scholar 

  • Levine, J.D.,Fields, H.L., and Basbaum, A.I., Peptides and the Primary Afferent Nociceptor, J. Neurosci., 1993, vol. 13, no. 6, pp. 2273–2286.

    PubMed  Google Scholar 

  • Liebmann, C.,Schrader, U., and Brant, V., Opioid Receptor Affinities of the Blood-Derived Tetrapeptides Hemorphin and Cytochronin, Eur. J. Pharmacol., 1989, vol. 166, pp. 523–526.

    PubMed  Google Scholar 

  • Lockwood, L.L.,Silbert, L.H.,Fleshner, M., et al., Morphine-Induced Decreased in Vivo Antibody Response, Brain Behav. Immun., 1994, vol. 8, pp. 24–36.

    PubMed  Google Scholar 

  • Malyukova, I.V.,Zakharova, L.A., and Metaxa, E.E., Indirect Involvement of the Opioid System in the Regulation of Nociception by MP1 and MP2 Peptide Fragments, Biokhimiya, 1996, vol. 61, no. 3, pp. 440–444.

    Google Scholar 

  • Marotti, T.,Gabrilovac, J.,Rabatic, S., et al., Met-Enkephal in Modulates Stress-Induced Alterations of the Immune Response in Mice, Pharmacol. Biochem. Behav., 1996, vol. 54, pp. 277–284.

    PubMed  Google Scholar 

  • Mattia, A.,Vanderah, T.,Mosberg, H., and Porreca, F., Lack of Antinociceptive Cross-Tolerance between [D-Pen5]Enkephalin and [D-Ala2]Deltorphin II in Mice: Evidence for Delta Receptor Subtypes, J. Pharmacol. Exp. Ther., 1991, vol. 258, pp. 583–597.

    PubMed  Google Scholar 

  • McCain, H.M.,Bilotta, J., and Lamster, I.B., Endorphinergic Modulation of Immune Function: Potent Action of the Dipeptide Glycyl-L-glutamine, Life Sci., 1987, vol. 41, pp. 169–176.

    PubMed  Google Scholar 

  • McConkey, D.J.,Jondal, M., and Orrenius, S., Cellular Signaling in Thymocyte Apoptosis, Semin. Immunol., 1992, vol. 4, pp. 371–377.

    PubMed  Google Scholar 

  • Meizerov, E.E., Neurophysiological Analysis of the Central Afferentation Mechanisms under Conditions of Physiological and Pathological Pain, Doctoral (Med.) Dissertation, Moscow, 1997.

  • Millan, M.J. andColpaert, F.C., Opioid Systems in the Response to Inflammatory Pain: Sustained Blockade Suggests Role of κ-but not γ-Opioid Receptors in the Modulation of Nociception, Behavior, and Pathology, Neuroscience, 1991, vol. 2, no. 2, pp. 541–553.

    Google Scholar 

  • Mogil, J.S.,Sternberg, W.F.,Marek, P., et al., The Genetics of Pain and Pain Inhibition, Proc. Natl. Acad. Sci. USA, 1996, vol. 93, pp. 3048–3055.

    PubMed  Google Scholar 

  • Molotkovskaya, I.M.,Malyukova, I.V., and Zakharova, L.A., Opioid Receptor Agonists Modulate Free Ca2+ Level in Concanavalin A-Activated Mouse Lymphocytes, Biokhimiya, 1999, vol. 64, no. 5, pp. 656–662.

    Google Scholar 

  • Mousa, S.A.,Schaefer, M.,Mitchell, W.M., et al., Local Upregulation of Corticotropin Releasing Hormone and Interleukin-1 Receptors in Rats with Painful Hindlimb Inflammation, Eur. J. Pharmacol., 1996, vol. 311, no. 2–3, pp. 221–231.

    PubMed  Google Scholar 

  • Muraki, T.,Oike, N.,Shibata, Y., and Nomoto, T., Analgesic Effect of μ-and κ-Opioid Agonists in Beige and CXBK Mice, J. Pharmacol., 1991, vol. 43, pp. 210–212.

    Google Scholar 

  • North, R.A., Opioid Action on Membrane Ion Channels, in Handbook of Experimental Pharmacology, Berlin: Springer, 1993, vol. 1, pp. 773–793.

    Google Scholar 

  • Nozdrachev, A.D. Axon Reflex: New Views in an Old Field, Ross. Fiziol. Zh., 1995, vol. 81, no. 11, pp. 135–142.

    Google Scholar 

  • Panerai, A.E.,Manfredi, B.,Granucci, F., and Sacerdote, P., The beta-Endorph in Inhibition of Mitogen-Induced Splenocyte Proliferation Is Mediated by Central and Peripheral Paracrine-Autocrine Effects of Opioid, J. Neuroimmunol., 1995, vol. 58, no. 1, pp. 71–76.

    PubMed  Google Scholar 

  • Pasternak, G.W., The Central Questions in Pain Perception May Be Peripheral, Anesth. Analg., 1998, vol. 87, no. 2, pp. 388–393.

    PubMed  Google Scholar 

  • Paul, D.,Bodnar, R.J.,Gistrak, M.A., and Pasternak, G.W., Different μ Receptor Subtypes Mediate Spinal and Supraspinal Analgesia in Mice, Eur. J. Pharmacol., 1989, vol. 168, pp. 307–314.

    PubMed  Google Scholar 

  • Petrov, R.V. andZakharova, L.A., Physiological Stress and Immune Response: Myelopeptides, in Stress and Immunity, Plotnikoff, N.,Margo, A.,Faith, R., and Wybran, J., Eds., Boca Raton: NRC, 1991, pp. 399–408.

    Google Scholar 

  • Pezzutto, A.,Dorken, B.,Rabinovitch, P.S., et al., CD19 Monoclonal Antibody HD37 Inhibits Anti-Immunoglobulin-Induced B-Cell Activation and Proliferation, J. Immunol., 1989, vol. 138, pp. 2793–2802.

    Google Scholar 

  • Prather, P.,McGinn, T.,Erickson, L., et al., Ability of κ-Opioid Receptors to Interact with Multiple G-Proteins Is Independent of Receptor Density, J. Biol. Chem., 1994, vol. 269, pp. 21293–21302.

    PubMed  Google Scholar 

  • Przewlocki, R.,Hassan, A.H.S.,Lason, W., et al., Gene Expression and Localization of Opioid Peptides in Immune Cells of Inflamed Tissue: Functional Role in Antinociception, Neuroscience, 1992, vol. 48, no. 2, pp. 491–500.

    PubMed  Google Scholar 

  • Radulovic, J.,Mancev, Z.,Stajevic, S., et al., Modulation of Humoral Immune Response by Central Administration of Leu-Enkephalin: Effects of μ-, γ-, and κ-Opioid Receptor Antagonists, J. Neuroimmunol., 1996, vol. 65, pp. 155–161. Brain Res., vol. 661, pp. 189–195.

    PubMed  Google Scholar 

  • Raffa, R.B.,Mathiasen, J.R.,Kimball, E.S., and Vauggyt, J.L., The Combined Immunological and Antinociceptive Defects of the Beige Mice: The Possible Existence of A “μ-Repressin,#x201D; Life Sci., 1993, vol. 52, no. 1, pp. 1–8.

    PubMed  Google Scholar 

  • Reisine, T. andBell, G.I., Molecular Biology of Opioid Receptors, Trends Neurosci., 1993, vol. 16, pp. 506–510.

    PubMed  Google Scholar 

  • Reshetnyak, V.K., Cortical Control of Antinociceptive Structures in Reflectory Analgesia, Doctoral (Med.) Dissertation, Moscow, 1989.

  • Robertson, B.,Xu, X.J.,Hao, J.X., et al., Interferon-gamma Receptors in Nociceptive Pathways: Role in Neuropathic Pain-Related Behaviour, Neuroreports, 1997, vol. 8, pp. 1311–1316.

    Google Scholar 

  • Roda, L.G.,Bongiorno, L.,Trani, E., et al., Positive and Negative Immunomodulation by Opioid Peptides, Int. J. Immunopharmacol., 1996, vol. 18, no. 1, pp. 1–16.

    PubMed  Google Scholar 

  • Roy, S.,Ge, B.-L.,Loh, H.H., and Lee, N.M., Characterization of [3H]Morphine Binding to Interleukin-1-Activated Thymocytes, J. Pharmacol. Exp. Ther., 1992, vol. 187, pp. 1187–1192.

    Google Scholar 

  • Sacerdot, P.,Manfredi, B.,Mantegazza, P., and Panerai, A.E., Antinociceptive and Immunosuppressive Effects of Opiate Drugs: A Structure-Related Activity Study, Br. J. Pharmacol., 1997, vol. 121, no. 2, pp. 834–840.

    PubMed  Google Scholar 

  • Schaefer, M.,Mousa, S.A.,Zhang, Q., et al., Expression of Corticotropin-Releasing Factor in Inflamed Tissue Is Required for Intrinsic Peripheral Opioid Analgesia, Proc. Natl. Acad. Sci. USA, 1996, vol. 93, no. 12, pp. 6096–6100.

    PubMed  Google Scholar 

  • Schaefer, M.,Mousa, S.A., and Stein, C., Corticotropin-Releasing Factor in Antinociception and Inflammation, Eur. J. Pharmacol., 1997, vol. 323, no. 1, pp. 1–10.

    PubMed  Google Scholar 

  • Scott, M. andCarr, D.J.J., Morphine Suppresses the Alloantigen-Driven CTL Response in a Dose-Dependent and Naltrexone-Reversible Manner, J. Pharmacol. Exp. Ther., 1996, vol. 278, pp. 980–988.

    PubMed  Google Scholar 

  • Selley, D.E. andBidlack, J.M., Effects of β-Endorph in on mu and κ-Opioid Receptor-Coupled G-Protein Activity: Low-K m CTPase Studies, J. Pharmacol. Exp. Ther., 1992, vol. 263, pp. 99–104.

    PubMed  Google Scholar 

  • Sharp, B.M.,Shahabi, N.A.,Heagy, W.,McAllen, K.,Bell, M.,Hutton, C., and McKean, D.J., Dual Signal Transduction through delta Opioid Receptors in a Transfected Human T-Cell Line, Proc. Natl. Acad. Sci. USA, 1996, vol. 93, pp. 8294–8299.

    PubMed  Google Scholar 

  • Shestak, K.I.,Sergeeva, M.G.,Zaitsev, S.V., et al., Analysis of New Opioid-Like Peptides by a Radioreceptor Method, Ukr. Biokhim. Zh., 1990, vol. 62, no. 2, pp. 23–29.

    PubMed  Google Scholar 

  • Srinivasan, V.,Wielbo, D.,Simpkins, J., et al., Analgesic and Immunomodulatory Effects of Codeine and Codeine 6-Glucuronide, Pharm. Res., 1996, vol. 13, no. 2, pp. 296–300.

    PubMed  Google Scholar 

  • Stein, C.,Schaefer, M., and Hassan, A.H.S., Peripheral Opioid Receptors, Ann. Med., 1995, vol. 27, no. 2, pp. 219–221.

    PubMed  Google Scholar 

  • Suarez-Roca, H.,Abdullah, L.,Zuniga, J., et al., Multiphasic Effect of Morphine on the Release of Substance P from Rat Trigeminal Nucleus Slices, Brain Res., 1992, vol. 579, pp. 402–406.

    Google Scholar 

  • Taiwo, Y.O. andLevine, J.D., μ-and κ-Opioids Block Sympathetically Dependent Hyperalgesia, J. Neurosci., 1991, vol. 11, pp. 928–932.

    PubMed  Google Scholar 

  • Takagi, H.,Shiomi, H.,Ueda, H., and Amano, H., A Novel Analgetic Dipeptide from Bovine Brain Is a Possible Met-Enkephalin Releaser, Nature, 1979, vol. 282, pp. 410–412.

    PubMed  Google Scholar 

  • Taub, D.D.,Eisenstein, T.K.,Geller, E.B., et al., Immunomodulatory Activity of μ-and κ-Selective Opioid Agonists, Proc. Natl. Acad. Sci. USA, 1991, vol. 88, pp. 360–364.

    PubMed  Google Scholar 

  • Tian, M.,Broxmeyer, H.E.,Fan, Yi., et al., Altered Hematopoiesis, Behaviour, and Sexual Function in κ-Opioid Receptor-Deficient Mice, J. Exp. Med., 1997, vol. 185, pp. 1517–1522.

    PubMed  Google Scholar 

  • Tsu, R.C.,Chan, J.S.C., and Wong, Y.H., Regulation of Multiple Effects by the Cloned κ-Opioid Receptor: Stimulation of Phospholipase C and Type II Adenylyl Cyclase, J. Neurochem., 1995, vol. 64, pp. 2700–2707.

    PubMed  Google Scholar 

  • Van Tits, L.J.H.,Michel, M.C.,Motulsky, H.J., et al., Cyclic AMP Counteracts Mitogen-Induced Inositol Phosphate Generation and Increases in Intracellular Ca2+ Concentration in Human Lymphocytes, Br. J. Pharmacol., 1991, vol. 103, pp. 1288–1294.

    PubMed  Google Scholar 

  • Vanderah, T.W.,Wild, K.D.,Takemori, A.E., et al., Modulation of Morphine Antinociception by Swim Stress in the Mouse: Involvement of Supraspinal Opioid γ2 Receptors, J. Pharmacol. Exp. Ther., 1993, vol. 267, pp. 449–455.

    PubMed  Google Scholar 

  • Vasilenko, A.V.,Zakharova, L.A.,Metaxa, E.E., and Malyukova, I.V., Interrelationship of Pa in Sensitivity and Immune Response in Mice: Changes in Pain Threshold, Antibody Production, and Ratio of μ, γ, and κTypes of Opioid Receptors on Spleen Cells Caused by Hot Plate Test, Analgesia, 1996, vol. 2, no. 2, pp. 21–24.

    Google Scholar 

  • Watkins, L.R.,Maier, S.F., and Goehler, L.E., Immune Activation: The Role of Pro-Inflammatory Cytokines in Inflammation, Illness Responses, and Pathological Pain States, Pain, 1995, vol. 63, pp. 289–302.

    PubMed  Google Scholar 

  • Yabuuchi, K.,Maruta, E.,Minami, M., and Satoh, M., Induction of Interleukin-1β mRNA in the Hypothalamus Following Subcutaneous Injection of Formalin into the Rat Hind Paw, Neurosci. Lett., 1996, vol. 207, no. 2, pp. 109–112.

    PubMed  Google Scholar 

  • Yang, S.W.,Chen, J.Y.,Zhang, Z.H., et al., Adenosine and Opiate-Like Substances Mediate Antinociception at the Spinal Cord, Brain Res., 1995, vol. 673, no. 1, pp. 170–174.

    PubMed  Google Scholar 

  • Yeager, M.P.,Colacchio, T.A.,Yu, C.T., et al., Morphine Inhibits Spontaneous and Cytokine-Enhanced Natural Killer Cell Cytotoxicity in Volunteers, Anesthesia, 1995, vol. 83, pp. 500–508.

    Google Scholar 

  • Yirmiya, R.,Rosen, H.,Donchin, O., and Ovadia, H., Behavioral Effects of Lipopolysaccharide in Rats: Involvement of Endogenous Opioids, Brain Res., 1994, vol. 648, pp. 80–86.

    PubMed  Google Scholar 

  • Zachariou, V. andGoldstein, B.D., κ-Opioid Receptor Modulation of the Release of Substance P in the Dorsal Horn, Brain Res., 1996, vol. 706, no. 1, pp. 80–88.

    PubMed  Google Scholar 

  • Zaitsev, A.A. andIgnatov, Yu.D., Neuropharmacology of Opiates and Opioids, in Bolevoi sindrom (The Pain Syndrome), Leningrad: Meditsina, 1990, pp. 65–118.

    Google Scholar 

  • Zaitsev, S.V.,Khegai, L.A.,Gavrilova, E.M., et al., Involvement of Opioid Receptors in Met-Enkephalin Modulation of Blast-Transformation of Mouse Splenocytes, Immunol. Lett., 1992, vol. 32, pp. 27–30.

    PubMed  Google Scholar 

  • Zaitsev, S.I.,Yarygin, K.N., and Varfolomeev, S.D., Narkomania. Neiropeptid-morfinovye retseptory (Narcotic Addiction: Neuropeptide-Morphine Receptors), Moscow: Mosk. Gos. Univ., 1993.

    Google Scholar 

  • Zakharova, L.,Belevskaya, R., and Yanovsky, O., Participation of Opioids in the Immunostimulatory Activity of Myelopeptides, Biomed. Sci., 1990, vol. 1, pp. 141–148.

    Google Scholar 

  • Zakharova, L.A.,Metaxa, E.E.,Malyukova, I.V., and Vasilenko, A.M., Hypoalgesia Induced by a Weak Stress-Inducing Action Is Accompanied by a Decreased Antibody Production and Changes in the Type of Opioid Receptors on Immunocompetent Cells, Dokl. Akad. Nauk SSSR, 1995, vol. 340, no. 5, pp. 691–693.

    Google Scholar 

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Zakharova, L.A., Vasilenko, A.M. The Opioidergic System in the Combined Regulation of Pain and Immunity. Biology Bulletin 28, 280–292 (2001). https://doi.org/10.1023/A:1016696605484

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