Alterations of Immune Status Induced by the Sympathetic Nervous System: Immunomodulatory Effects of DMPP Alone and in Combination with Morphine

doi:10.1006/brbi.1993.1026

Brain, Behavior, and Immunity

Volume 7, Issue 3, September 1993, Pages 253-270

https://doi.org/10.1006/brbi.1993.1026 Get rights and content

Abstract

The aim of the present study was to explore the involvement of the sympathetic nervous system (SNS) in the immunomodulatory effects of morphine in Lewis rats and to assess the effects of alterations in SNS activity on immune status. In the first experiment, sympathetic tone was elevated by administering the ganglionic stimulant 1,1-di-methyl-4-phenylpiperazinium (DMPP) in doses of 0, 0.01, 0.1, and 1.0 mg/kg, sc, 5 min before the sc administration of 15 mg/kg morphine or saline. Animals were sacrificed 1 h after the morphine injection and multiple in vitro immune assays were then conducted. Although DMPP did not significantly enhance morphine"s suppressive effects in the spleen and blood mitogen stimulation assays or the splenic natural killer (NK) cell assay, DMPP alone produced effects on immune status in saline-treated animals. Therefore, a second experiment was conducted to examine the immunomodulatory effects of increasing peripheral sympathetic outflow in greater detail. Animals were administered a wider dose range of DMPP (0, 0.005, 0.05, 0.5. and 5.0 mg/kg, sc) 30 min prior to sacrifice and an expanded repertoire of immune assays was conducted. DMPP dose-dependently suppressed the mitogenic responsiveness of splenic T lymphocytes, splenic NK cell activity, and interleukin-2 (IL-2) and γ-interferon production by stimulated splenocytes. DMPP did not alter the total number of splenic leukocytes or the proliferative response of splenic B lymphocytes. In the mesenteric lymph nodes, DMPP had no effect on mitogenic responsiveness, the production of IL-2 or the total number of leukocytes. In the blood, however, DMPP increased mitogenic responsiveness at intermediate doses and decreased proliferation at higher doses. DMPP also dose-dependently decreased the number of blood leukocytes/ml. Taken together, these results indicate that increasing peripheral sympathetic outflow results in profound effects on immune status that depend upon the degree to which SNS activity is altered, the compartment of the immune system, and the lymphocyte subtype.

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Cited by (30)

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Opioids are excellent analgesics for the clinical treatment of various types of acute and chronic pain, particularly cancer-related pain. Nevertheless, it is well known that opioids have some nasty side effects, including immunosuppression, which is commonly overlooked. As a result, the incidence of opportunistic bacterial and viral infections increases in patients with long-term opioid use. Nowadays, there are no effective medications to alleviate opioid-induced immunosuppression. Understanding the underlying molecular mechanism of opioids in immunosuppression can enable researchers to devise effective therapeutic interventions. This review comprehensively summarized the exogenous opioids-induced immunosuppressive effects and their underlying mechanisms, the regulatory roles of endogenous opioids on the immune system, the potential link between opioid immunosuppressive effect and the function of the central nervous system (CNS), and the future perspectives in this field.
Interleukin-1 signaling in the basolateral amygdala is necessary for heroin-conditioned immunosuppression
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Consistent with the latter, heroin users exhibit decreases in circulating lymphocytes, natural killer (NK) cell activity, cytokine production, and antibody-dependent cellular cytotoxicity (Govitrapong et al., 1998; Nair et al., 1986; Yardeni et al., 2008). Similarly, rats treated with morphine, the centrally active metabolite of heroin, exhibit lower rates of lymphocyte proliferation, splenic NK cell activity, blood lymphocyte proliferation, and proinflammatory cytokine production (Fecho et al., 1993a; Fecho et al., 1993b, 1996a,b; Lysle et al., 1993; Saurer et al., 2006a,b). Rats treated with heroin also show decreased measures of nitric oxide (NO), a vital component of pathogen resistance (Lysle and How, 2000).
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Felten and colleagues84 described catecholamine involvement in the alteration of immune function mediated by opioids that is related to the heavy sympathetic innervation of bone marrow, spleen, and lymph nodes.54 Adrenoceptors (α and β) were identified on rodent lymphocytes and macrophages85–87 and these receptors were linked to the immunomodulatory effects of opioids. Acute administration of opioids can alter sympathetic system outflow altering immune function in a similar way to the effect of ganglion stimulants.87
Opioid addicts are more likely to present with infections suggesting opioids are immune modulators. The potential sites/mechanism(s) for this modulation are controversial and on close inspection not well supported by the current literature. It has long been assumed that opioid-induced immune modulation occurs via a combination of direct actions on the immune cell itself, via the hypothalamic-pituitary-adrenal (HPA) axis, or both. Opioid receptors are classified as MOP (μ, mu), DOP (δ, delta), and KOP (κ, kappa)'classical naloxone sensitive receptors'or NOP (the receptor for nociceptin/orphanin FQ), which is naloxone insensitive. Opioids currently used in clinical practice predominantly target the MOP receptor. There do not appear to be classical opioid receptors present on immune cells. The evidence for HPA activation is also poor and shows some species dependence. Most opioids used clinically or as drugs of abuse do not target the NOP receptor. Other possible target sites for immune modulation include the sympathetic nervous system and central sites. We are currently unable to accurately define the cellular target for immune modulation and suggest further investigation is required. Based on the differences observed when comparing studies in laboratory animals and those performed in humans we suggest that further studies in the clinical setting are needed.
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Overwhelming evidence supports the concept that drug-induced plastic neuronal adaptive changes occur in mesolimbic dopamine brain reward pathways and are related to human addictive behavioral states (Hyman et al., 2006; Wise and Bozarth, 1985; Self, 2004). Since it has been established that μ-opioids act in the CNS to cause changes in the SNS and HPA axis with subsequent alterations in immune function in experimenter-delivered paradigms (Gomez-Flores and Weber, 1999a,b; Hall et al., 1998; Fecho et al., 1993b; Mellon and Bayer, 1998a; Liang-Suo et al., 2002), we hypothesized that neuroadaptive changes in the CNS in models of opioid self-administration would result in a different profile of neuroendocrine and immune functions than those seen in passive administration models. We employed a limited access, chronic self-administration paradigm to study the effects of heroin on CNS regulation and control of neuroendocrine and immune function.
Opioid receptor-mediated action in the central nervous system (CNS) has been consistently shown to trigger changes in the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) and suppress a variety of parameters of immune function in investigator-delivered paradigms. Overwhelming evidence supports the concept that the CNS undergoes numerous and complex neuronal adaptive changes in addicts, and in animal models of heroin addiction as a result of the training of drug stimuli to serve as reinforcers, altering the function of individual neurons and the larger neural circuits within which the neurons operate. Taken together, these advances suggest that since plastic neuronal changes occur in drug addiction and related animal model paradigms, profiles of neuroendocrine and immune function would differ in a rat model of heroin self-administration compared to passive infusion of drug. Self-administration of heroin induces neuronal circuitry adaptations in specific brain regions that may be related to alterations in neuroendocrine and T lymphocyte function also observed. Animals self-administering (SA) heroin exhibit increased μ-opioid receptor agonist ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO))-stimulated guanosine-5′-O-(γ-thio)-triphosphate ([³⁵S]GTPγS) binding in the anterior hypothalamus (50% and 33%) and rostral medial thalamus (33% and 36%) compared with control animals receiving identical non-contingent injections of yoked-heroin (YH) or yoked-saline (YS), respectively. No changes in agonist-stimulated G-protein sensitization were observed in 14 other brain regions studied. No changes in μ-opioid receptor density, (³H-DAMGO binding) were seen in all brain regions examined. The neuronal changes in SA animals were correlated with elevated adrenocorticotrophic hormone (ACTH) (64% and 104%) and glucocorticoid production (198% and 79%) compared with YH and YS groups, respectively. Neuroendocrine adaptive changes in SA animals were associated with thymic hypoplasia. Splenic T lymphocytes from animals that had self-administered heroin showed a profoundly reduced ability to proliferate in response to concanavalin A (50% and 48% compared with YH and YS controls, respectively; Fig. 1A), or a monoclonal antibody (R73) to the CD3/T-cell receptor complex (anti-TCR) plus IL-2 (55% and 59% compared with YH and YS controls, respectively; Fig. 1B). Self-administration of heroin selectively alters T lymphocyte function, as no effects on natural killer cell activity or macrophage functions were observed. These findings may have relevance to the acquisition and documented increased incidence of infectious diseases, including HIV, in heroin addicts, due to a pre-existing T-cell immunodeficient state.
Could anaesthesia, analgesia and sympathetic modulation affect neoplasic recurrence after surgery? A systematic review centred over the modulation of natural killer cells activity
2009, Annales Francaises d'Anesthesie et de Reanimation
Les lymphocytes natural killer (NK) représentent une part importante de l’immunité cellulaire non-spécifique et antitumorale. Le but de cette revue est de récapituler les données publiées concernant l’activité des lymphocytes NK durant la période périopératoire et l’influence de l’anesthésie, de l’analgésie et de la modulation du système sympathique.
Bases de données Pubmed/Medline.
Sélection sur base de mots-clés, sans période définie : travaux de recherche fondamentale, essais cliniques randomisés et études comparatives non randomisées.
Chez l’être humain comme chez l’animal, une corrélation importante existe entre l’activité NK et le pronostic lié au développement de métastases. La forte dépression de cette cytotoxicité durant la période périopératoire est susceptible d’altérer les mécanismes de défenses des patients. Les effets des médicaments anesthésiques et analgésiques peuvent être importants. Les effets des opioïdes, des agonistes et antagonistes du système sympathique, des prostaglandines et des AINS, de la kétamine, des hypnotiques, ainsi que de l’anesthésie locorégionale sont revus systématiquement. Les limites des modèles expérimentaux sont aussi abordées.
Les effets des médicaments et des techniques d’anesthésie, d’analgésie et de modulation sympathique sur l’activité des lymphocytes NK sont importants et parfois opposés. Il est important, pour l’anesthésiste-réanimateur de garder à l’esprit que l’impact à long terme de ces techniques sur le pronostic des patients doit encore être clarifié.
The Natural Killer cells (NK) are an important part of non-specific cellular-mediated and antitumoral immunity. The goal of this review is to recapitulate data published over NK activity during the perioperative period and the influence of anaesthesia, analgesia and modulation of sympathetic system.
Pubmed/Medline database.
Keywords-based selection, without limit of date: fundamental studies, randomized controlled trials and non-randomized comparative studies.
In human as in animal studies, an important correlation exists between NK activity and prognosis linked to the development of metastasis. The great depression of this cytotoxicity during the perioperative period could be able to compromise host defenses. The influence of anaesthetics and analgesics is important. The effects of the opioids, the agonists and the antagonists of the sympathetic nervous system, the prostaglandins, the NSAIDs, the ketamine, the hypnotics and the locoregional anaesthesia are systematically reviewed. The limits of experimental model presented are covered.
The effects of anaesthetic/analgesic drugs and techniques, the consequences of sympathomodulation on NK activity are numerous and sometimes opposite. It is important for the anaesthesiologist to keep in mind that the long term consequences of his techniques on the patients’ outcome must be clarified.
Suppression of natural killer cell activity by morphine is mediated by the nucleus accumbens shell
2006, Journal of Neuroimmunology
Despite a wealth of data indicating that morphine modulates immune status by acting at μ-opioid receptors in the brain, there is little known about how the opioid system interacts with other neurotransmitter systems to modulate specific immune parameters. The aim of the present study was to investigate whether dopaminergic projections to the nucleus accumbens are involved in morphine-induced suppression of splenic natural killer (NK) cell activity. The results indicate that administration of the dopamine D₁ antagonist SCH-23390 into the nucleus accumbens shell, but not core, blocked morphine's suppressive effect on NK activity in male Lewis rats. In support of these findings, the effect of morphine was also prevented by intra-accumbens microinfusions of the dopaminergic immunotoxin anti-DAT-saporin. Additionally, administration of the D₁ agonist SKF-38393 into the nucleus accumbens shell produced reductions in splenic NK activity comparable to morphine, suggesting a critical role for D₁ receptors in the modulation of NK activity. Collectively, these findings demonstrate that dopaminergic inputs to the nucleus accumbens are critically involved in opioid-induced immunosuppression and suggest that opioid-induced increases in D₁ receptor activation may have adverse consequences on immune status.

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Regular ArticleAlterations of Immune Status Induced by the Sympathetic Nervous System: Immunomodulatory Effects of DMPP Alone and in Combination with Morphine

Abstract

Regular Article
Alterations of Immune Status Induced by the Sympathetic Nervous System: Immunomodulatory Effects of DMPP Alone and in Combination with Morphine