Abrupt or precipitated withdrawal from morphine induces immunosuppression

Rahim, Rahil T.; Adler, Martin W.; Meissler, Joseph J.; Cowan, Alan; Rogers, Thomas J.; Geller, Ellen B.; Eisenstein, Toby K.

doi:10.1016/s0165-5728(02)00103-0

Cited by 50 publications

(49 citation statements)

References 16 publications

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“…We have previously shown that 24 h after withdrawal from morphine, mice are immunosuppressed, as assessed by the capacity of spleen cells to mount an ex vivo antibody response, by depression of the expression of proinflammatory cytokines in response to LPS in vitro, and by the reduction in levels of B7.2 on macrophages stimulated with LPS (35,36). Other studies reported in the literature on the effects of withdrawal from morphine on immune responses have also shown suppression of T-cell proliferation to mitogens (4,19) and suppression of NK cell activity (7,45), as well as alterations in T-cell subsets (19).…”

Section: Discussionmentioning

confidence: 99%

“…The levels of morphine attained in the blood are comparable to doses that are physiological in human (9,22). In all experiments, pellets were left in place for 96 h, at which time the animals were dependent on morphine, based on our previous work (35). Withdrawal was initiated by surgically removing the morphine pellets while the mice were under anesthesia.…”

Section: Methodsmentioning

confidence: 99%

“…Yet, there are only a few studies of the effects of withdrawal from morphine on immune responses (4,7,19,35,36,45), and there are, so far, only two papers of which we are aware on the effects of morphine withdrawal on infection (5, 14). The lack of investigation in this area is particularly surprising considering that opioid abuse and dependence remain major public health problems related to the acquisition of various infectious diseases.…”

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confidence: 99%

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Increased Sensitivity to Salmonella enterica Serovar Typhimurium Infection in Mice Undergoing Withdrawal from Morphine Is Associated with Suppression of Interleukin-12

Feng¹,

Wilson²,

Meissler³

et al. 2005

Infect Immun

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We have shown previously that withdrawal from morphine induces immunosuppression in mice. The present study reports the effects of morphine withdrawal on infection with Salmonella enterica serovar Typhimurium. Mice were made dependent on morphine by the implantation of a slow-release morphine pellet for 96 h. Controls received a placebo pellet. Withdrawal was induced by pellet removal. Mice were inoculated intraperitoneally with Salmonella 24 h postwithdrawal. Morphine withdrawal sensitized mice to Salmonella infection, as evidenced by increased mortality, shortened mean survival time, and increased bacterial load in the blood, spleen, and liver. Examination of the levels of a panel of proinflammatory cytokines in sera of infected, morphine-withdrawn mice showed that morphine withdrawal inhibited the elevation of interleukin-12p70 (IL-12p70). The production of IL-12p40 in morphine withdrawal mice was also suppressed. The administration of exogenous IL-12 significantly decreased the bacterial burden in morphine-withdrawn mice. These studies show a correlation between the suppression of IL-12 production and a heightened susceptibility to Salmonella infection in mice undergoing withdrawal from morphine.Opioid abuse has been clinically observed to correlate with an increased incidence of infectious diseases (21,23,27). Intravenous drug use is the second most frequently reported risk behavior for human immunodeficiency virus (HIV) infection. It is well documented that HIV-infected patients have a greater risk of Salmonella infections than the general population (3,10,18,20,24,26,39). A substantial body of literature has shown that opioids are immunosuppressive in laboratory animal models, and impaired immunity has been proposed as a major cause of increased infections in intravenous drug abusers (17,31,37). Our laboratory has shown that subacute administration of morphine can potentiate oral Salmonella infection (28). In laboratory models, acute, subacute, or chronic administration of morphine has been shown to sensitize individuals to several other pathogens, including Streptococcus pneumoniae (43), Toxoplasma gondii (12), Klebsiella pneumoniae (42), Candida albicans (42), and herpes simplex virus type 1 (32).Most opioid abusers experience periods of withdrawal between "hits." Yet, there are only a few studies of the effects of withdrawal from morphine on immune responses (4,7,19,35,36,45), and there are, so far, only two papers of which we are aware on the effects of morphine withdrawal on infection (5, 14). The lack of investigation in this area is particularly surprising considering that opioid abuse and dependence remain major public health problems related to the acquisition of various infectious diseases. Development of opioid tolerance and an abstinence syndrome upon termination of the drug (manifestations of withdrawal) are among the defining characteristics of opioid addiction. The phenomena of opioid tolerance, leading to a state of physical dependence, and abstinence have been examined extensively at the ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Increased Sensitivity to Salmonella enterica Serovar Typhimurium Infection in Mice Undergoing Withdrawal from Morphine Is Associated with Suppression of Interleukin-12

Feng¹,

Wilson²,

Meissler³

et al. 2005

Infect Immun

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“…Initial studies by Tomei and Renaud (7) demonstrated that opioid withdrawal in an in vitro model significantly decreases Fc␥R-mediated macrophage phagocytosis and the decrease correlated with altered intracellular cAMP levels (8). More recent studies from Eisenstein and colleagues (9,10) show that both abrupt and precipitated morphine withdrawal results in significant immunosuppression and the observed dysfunction was a result of impaired macrophage function, as evidenced by the findings that macrophages obtained from withdrawn spleens displayed reduced expression of the costimulatory molecule B7.2 and had depressed cytokine production. Additional studies from this group (11,12) further demonstrated that morphine-withdrawn mice when administered a sublethal dose of LPS exhibited 100% lethality that was accompanied by a decrease in IL-12 production.…”

mentioning

confidence: 99%

Morphine Withdrawal Inhibits IL-12 Induction in a Macrophage Cell Line through a Mechanism That Involves cAMP

Kelschenbach

Ninković

Wang

et al. 2008

The Journal of Immunology

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There are very few studies that examine the effects that morphine withdrawal has on immune functioning, and of these even fewer describe the mechanisms by which withdrawal brings about these changes. Our previous work demonstrated that morphine withdrawal contributed to Th cell differentiation by biasing cells toward the Th2 lineage. A major finding from these studies was that IL-12 was decreased following withdrawal, and it was concluded that this decrease may be a mechanism by which morphine withdrawal is mediating Th2 polarization. Therefore, it was the aim of the current studies to develop an in vitro model to examine the process of morphine withdrawal and to understand the signaling mechanisms that withdrawal may use to effect IL-12 production through the use of this model. It was demonstrated and concluded that morphine withdrawal may be effecting IL-12 production by increasing cAMP levels, which activates protein kinase A. Protein kinase A activation then prevents the phosphorylation and subsequent degradation of IκB, which in turn prevents translocation of the NF-κB p65 subunit to the nucleus to transactivate the IL-12 p40 gene, ultimately resulting in decreased IL-12 production following LPS stimulation.

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“…9 -15 Opioid withdrawal is a crucial and recurring event during the course of opioid abuse. The phenomenon of opioid tolerance is well established; once tolerance develops, termination of the drug by withdrawal (drug cessation) or precipitated withdrawal (PW) (administration of an opioid antagonist with or without drug cessation) can lead to an abstinence syndrome indicating a state of physical dependence, 16 which is among the defining characteristics of opioid addiction. Although opiate addicts may not suffer immune dysfunction when getting the drug on a regular basis, 17 opioid withdrawal has a negative impact on the immune system, 16,18 -24 thus having a co-factor role in promoting viral infections.…”

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confidence: 99%

An in Vitro Model of Morphine Withdrawal Manifests the Enhancing Effect on Human Immunodeficiency Virus Infection of Human T Lymphocytes through the Induction of Substance P

Wang

Douglas

Peng

et al. 2006

The American Journal of Pathology

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Opioid withdrawal is a crucial and recurring event during the course of opioid abuse that has a negative impact on the immune system. In this study, we investigated whether abrupt withdrawal (AW) or precipitated withdrawal (PW) potentiates human immunodeficiency virus (HIV) infection of human T lymphocytes. AW and PW enhanced HIV infection of peripheral blood lymphocytes and T-cell lines (Jurkat and CEMX174). In addition, both AW and PW induced HIV replication in a latently HIV-infected human T-cell line (J1.1). The enhancing effect of AW and PW was associated with the induction of neuropeptide substance P in both peripheral blood lymphocytes and the T-cell lines. The substance P receptor antagonist , CP-96 ,345 , not only blocked AW-or PW-induced endogenous substance P expression but also abrogated AW-or PW-induced HIV replication in T cells. These findings provide a cellular mechanism that supports the notion that opioids have a co-factor role in promoting HIV infection of the immune cells.

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Abrupt or precipitated withdrawal from morphine induces immunosuppression

Cited by 50 publications

References 16 publications

Increased Sensitivity to Salmonella enterica Serovar Typhimurium Infection in Mice Undergoing Withdrawal from Morphine Is Associated with Suppression of Interleukin-12

Increased Sensitivity to Salmonella enterica Serovar Typhimurium Infection in Mice Undergoing Withdrawal from Morphine Is Associated with Suppression of Interleukin-12

Morphine Withdrawal Inhibits IL-12 Induction in a Macrophage Cell Line through a Mechanism That Involves cAMP

An in Vitro Model of Morphine Withdrawal Manifests the Enhancing Effect on Human Immunodeficiency Virus Infection of Human T Lymphocytes through the Induction of Substance P

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