Distinction between the in vitro and in vivo inhibitory effects of morphine on lymphocyte proliferation based on agonist sensitivity and naltrexone reversibility

Bayer, Barbara; Gastonguay, Marc R.; Hernandez, Monica C.

doi:10.1016/0162-3109(92)90035-b

Cited by 55 publications

(15 citation statements)

References 19 publications

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“…The results of the present study sug gest that immunomodulation produced by morphine is at least partially independent from its pharmacological characteristics. This hypothesis is consonant with the findings of other investigators [25][26][27][28], In summary, in vitro exposure to mor phine and its metabolites resulted in modula tion of a variety of immune regulatory and effector functions. In general, the metabolites of morphine appear to exhibit greater immu nomodulatory potential in vitro than the par ent compound.…”

Section: Discussionsupporting

confidence: 79%

Immunomodulatory Effects of in vitro Exposure to Morphine and Its Metabolites

Thomas

Bhargava²,

House³

1995

Pharmacology

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Both in vivo and in vitro exposure to morphine have been reported to produce a number of immunomodulatory effects in both laboratory animals and humans. The current study was performed to assess the direct in vitro effect of exposure to morphine or morphine metabolites on immune response parameters. Murine B6C3F1 splenic lymphocytes or peritoneal macrophages were cultured in vitro at concentrations of 0.0001-100 µmol/l morphine sulfate, morphine-3-glucuronide, morphine-6-glucuronide, or normorphine. B cell proliferation was significantly suppressed following exposure to all drugs. Production of interleukin (IL)-2, IL·4, and IL·6 was affected only moderately by all drugs except morphine-6-glucuronide, which produced a marked suppression at 100 µmol/l. Both basal and augmented natural killer (NK) cell function were unaffected by any drug except morphine-6-glucuronide, which enhanced NK cell activity at concentrations between 0.0001 and 1.0 µmol/l. In contrast, both morphine-3-glucuronide and morphine-6-glucuronide significantly inhibited cytotoxic T lymphocyte induction at concentrations between 0.0001 and 100 µmol/l, whereas morphine and normorphine were inactive in this assay. In summary, in the absence of direct cellular cytotoxicity, a differential immunomodulation was observed following in vitro exposure to morphine and its metabolites.

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Section: Discussionsupporting

confidence: 79%

Immunomodulatory Effects of in vitro Exposure to Morphine and Its Metabolites

Thomas

Bhargava²,

House³

1995

Pharmacology

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“…Morphine increased mortality of infected mice (Chao et al 1990;Tubaro et al 1983). Also, morphine inhibited the cytolytic activity of NK cells and mitogen-stimulated proliferation (Bayer et al 1990(Bayer et al , 1992Fecho et al 1993;Weber and Pert 1989). Morphine was shown to affect the brain-immune axis by modulating an IL-1β-dependent pathway (Chang et al 1996).…”

Section: Functional Evidence For the Presence Of Mu Opioid Receptors mentioning

confidence: 94%

Opioid Receptors and Signaling on Cells from the Immune System

Bidlack

Khimich

Parkhill

et al. 2006

Jrnl Neuroimmune Pharm

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This review discusses the criteria for determining whether a binding site or functional response is directly mediated by either the mu, delta, or kappa opioid receptors. In 1988, Sibinga and Goldstein published the first review that addressed whether cells from the immune system express opioid receptors. The criteria that they used, namely, structure-activity relationships, stereoselectivity, dose- and concentration-dependence, and saturability are still relevant criteria today for determining if an immunological response is mediated by either the mu, delta or kappa opioid receptors. Radioligand receptor binding studies and functional studies that clearly show the presence of an opioid receptor on immunocytes are presented. Selective agonists and antagonists for the mu, delta, and kappa opioid receptors are discussed, and the need for their use in experiments is emphasized. Conditions used in functional assays are very important. Receptor desensitization and downregulation occur within minutes after the application of an agonist. However, many immunological assays are applying an agonist for days before measuring an immunological effect. The results obtained may reflect changes that are results of receptor desensitization and/or downregulation instead of changes that are observed with acute activation of the receptor. The future of receptor pharmacology lies in the crosstalk and dimerization of G protein-coupled receptors. In transfected systems, opioid receptors have been shown to dimerize with chemokine and cannabinoid receptors, resulting in crosstalk between different types of receptors.

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“…These data suggest that morphine acts through a receptor-mediated effect with an ED 50 value of 13.8 mg/kg. However, this dose is relatively higher than the dose of morphine required to inhibit lymphocyte proliferative responses (Bayer et al, 1992) or to produce analgesic responses (for review, see Martin, 1984). The highdose requirements suggest the effect of morphine on plasma IL-6 may have greater impact during the clinical use of opioids to produce anesthesia or in the recreational illicit use of these drugs.…”

Section: Discussionmentioning

confidence: 99%

Rapid Elevation of Plasma Interleukin-6 by Morphine Is Dependent on Autonomic Stimulation of Adrenal Gland

Houghtling

Bayer²

2002

The Journal of Pharmacology and Experimental Therapeutics

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Several studies have demonstrated that opioids regulate a number of immune cell functions either through direct mechanisms or through the modulation of central nervous system outputs. It has been previously shown that morphine increases serum interleukin-6 (IL-6) levels; however, the mechanism by which this effect is produced is unknown. In the present study, experiments were designed to address the potential role of central opioid receptors, peripheral autonomic ganglia, and activation of the adrenals in the elevation of plasma IL-6 after morphine administration. A rapid and significant (2-fold) increase in plasma IL-6 was observed after morphine administration (10 mg/kg s.c.) to rats. This effect of morphine peaked within 30 min and remained elevated for at least 2 h. Central microinjection of morphine (10 g/2 l i.c.v.) mimicked the effects of peripherally administered morphine and was completely blocked by naltrexone (10 mg/kg s.c.) pretreatment. Pretreatment with a ganglionic blocker, chlorisondamine (0.5 mg/kg i.p.), also blocked the elevation of IL-6 by morphine, suggesting a role of the autonomic nervous system. In adrenalectomized animals, morphine administration did not increase IL-6 levels, whereas in adrenal demedullated animals, the effect of morphine remained intact. Thus, the adrenal cortex may be a potential source of IL-6, because IL-6 mRNA has been localized in the adrenal gland. Collectively, these data suggest a unique mechanism by which stimulation of central opioid receptors results in the elevation of plasma IL-6 through autonomic activation specifically of the adrenal cortex.

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Distinction between the in vitro and in vivo inhibitory effects of morphine on lymphocyte proliferation based on agonist sensitivity and naltrexone reversibility

Cited by 55 publications

References 19 publications

Immunomodulatory Effects of in vitro Exposure to Morphine and Its Metabolites

Immunomodulatory Effects of in vitro Exposure to Morphine and Its Metabolites

Opioid Receptors and Signaling on Cells from the Immune System

Rapid Elevation of Plasma Interleukin-6 by Morphine Is Dependent on Autonomic Stimulation of Adrenal Gland

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