Abolition of morphine-immunosuppression in mice lacking the μ-opioid receptor gene

Gavériaux‐Ruff, Claire; Matthes, Hans W. D.; Peluso, John J.; Kieffer, Brigitte L.

doi:10.1073/pnas.95.11.6326

Cited by 152 publications

(93 citation statements)

References 26 publications

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“…[11][12][13]17 Opioid-induced splenocyte apoptosis was prevented by either opioid receptor antagonists or recombinant Fas-Ig or anti-FasL antibodies. 11,12 A similar opioid effect in adrenalectomized and sham-operated mice ruled out a mechanism dependent on the hypothalamicpituitary-adrenal axis.…”

Section: Resultsmentioning

confidence: 99%

“…12,13 The major role of the MOR in the sensitization of splenocytes to Fas-mediated apoptosis was supported by the abrogation of the opioid-induced spleen atrophy in MOR knockout mice. 13,17 In vitro, experiments performed on immune cells-including lymphocytes and macrophages-showed that a direct interaction with morphine resulted in up-regulation of Fas mRNA. 11,18 Together, these data assume that spleen cell sensitization to Fas-mediated apoptosis induced by opioids was a paracrine/autocrine MOR-mediated effect associated with an increase in Fas mRNA.…”

Section: Resultsmentioning

confidence: 99%

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Opioid receptor blockade reduces Fas-induced hepatitis in mice

et al. 2004

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Fas (CD95)-induced hepatocyte apoptosis and cytotoxic activity of neutrophils infiltrating the injured liver are two major events leading to hepatitis. Because it has been reported that opioids, via a direct interaction, sensitize splenocytes to Fas-mediated apoptosis by upregulating Fas messenger RNA (mRNA) and modulated neutrophil activity, we assumed that opioids may participate in the pathophysiology of hepatitis. Using the hepatitis model induced by agonistic anti-Fas antibody in mice, we showed that opioid receptor blockade reduced liver damage and consequently increased the survival rate of animals when the antagonist naltrexone was injected simultaneously or prior to antibody administration. Treatment of mice with morphine enhanced mortality. Naloxone methiodide-a selective peripheral opioid antagonist-had a protective effect, but the absence of opioid receptors in the liver, together with lack of morphine effect in Fas-induced apoptosis of primary cultured hepatocytes, ruled out a direct effect of opioids on hepatocytes. In addition, the neutralization of opioid activity by naltrexone did not modify Fas mRNA expression in the liver as assessed with real-time quantitative polymerase chain reaction. Injured livers were infiltrated by neutrophils, but granulocyte-depleted mice were not protected against the enhancing apoptotic effect of morphine. In conclusion, opioid receptor blockade improves the resistance of mice to Fas-induced hepatitis via a peripheral mechanism that does not involve a down-modulation of Fas mRNA in hepatocytes nor a decrease in proinflammatory activity of neutrophils.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Opioid receptor blockade reduces Fas-induced hepatitis in mice

et al. 2004

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“…Recently, mor-null mouse studies have confirmed that MOR is involved in morphine immunosuppression (Gaveriaux-Ruff et al 1998;Roy et al 1998a). The transcription factor NF-κB is one of the most important transcription factors in immune cells (Li and Verma 2002).…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor κB Signaling in Opioid Functions and Receptor Gene Expression

Chen

Law

Loh

2006

Jrnl Neuroimmune Pharm

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Opiates are the most powerful of all known analgesics. The prototype opiate morphine has been used as a painkiller for several thousand years. Chronic usage of opiates not only causes drug tolerance, dependence, and addiction, but also suppresses immune functions and affects cell proliferation and cell survival. The diverse functions of opiates underscore the complexity of opioid receptor signaling. Several downstream signaling effector systems, including adenylyl cyclase, mitogen-activated protein kinase, Ca 2+ channels, K + channels, and phosphatidylinositol 3-kinase/Akt, have been identified to be critical in opioid functions. Nuclear factor-κB (NF-κB), one of the most diverse and critical transcription factors, is one of the downstream molecules that may either directly or indirectly transmit the receptor-mediated upstream signals to the nucleus, resulting in the regulation of the NF-κB-dependent genes, which are critical for the opioid-induced biological responses of neuronal and immune cells. In this minireview, we focus on current understanding of the involvement of NF-κB signaling in opioid functions and receptor gene expression in cells.

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“…Three major mechanisms have been hypothesized for these effects: direct involvement of opioid receptors, hypothalamic pituitary adrenal (HPA) axis activation, and increased sympathetic nervous system activity. There is clear evidence for a role of opioid receptors, as mu-opiate receptor knockout (MORKO) animals did not display the same degree of immunosuppression as wildtype mice (Gavériaux-Ruff et al, 1998;Roy et al, 1998). Pharmacological studies have likewise implicated mu opiate receptors (e.g., Nelson et al, 2000; reviewed by Carr et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Prenatal opiate exposure attenuates LPS-induced fever in adult rats: Role of interleukin-1β

Hamilton¹,

Franklin²,

Roy³

et al. 2007

Brain Research

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Much is known about the immunomodulatory effects of opiate exposure and withdrawal in adult rats. However, little research has delved into understanding the immunological consequences of prenatal opiate exposure and postnatal withdrawal. The purpose of the current study was to measure changes in responding to immune stimulation in adult rats following prenatal opiate exposure. Further, we sought to characterize the role of interleukin (IL)-1β in these changes. Following prenatal exposure to the long-acting opiate l-alpha-acetylmethadol (LAAM), adult male and female rats were assessed for their fever response to lipopolysaccharide (LPS). Blood and tissue samples were collected to measure circulating IL-1β and IL-1β protein in the hypothalamus and spleen. Prenatal LAAM exposure resulted in a blunted fever response to LPS injection without any changes in basal body temperature or in response to saline injection. Circulating IL-1β was not affected by prenatal LAAM exposure, nor was IL-1β protein in the spleen. Interestingly, mature IL-1β protein was elevated in the hypothalamus of prenatally LAAM-treated rats. These results indicate that prenatal opiate exposure blunts the fever response of adult offspring. Direct action of IL-1β is likely not the cause of the dysfunction reported here. However, alterations in signaling mechanisms downstream from IL-1β may play a role in the altered fever response in adult rats treated prenatally with opiates.

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Abolition of morphine-immunosuppression in mice lacking the μ-opioid receptor gene

Cited by 152 publications

References 26 publications

Opioid receptor blockade reduces Fas-induced hepatitis in mice

Opioid receptor blockade reduces Fas-induced hepatitis in mice

Nuclear Factor κB Signaling in Opioid Functions and Receptor Gene Expression

Prenatal opiate exposure attenuates LPS-induced fever in adult rats: Role of interleukin-1β

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