Fas-mediated cell death promoted by opioids

Yin, Deling; Mufson, R. A.; Wang, Ruoxiang; Shi, Yufang

doi:10.1038/16612

Cited by 170 publications

(118 citation statements)

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“…In addition, exposure of human PBLs to ␤-endorphin has been shown to induce apoptotic cell death (35). Furthermore, it has been shown that up-regulated Fas may mediate the morphine-induced T cell apoptosis (18). Blocking of endogenous opioids with naloxone has been demonstrated to attenuate or reverse stress-induced immune alterations (13,14).…”

Section: Discussionmentioning

confidence: 99%

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μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

Wang

Charboneau

Barke

et al. 2002

The Journal of Immunology

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Psychological stress is associated with immunosuppression in both humans and animals. Although it was well established that psychological stressors stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting in the release of various hormones and neurotransmitters, the mechanisms underlying these phenomena are poorly understood. In this study, μ-opioid receptor knockout (MORKO) mice were used to investigate whether the μ-opioid receptor mediates the immunosuppression induced by restraint stress. Our results showed that wild-type (WT) mice subjected to chronic 12-h daily restraint stress for 2 days exhibited a significant decrease in splenocyte number with a substantial increase in apoptosis and CD95 (Fas/APO-1) expression of splenocytes. The effects are essentially abolished in MORKO mice. Furthermore, inhibition of splenic lymphocyte proliferation, IL-2, and IFN-γ production induced by restraint stress in WT mice was also significantly abolished in MORKO mice. Interestingly, both stressed WT and MORKO mice showed a significant elevation in plasma corticosterone and pituitary proopiomelanocortin mRNA expression, although the increase was significantly lower in MORKO mice. Adrenalectomy did not reverse restraint stress-induced immunosuppression in WT mice. These data clearly established that the μ-opioid receptor is involved in restraint stress-induced immune alterations via a mechanism of apoptotic cell death, and that the effect is not mediated exclusively through the glucocorticoid pathway.

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Section: Discussionmentioning

confidence: 99%

“…Previous studies by Yin et al (13,18) have shown that chronic restraint stress results in decreased splenic cellularity by a mechanism associated with CD95-mediated apoptosis. Naloxone (an opioid antagonist) and Fas antagonists attenuated this effect, implicating endogenous opioids involvement in CD95-mediated splenocyte apoptosis.…”

mentioning

confidence: 99%

μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

Wang

Charboneau

Barke

et al. 2002

The Journal of Immunology

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“…In this context, Fas proteins (native and glycosylated receptor, and complexes of monomers relevant in Fas signaling) were shown to be upregulated after chronic heroin and morphine treatments and heroin withdrawal in rat brain (Boronat et al, 2001;García-Fuster et al, 2003a, 2004a, which suggested a role for Fas in opiate addiction either as promoter of abnormal cell death (see Yin et al, 1999;Wang et al, 2002) or as a possible nonapoptotic signal transducer of opioid receptors (see Tegeder and Geisslinger, 2004). To clarify this issue, the present study was designed to assess the modulation of FADD (the transmitter of Fas signal) and effector caspase-8/3 in the brain after the acute and chronic treatments with selective m-, d-, and k-opioid peptide (MOP-, DOP-, and KOP-) receptor agonists, and during the induction of opiate withdrawal in rats.…”

Section: Introductionmentioning

confidence: 99%

Effects of Opiate Drugs on Fas-Associated Protein with Death Domain (FADD) and Effector Caspases in the Rat Brain: Regulation by the ERK1/2 MAP Kinase Pathway

García-Fuster

Miralles

Garcı́a-Sevilla

2006

Neuropsychopharmacol

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This study was designed to assess the effects of opiate treatment on the expression of Fas-associated protein with death domain (FADD) in the rat brain. FADD is involved in the transmission of Fas-death signals that have been suggested to contribute to the development of opiate tolerance and addiction. Acute treatments with high doses of sufentanil and morphine (m-agonists), , and U50488H (k-agonist) induced significant decreases (30-60%) in FADD immunodensity in the cerebral cortex, through specific opioid receptor mechanisms (effects antagonized by naloxone, naltrindole, or nor-binaltorphimine). The cannabinoid CB 1 receptor agonist WIN 55,212-2 did not alter FADD content in the brain. Chronic (5 days) morphine (10-100 mg/kg), SNC-80 (10 mg/kg), or U50488H (10 mg/kg) was associated with the induction of tachyphylaxis to the acute effects. In morphine-and SNC-80-tolerant rats, antagonistprecipitated (2 h) or spontaneous withdrawal (24-48 h) induced a new and sustained inhibition of FADD (13-50%). None of these treatments altered the densities of caspases 8/3 (including the active cleaved forms) in the brain. Pretreatment of rats with SL 327 (a selective MEK1/2 inhibitor that blocks ERK activation) fully prevented the reduction of FADD content induced by SNC-80 in the cerebral cortex (43%) and corpus striatum (29%), demonstrating the direct involvement of ERK1/2 signaling in the regulation of FADD by the opiate agonist. The results indicate that m-and d-opioid receptors have a prominent role in the modulation of FADD (opposite to that of Fas) shortly after initiating treatment. Opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of the antiapoptotic ERK1/2 signaling pathway.

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“…Endogenous opiates may even constitute a new class of signaling molecules. The identification of the genes and enzymes responsible for morphine biosynthesis in humans and animals will possibly indicate how the pathway arose in the animal kingdom and may provide new pharmacological targets for the modulation of pain, immune responses (28,29), and cell death (30).…”

Section: Stereochemistry Of Reticuline and Morphinementioning

confidence: 99%