A δ2-Opioid Agonist Inhibits p38 MAPK and Suppresses Activation of Murine Macrophages

Husted, Thomas L.; Govindaswami, Meera; Oeltgen, Peter R.; Rudich, Steven M.; Lentsch, Alex B.

doi:10.1016/j.jss.2005.04.003

Cited by 29 publications

(21 citation statements)

References 20 publications

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“…In this study, we found that DADLE, a synthetic opioid peptide, can inhibit the HMGB1 release from macrophages through a δ-opioid receptor (DOR)-dependent pathway. Earlier studies have found that HMGB1 has immunomodulatory and signal transduction effects by activating δ-opioid receptors that are widely expressed on immune cells (Quock et al 1999;Bidlack 2000;Husted et al 2005), and those effects could be blocked by the δ-opioid-selective antagonist naltrindole. Our results indicate that this δ-opioid agonist suppressed HMGB1 release through a novel anti- inflammatory pathway.…”

Section: Discussionmentioning

confidence: 99%

Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

Tang

Feng

et al. 2011

Tohoku J. Exp. Med.

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Sepsis is the major cause of death in intensive care units, despite enormous efforts in the development of antimicrobial therapies. Sepsis is mediated by early [e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β] and late [e.g., high-mobility group box 1 protein (HMGB1)] proinflammatory cytokines. HMGB1, which is secreted into extracellular milieu by activated macrophages or passively released by destroyed macrophages, stimulates intensive inflammatory responses. D-Ala2-D-Leu5-enkephalin (DADLE), a synthetic δ-opioid receptor agonist, has been shown to protect rats from sepsis. Here we elucidated the mechanism for protective effect of DADLE against sepsis. Sepsis was established in Sprague-Dawley rats by means of cecal ligation and puncture (CLP). In this model, the serum levels of TNF-α and IL-1β were increased after 2-3 h, while those of HMGB1 were increased after 18 h. Administration of DADLE (5 mg/ kg) concurrently with CLP improved survival, which was associated with the decreases in the serum levels of TNF-α, IL-1β and HMGB1. Importantly, DADLE administrated 4 h after CLP showed comparable protective effect as the concurrent administration, with decreased serum HMGB1 levels. Moreover, peritoneal macrophages isolated from rats were challenged with lipopolysaccharide (LPS). Concurrent or delayed DADLE administration at 10 −6 M suppressed the LPS-induced cell death. DADLE also suppressed the release of HMGB1 from macrophages that was induced by LPS, TNF-α or interferon-γ. In conclusion, DADLE protects rats from sepsis probably by decreasing the serum level of HMGB1. We propose DADLE as a candidate for septic shock therapy, even if it is administered after the onset of sepsis.

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Section: Discussionmentioning

confidence: 99%

Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

Tang

Feng

et al. 2011

Tohoku J. Exp. Med.

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“…One representative experiment of 3 is shown mediated through MOR is interconnected with LPSinduced TLR signaling in activated DCs. Previous studies have shown that opioids can modulate not only LPSinduced MAP kinase including p38 and ERK (Husted et al 2005;Korzh et al 2008;Macey et al 2006;Messmer et al 2006), but also LPS-induced NF-κB signaling (Frassdorf et al 2005;Azuma and Ohura 2002;Roy et al 1998b). Although the detailed mechanism of the interconnection remains unclear, it is predicted that regulatory molecules in GPCR signaling can interact with signaling components in other signaling pathways such as MAPK and allow these proteins to mediate signaling crosstalk, thus enabling the coordination of a precise and appreciable cellular response.…”

Section: Discussionmentioning

confidence: 99%

Inducible Expression of Functional Mu Opioid Receptors in Murine Dendritic Cells

Chu

Shan³

et al. 2009

J Neuroimmune Pharmacol

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Opioids are known to exert direct effects on the immune system, and the expression of functional opioid receptors has been reported on several immune cell types. Dendritic cells (DCs) are important inducers and regulators of immune responses. In this study, we investigated whether murine dendritic cells express functional mu opioid receptors (MOR). RT-PCR analysis and double immunofluorescence staining revealed the expression of MOR in activated murine dendritic cells. We also studied the dynamic expression of MOR messenger RNA in murine dendritic cells in response to different Toll-like receptor ligands. Functionally, treatment of DCs with endomorphin 1 (EM1), a specific agonist of MOR, can inhibit the forskolin-induced formation of cyclic adenosine monophosphate level in activated DCs. Moreover, EM1 treatment resulted in less activation of p38 MAPK and more activation of ERK signaling in lipopolysaccharide-stimulated DCs. Consistently, treatment of DCs with EM1 altered cytokine production by increasing IL-10 and decreasing IL-12 and IL-23. Our results suggest that MOR is inducibly expressed on activated DCs and functionally mediates EM1-induced effects on DCs. Thus, dendritic cells might be involved in crosstalk between the neuroendocrine and the immune system.

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“…In aging animals, DOPr stimulation induced no p38 activation and no increase in contractility upon recovery from ischemia (Peart et al, 2007). DOPr agonists also resulted in p38 activation in a murine macrophage cell line (Husted et al, 2005) and in cultured astrocytes (Liang et al, 2014). In the former, p38 activity reduced proinflammatory cytokine production; in the latter, it contributed together with ERK1/2 to the upregulation of excitatory amino acid transporters (Liang et al, 2014).…”

Section: B D-opioid Receptors and Mitogen-activated Protein Kinase Smentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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A δ2-Opioid Agonist Inhibits p38 MAPK and Suppresses Activation of Murine Macrophages

Cited by 29 publications

References 20 publications

Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

Inducible Expression of Functional Mu Opioid Receptors in Murine Dendritic Cells

Molecular Pharmacology ofδ-Opioid Receptors

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