Original articlesIncreased tumor necrosis factor-α and nitric oxide production by rat macrophages following in vitro stimulation and intravenous administration of the δ-opioid agonist SNC 80
Abstract
Opioids alter immune function by binding to opioid receptors on cells of the immune system, or indirectly by acting on receptors within the central nervous system. Mu-selective opioid agonists are generally associated with immunosuppression, whereas δ-opioid receptor-selective agonists are commonly associated with immunopotentiation. We have previously shown that intracerebroventricular administration of the non-peptide δ-opioid receptor agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC 80) did not alter certain parameters of immunocompetence. In the present study, we studied the in vitro and ex vivo effects of SNC 80 on rat macrophage and lymphocyte functions. We showed that SNC 80 at concentrations of 10−7 M and 10−6 M, significantly (P < 0.01) stimulated the in vitro production of tumor necrosis factor-alpha (TNF-α) (60–100% increase) and nitric oxide (34–67% increase) by resident and LPS-stimulated peritoneal macrophages. Similarly, intravenous administration of SNC 80 (6.8 mg/kg) significantly (P < 0.01) increased the production of TNF-α and nitric oxide (2- and 1.5-fold increases respectively, compared with saline-injected control) by LPS-stimulated splenic macrophages. In addition, intravenous injection of SNC 80 plus Con A potentiated ex vivo LPS-stimulated macrophage functions. SNC 80 could potentially be utilized in various clinical situations where immunosuppression is undesirable.
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The stimulative effects of endogenous opioids on endothelial cell proliferation, migration and angiogenesis in vitro
2010, European Journal of PharmacologyThe opioid peptides modulate extensive bioactivities, including pain, cardiovascular response, development and further responses. In the present study, the stimulative effects of endogenous opioid peptides on angiogenesis are evaluated in the proliferation, migration, adhesion and tube formation assays of the human umbilical vein endothelial cell (HUVEC) for the first time. Endomorphin-1, endomorphin-2 and deltorphin I at physiological concentrations could stimulate HUVECs proliferation, migration, adhesion and tube formation in a dose dependent manner; whereas, they exhibited the cytotoxic effects on HUVECs at the higher doses in these assays. Naloxone, the nonselective opioid receptor antagonist, did not influence angiogenesis when it was administrated on its own; but it could antagonize the stimulative effects of the opioid peptides on angiogenesis when it was administrated in combination with the opioid peptides. Taken altogether, the results suggested that endogenous opioid peptides (endomorphin-1 and -2 and deltorphin I) stimulated angiogenesis at the cellular level, and these effects were mediated by the opioid receptors. These data are significant for potential clinical implementation in future.
Reduction of lipopolysaccharide-induced interleukin-6 production by the kappa opioid U50,488 in a mouse monocyte-like cell line
2006, International ImmunopharmacologySeveral studies demonstrate that opioids modulate the immune response via opioid receptors expressed directly on the immune cells themselves. Recently, it has been suggested that the kappa opioid system has a modulatory role in various inflammatory diseases including rheumatoid arthritis. This modulation may occur via changes in cytokine secretion by monocyte-derived cells. To further study this opioid–immune relationship, we stimulated P388D1 cells, a mouse monocyte-like cell line, with lipopolysaccharide (LPS) in the presence or absence of the kappa opioid-selective ligand, U50,488. Pretreatment with U50,488 significantly reduced LPS-stimulated interleukin-6 (IL-6) production as measured by ELISA. This effect was mediated by the kappa opioid receptor, because nor-binaltorphimine (nor-BNI), a kappa-selective antagonist, blocked this inhibition. It is likely that this reduction of IL-6 protein by U50,488 treatment is attributed to decreases in IL-6 mRNA. RT-PCR experiments demonstrated that U50,488 treatment significantly reduced the LPS-mediated increase in IL-6 mRNA and that this effect was also blocked by nor-BNI. Understanding the mechanism behind the reduction of proinflammatory cytokine production by opioids may lead to the development of more effective therapeutics for inflammatory diseases.
Nitric oxide synthase mediates delta opioid receptor-induced hypothermia in rats
2006, European Journal of PharmacologyThe role of nitric oxide (NO) production in delta opioid receptor-induced hypothermia has not been reported. The present study investigated the effect of nitric oxide synthase (NOS) inhibitors on the hypothermic effect of (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), a nonpeptide delta opioid agonist. SNC-80 (35 mg/kg, i.p.) administered to rats caused a significant hypothermia. N-nitro-l-arginine methyl ester (l-NAME) (10, 25 and 50 mg/kg, i.p.), a NOS inhibitor, and 7-nitroindazole (7-NI) (5 and 10 mg/kg, i.p.), a neuronal NOS inhibitor, were ineffective. For combined administration, l-NAME (50 mg/kg, i.p.) or 7-NI (10 mg/kg, i.p.) attenuated SNC-80-evoked hypothermia. To determine the involvement of central NOS, l-NAME (0.25, 0.5 and 1 mg/rat) was administered i.c.v. 30 min prior to SNC-80 (35 mg/kg, i.p.). Experiments revealed that l-NAME (1 mg/rat, i.c.v.) attenuated SNC-80-induced hypothermia. The present data demonstrate that central NO production is necessary for delta opioid receptor-induced hypothermia.
Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit
2006, European Journal of PharmacologyOur laboratory has shown previously that subcutaneously implanted, slow-release morphine pellets markedly enhanced susceptibility to oral infection with Salmonella typhimurium. Further, morphine, kappa and delta opioid receptor agonists infused via osmotic minipumps were immunosuppressive. The present study compared morphine pellets to morphine pumps and also examined the differential effects of morphine versus U50,488H (kappa agonist), deltorphin II (delta2 agonist), and (D-Pen2, D-Pen5)-enkephalin (DPDPE, delta1 agonist), administered via Alzet® minipumps, on oral Salmonella infection and on gastrointestinal transit. The results show that all morphine-pelleted mice (26 / 26) had a marked increase in Salmonella burden in the Peyer's Patches, mesenteric lymph nodes and spleen. In comparison, only 8 / 20 mice receiving morphine by minipump at doses ranging from 1 to 25 mg/kg/day had any culturable Salmonella in their organs and the number of bacteria was very low. The level of Salmonella colonization correlated with blood morphine levels and gut transit measured using an intragastric charcoal meal. Morphine pellets inhibited gut transit by 38%, while mice receiving morphine by minipump at doses of 1 to 25 mg/kg/day showed only a dose-dependent 7% to 17% inhibition. Mice receiving various doses of U50,488H or DPDPE had no culturable Salmonella in the three sites. Deltorphin II given by minipump resulted in a moderate level of Salmonella in the spleen. Deltorphin II and U50,488H (0.1 to 10 mg/kg/day) did not suppress gut transit. The present studies indicate that a predominantly mu opioid receptor agonist, morphine, given by slow-release pellet, potentiated Salmonella infection and inhibited gastrointestinal transit. In contrast, morphine in pumps slightly inhibited intestinal transit, but did not sensitize to Salmonella infection. A delta1 opioid receptor agonist did not sensitize to infection, and a delta2 and a kappa opioid receptor agonist had minimal effects on either parameter.
Delta opioid agonists attenuate TAT<inf>1-72</inf>-induced oxidative stress in SK-N-SH cells
2006, NeuroToxicologyPrevious reports have indicated that the use of δ agonists may prove to be a viable therapeutic tool as an analgesic agent without conventional opioid side effects. In addition, recent evidence suggests that δ ligands may exert neuroprotective effects under a variety of toxin insults. The aim of the present studies was to assess the ability of δ agonists (peptide: [D-Pen2,5] enkephalin (DPDPE), non-peptide: (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80)) and antagonists (naltrindole) to modify dichlorofluorescein (DCFH) fluorescence in the presence of the peroxynitrite generator, 3-morpholinylsydnoneimine chloride (SIN-1) or HIV-protein, TAT1–72 (TAT) in SK-N-SH cells. Both DPDPE (100 nM) and SNC-80 (250 nM) attenuated (30–50%) the increased oxidative stress in the presence of SIN-1. This effect was partially reversed by addition of naltrindole, suggesting involvement of δ receptors. Peroxynitrite radicals are involved in neurotoxicity associated with TAT. Incubation with TAT (10–250 nM) demonstrated a concentration-dependent increase in oxidative stress up to 200% over control values. Preincubation with δ agonists reduced 50 nM TAT-mediated oxidative stress 15–40%, which was partially reversed by naltrindole. Increasing log-concentrations of DPDPE or SNC-80 (0.01–100 μM) attenuated TAT-mediated oxidative stress up to 50% at 100 μM. In conclusion, these data demonstrate that both peptide and non-peptide delta agonists can partially attenuate intracellular oxidative stress, in part through a receptor-mediated mechanism. This suggests that delta ligands may have therapeutic usefulness in HIV patients beyond analgesia.
Potentiation of rat lymphocyte proliferation by novel non-peptidic synthetic opioids
2005, International ImmunopharmacologyOpioids represent a major source of relief for acute and chronic, moderate to severe nonmalignant pain. However, opioid abuse may cause immunosuppression leading to infections and cancer development. Recently we reported results on novel non-peptidic delta- and mu-selective opioids that induced immunopotentiation in vitro and ex vivo. In the present study, we investigated the effects of the delta agonist SNC 80, and mu agonists, naltrindole and naltrexone derivatives for their capacity to alter lymphoproliferation in vitro. They were observed to stimulate lymphoproliferation at concentrations ranging from 10− 10 to 10− 5 M. SNC 80 significantly (p < 0.05) stimulated (43–311%) proliferation of resident and concanavalin A (Con A)-treated lymphocytes; the naltrindole derivatives 9332 and 9333 caused significant (p < 0.05) 26–47% and 13–43%, respectively, stimulation of Con A-treated lymphoproliferation; whereas the naltrexone derivatives 9334 and 9336 significantly (p < 0.05) stimulated 9–40% and 15–69%, respectively, proliferation of resident and Con A-treated lymphocytes. These novel opioid ligands could serve as immunotherapeutic agents by increasing the pool of lymphocytes with potential use in the treatment of infectious diseases including AIDS. This study provides evidence of the relationship structure/function of opioids on lymphoproliferation, and supports further evaluation of opioids with immunomodulatory potential in preclinical and clinical studies.