Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunomodulatory effects of morphine are well established; however, suprisingly little is known about the immunomodulatory properties of the major metabolites of morphine. The present study tests the hypothesis that expression of inducible nitric oxide synthase (iNOS) is modulated by the administration of the morphine metabolite, morphine-6beta-glucuronide. The initial study using rats shows that morphine-6beta-glucuronide administration (0, 1.0, 3.163, 10 mg/kg s.c.) results in a pronounced reduction in lipopolysaccharide (LPS)-induced expression of iNOS (inducible nitricoxide synthease) in spleen, lung, and liver tissue as measured by western blotting. Morphine-6beta-glucuronide also produces a reduction in the level of plasma nitrite/nitrate, the more stable end-product of nitric oxide degradation. In a subsequent study, administration of the opioid receptor antagonist, naltrexone (0.1 mg/kg) prior to the injection of morphine-6beta-glucuronide (10 mg/kg) blocks the morphine-6beta-glucuronide induced reduction of iNOS expression and plasma nitrite/nitrite levels indicating that the effect is mediated via the opioid-receptor. This study provides the first evidence that morphine-6beta-glucuronide alters the expression of iNOS.
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PMID:Morphine-6beta-glucuronide modulates the expression of inducible nitric oxide synthase. 1158 Jan 3

In the present work, the effect of intrahippocampal microinjection of opioid receptor antagonist naloxone on the enhancement of cellular immune responses induced by enkephalin was studied in rat. The results showed that (1) the proliferation activity of splenic lymphocytes stimulated by Con A and natural killer (NK) cell activity were decreased with microinjection of 1 microl lipopolysaccharide (LPS,50 ng/microl) into bilateral hippocampus; (2) the decrease of cellular immune responses induced by LPS could be inhibited by a preceding intrahippocampal injection of 1 microl met-enkephalin (10 microg/1 microl); (3) the enhancement of cellular immune responses induced by met-enkephalin could be blocked by an opioid receptor antagonist naloxon (10 microg/microl); and (4) cellular immune responses were also inhibited when naloxon was injected intrahippocampally alone. The above results suggest that the enhancement of cellular immune responses induced by enkephalin was mediated by opioid receptors in hippocampus.
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PMID:[Opioid receptor mediated modulation of intrahippocampal enkephalin induced cellular immune function]. 1197 84

The endogenous opioid system has been found to be involved in fever caused by pyrogens. Recent work in our laboratory has demonstrated that the mu-opioid receptor is involved in interleukin-1beta (IL-1beta)- and in lipopolysaccharide (LPS)-induced fevers. In the present study, we have investigated the role of the mu-opioid receptor in the preoptic anterior hypothalamus (POAH) in fever induced by interleukin-6 (IL-6). Following stereotaxic implantation of a guide cannula into the POAH for microinjection, radio transmitters to monitor body temperature (Tb) continuously were inserted intraperitoneally. Adult male Sprague-Dawley rats were microinjected with 0.5 microg of the selective mu-opioid receptor antagonist, cyclic D-phe-Cys-Try-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), into the POAH. Thirty min later, IL-6 (100 ng) was injected into the POAH. CTAP significantly blocked the IL-6 fever. CTAP alone had no effect on Tb during the 390-min recording period. These data indicate that mu-opioid receptors within the POAH mediate IL-6 fever and add to the increasing evidence that the opioid system is involved in the pathogenesis of fever in rats.
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PMID:Effect of a mu-opioid receptor-selective antagonist on interleukin-6 fever. 1200 6

Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.
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PMID:Role of nitric oxide in inflammation-mediated neurodegeneration. 1207 84

At first, we investigated whether both beta-endorphin release level in the hypothalamus and body temperature can be altered after intracerebroventricular (i.c.v.) injection of either lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), or prostaglandin E(2) (PGE(2)) in rats. It was found that in the rat, i.c.v. administration of either LPS (0.5 microg in 10 microl), IL-1beta (10 ng in 10 microl), or PGE(2) (200 ng in 10 microl), in addition to producing fever, upregulated the immunoreactivity of beta-endorphin in the preoptic anterior hypothalamus of rat brain. Secondarily, we assessed whether the fever induced by either LPS, IL-1beta, or PGE(2) can be altered by pretreatment with buprenorphine (an opioid receptor antagonist). The results revealed that i.c.v. administration of buprenorphine (1 - 10 microg in 10 microl) alone had an insignificant effect on the body temperature. However, the fever induced by i.c.v. injection of either LPS, IL-1beta, or PGE(2) was significantly attenuated by pretreatment with i.c.v. injection of buprenorphine 1 h before the pyrogen injection in rats. The results suggest that pyrogens enhance beta-endorphin release in the hypothalamus and trigger fever which can be attenuated by buprenorphine, an opioid receptor antagonist.
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PMID:Pyrogens enhance beta-endorphin release in hypothalamus and trigger fever that can be attenuated by buprenorphine. 1457 83

Central nervous system (CNS) inflammation in cases such as head trauma, infection and stroke has been associated with the occurrence of epileptic seizures. Microglia, the principal immune cells in the brain, readily become activated in response to injury, infection or inflammation. The bacterial endotoxin lipopolysaccharide (LPS) induces the activation of microglia and the production of proinflammatory factors including nitric oxide (NO) and prostaglandins (PGs). We examined the effect of LPS on seizure susceptibility of mice, by using the sensitive test, threshold of clonic seizures induced by i.v. infusion of pentylenetetrazole. LPS decreased the seizure threshold in a dose- and time-dependent manner. Pretreatment of mice with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester or cyclooxygenase inhibitor, piroxicam or the opioid receptor antagonist, (-)-naloxone completely reversed the proconvulsant effect of LPS. These results indicate that NO, PGs and endogenous opioid peptides seem to be involved in LPS-induced decrease in seizure threshold.
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PMID:The bacterial endotoxin lipopolysaccharide enhances seizure susceptibility in mice: involvement of proinflammatory factors: nitric oxide and prostaglandins. 1464 73

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP opioid receptor (previously referred to as ORL1 or OP4 receptor), exerts a variety of behavioral effects. N/OFQ as well as the synthetic NOP receptor agonist Ro 64-6198 have been reported to possess antistress properties and to elicit a pronounced hyperphagic effect in freely feeding rats. These findings have raised our interest to investigate possible interactions in the control of ingestive behavior between N/OFQ and corticotropin-releasing factor (CRF), which is well known to be a major mediator of stress and to possess anorectic properties. These studies have shown that intracerebroventricular injections of N/OFQ or of Ro 64-6198 reverse the anorectic action evoked by intracerebroventricular administration of CRF. The anti-anorectic effect of N/OFQ or Ro 64-6198 is antagonized by the selective NOP receptor antagonist [Nphe1]N/OFQ1-13NH2, providing evidence that it is mediated by this receptor. The effect occurs at doses that are not hyperphagic per se and is clearly selective versus the anorectic action of CRF since N/OFQ or Ro 64-6198 do not influence the anorectic effect of Escherichia coli lipopolysaccharide (LPS). Neither N/OFQ nor Ro 64-6198 shows affinity for CRF receptors, suggesting that NOP receptor agonists might act as functional antagonists of CRF with regard to its anorectic action. Microinjection studies have revealed that the bed nucleus of the stria terminalis (BNST) is highly sensitive to the anorectic action of CRF, as well as to the anti-anorectic action of N/OFQ; pretreatment with 0.025-0.25 microg/site of N/OFQ into the BNST blocked the anorectic action of 0.1 microg/site of CRF given in the same area. On the other hand, intra-BNST microinjection of 0.025-0.25 microg/site of N/OFQ did not modify basal food intake. Thus, the BNST may be the site where the functional antagonism between N/OFQ and CRF takes place. These findings raise interest for the N/OFQ-NOP receptor system as a pharmacological target to block the anorectic effect of CRF. In comparison to CRF receptor antagonists, NOP receptor agonists may have the advantage of not inhibiting the hypothalamic-pituitary-adrenal (HPA) axis.
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PMID:Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect. 1523 92

Septic shock is believed to be a consequence of excessive stimulation of the immune system by bacterial toxins that results in systemic overproduction of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), IL-1, and IL-6. Various studies have shown that TNF-alpha, a major mediator of septic shock, induces tissue injury, loss of blood pressure, organ failure, and ultimately death. Administration of the opioid antagonist naloxone has been reported to reverse opiate-mediated hypotension, promote organ perfusion and increase patient survival. In this study, we examined the mechanism by which the opioid receptor antagonist, naltrexone, modulates the septic shock response in BALB/c mice after injection with lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) in combination with d-galactosamine (d-gal), or with agonistic anti-Fas antibody (Jo2) alone. Each of these treatments induced rapid-onset, acute shock, and ultimately mortality (6-9h after injection), although different mechanisms are involved. Administration of the opioid antagonist naltrexone protected mice from shock induced by LPS+d-gal, but not SEB+d-gal or Jo2 antibody, a protective effect that was reversed by morphine. Naltrexone significantly inhibited the production of TNF-alpha induced by LPS, but not SEB in vivo. When bone marrow-derived, splenic or peritoneal macrophages were treated with LPS in vitro, administration of naltrexone had no direct effect on TNF-alpha production. These results suggest that naltrexone is capable of preventing LPS-induced septic shock mortality by indirect inhibition of TNF-alpha production in vivo.
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PMID:The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production. 1526 41

Intraperitoneal (i.p.) injection of toxins, such as the bacterial endotoxin lipopolysaccharide (LPS), is associated with a well-characterized increase in sensitivity to painful stimuli (hyperalgesia) [Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 1995;63:289-302. [53]] and a longer-lasting reduction in opioid analgesia (anti-analgesia) when pain sensitivity returns to basal levels [Johnston IN, Westbrook RF. Acute and conditioned sickness reduces morphine analgesia. Behav Brain Res 2003;142:89-97]. Here we show that this inhibition of morphine analgesia 24 h after a single i.p. injection of LPS involves mechanisms that contribute to illness-induced hyperalgesia and the development of analgesic tolerance to morphine. Specifically, morphine analgesia was restored if LPS was preceded by systemic administration of a non-competitive NMDA receptor antagonist (MK-801), spinal infusion of a glial metabolic inhibitor (fluorocitrate), or intracerebroventricular microinjection of an opioid receptor antagonist (naloxone). Morphine analgesia was also restored if MK-801 was administered after LPS. These results demonstrate that LPS recruits similar, if not the same mechanisms that reduce morphine tolerance following opiate administration: namely, stimulation of opioid and NMDA receptors and recruitment of spinal glia.
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PMID:Inhibition of morphine analgesia by LPS: role of opioid and NMDA receptors and spinal glia. 1547 52

Recently, we demonstrated that lipopolysaccharide (LPS)-induced fever could be suppressed by a selective mu-opioid receptor antagonist, indicating that the mu-opioid system is involved in the LPS fever. In the present study, to confirm the role of the mu-opioid system in the pathogenesis of LPS fever, we used mice lacking the mu-opioid receptor. In the wild type (WT), following intraperitoneal (i.p.) injection of 100 microg kg(-1) of LPS, body temperature (T(b)) increased approximately 1 degrees C and remained elevated during the 360-min recording period. In the mu-opioid receptor knockout (MOR-KO) mice, the administration of 100 microg kg(-1) i.p. of LPS did not induce fever during the recording period. Saline by itself, given i.p., did not alter the T(b), either in WT or MOR-KO. These results confirm that the mu-opioid system is involved in LPS-induced fever.
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PMID:Unresponsiveness of mu-opioid receptor knockout mice to lipopolysaccharide-induced fever. 1570 26


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