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Biomedical subjects

S Poole

Publications and source records attributed to S Poole.

At least 91 records · Page 5Linked to original sources
PubMed1996

Zinc reduces the hyperalgesia and upregulation of NGF and IL-1 beta produced by peripheral inflammation in the rat.

The effect of systemic zinc administration on the inflammatory hyperalgesia induced by intraplantar injections of either complete Freund's adjuvant (CFA) or bacterial endotoxin/lipopolysaccharide (LPS) in a hindpaw of adult rats was investigated. CFA injection resulted in mechanical and thermal hyperalgesia and an elevation in the levels of interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) in the ipsilateral hindpaw. Zinc treatment (20 nmole) significantly reduced sensitivity in the early phase of the inflammation and diminished the increase in the levels of IL-1 beta and NGF without affecting paw swelling. Intraplantar LPS injection also produced mechanical hyperalgesia and this too was reduced by zinc administration in a dose-dependent fashion (0.1-20 nmoles). Our results indicate that zinc has an analgesic action during early inflammation and that this may be the consequence of reducing levels of the inflammatory cytokine IL-beta and the growth factor NGF.

Animals↗
PubMed1996

Microbial/host interactions in health and disease: who controls the cytokine network?

The interacting cellular and molecular systems which we classify as immunity and inflammation evolved to protect the organism from exogenous parasites including viruses and bacteria. Cytokines play a pivotal, but paradoxical, role both in immunity and inflammation. These local peptide hormone-like molecules form a major arm of the organisms, defenses against infectious microorganisms but they are also implicated as potent mediators of the pathology of infectious diseases. The apparently lethal effects of interleukin-1 and tumor necrosis factor in experimental septic shock testify to the latter. In the current paradigm, cytokine induction, as a protective or pathological mechanism, is a direct response to the presence of infectious microorganisms. Evidence is now accumulating that cytokines play a much more complex role in the interplay between exogenous microorganisms and the host. For example, it has been established that viruses have evolved pro-active methods of subverting the cytokine network by producing: (i) soluble cytokine receptors which bind and inactivate cytokines, (ii) immunomodulatory cytokine homologues, and (iii) ICE inhibitors. The possibility exists that the major role of these 'viral cytokines' is to neutralize certain host responses. Recent cytokine transgenic knockouts demonstrate that the normal benign response to commensal gut microflora becomes a lethal inflammatory state in the absence of the cytokines interleukin 2 or interleukin 10. The human body contains an enormous number of microorganisms which constitute the normal microflora. It is estimated that the average human contains 10(13) eukaryotic cells but 10(14) bacteria. We propose that the ability of the multicellular organism to live harmoniously with its commensal microflora must depend on mutual signalling involving eukaryotic cytokines and prokaryotic cytokine-like molecules. Such interactive signalling sets up non-inflammatory cytokine networks in tissues which form the background on which responses to infectious microorganisms must be built and related. The capacity of bacteria to induce cytokine synthesis was believed to be due to a small number of components, such as lipopolysaccharide (LPS), which is only active as a complex with host factors (lipopolysaccharide binding protein and CD14). However, it is now clear that bacteria contain and produce a large number of diverse molecules which can selectively induce the synthesis of both pro-inflammatory and immunomodulatory/anti-inflammatory cytokines. Many toxins are potent inducers of cytokine release or synthesis and some can inhibit LPS-induced cell activation. We have introduced the term bacteriokine to describe these bacterial cytokine inducers. The question that has to be addressed therefore is - who controls the cytokine network (eukaryotic or prokaryotic cells) and how is it controlled? It is proposed that an understanding of this question will bring with it an understanding of how to control the pathological inflammatory response and may allow the development of truly effective anti-inflammatory agents.

Animals↗
PubMed1996

Primitive neuroectodermal tumour of the masseter muscle.

Masseter muscle enlargement is one of the differential diagnoses of swelling of the cheek. We discuss a unique case of a malignant tumour of the masseter which was found to be a peripheral primitive neuroectodermal tumour (PNET). A review of tumours of the masseter is presented.

Adult↗
PubMed1996

The effect of temperature on the surface nature of an adsorbed layer of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymers.

PURPOSE: To investigate the influence of the temperature at which adsorption takes place and the temperature at which the adsorbed surface is studied on the polarity of Poloxamer adsorbed to a hydrophobic surface. The implication is that changes in surface nature of adsorbed Poloxamer may subsequently be related to functionality, such as changes in opsonisation of Poloxamer coated latex in animals. METHODS: The surface energies of Poloxamer surfactant have been calculated following adsorption to silanised glass plates. The adsorption to the plates was undertaken at a range of concentrations and at different controlled temperatures. The contact angles were measured using three different liquids on each surface, at a range of controlled temperatures. The surface energies were calculated using the harmonic mean and the acid-base models, via Wilhelmy plate contact angle measurements. These data were compared with previously published adsorption and hydrophobic interaction chromatography studies. RESULTS: The apolar surface energy term remained consistent, but the polar contribution (which was totally of the electron donor type) changed depending upon the temperature of adsorption (and to a lesser extent the temperature at which the surface energy was measured). The polar nature was most elevated at the critical micelle concentration/temperature. The data are consistent with estimates of surface hydrophobicity made using hydrophobic interaction chromatography. CONCLUSIONS: It is argued that the changes in surface energy, which result from the different adsorption conditions, can be expected to influence the functionality of the adsorbed coat, especially for application such as drug targeting.

Adsorption↗
PubMed1996

Intracerebral NMDA injection stimulates production of interleukin-1 beta in perinatal rat brain.

Susceptibility to NMDA neurotoxicity peaks in the early postnatal period in rats. Although indirect evidence suggests that interleukin-1 beta is a mediator of NMDA neurotoxicity in perinatal rats, direct confirmation of NMDA-induced interleukin-1 beta production in the brain has not been reported previously. The primary goal of this study was to determine if intracerebral injection of a neurotoxic dose of NMDA stimulates interleukin-1 beta production acutely. We used a rat-specific interleukin-1 beta ELISA to quantify brain tissue homogenate interleukin-1 beta content, and an immunocytochemical assay with a monoclonal antirat interleukin-1 beta antibody to visualize its distribution. NMDA (10 nmol) was injected stereotaxically into 7-day-old rats, using coordinates that targeted the striatum and overlying dorsal hippocampus. Interleukin-1 beta concentrations were measured in samples from the injected and contralateral cerebral hemispheres 0-12 h later; In addition, the impact of treatment with the noncompetitive NMDA antagonist MK-801 on interleukin-1 beta production was assessed. We found marked increases in tissue content of interleukin-1 beta in the lesioned hemisphere; values peaked at 6 h post injection. Treatment with MK-801 (1 mg/kg) blocked NMDA-induced increases in interleukin-1 beta. Preliminary immunocytochemical analysis demonstrated high concentrations of interleukin-1 beta-immunoreactive cells in the lesioned hippocampus, and concurrent increases in interleukin-1 beta immunoreactivity diffusely in the ependyma at 6 h after NMDA administration. Our data provide the first direct evidence that NMDA-induced excitotoxic injury stimulates interleukin-1 beta production in vivo.

Animals↗
PubMed1996

Comparison of the pro-inflammatory cytokine-stimulating activity of the surface-associated proteins of periodontopathic bacteria.

Saline extraction of the periodontopathic bacterium, Actinobacillus actinomycetemcomitans, releases surface-associated material (SAM), a complex mixture of proteins and carbohydrates with potent biological actions on isolated bone and on various mammalian cell populations. In this study, the relative ability of the SAM from 5 organisms, implicated in the pathology of periodontal disease, to stimulate human mesenchymal and myelomonocytic cells to synthesize the proinflammatory cytokines - interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF)alpha has been investigated. The bacteria investigated were Actinobacillus actinomycetemcomitans, Eikenella corrodens, Porphyromonas gingivalis, Prevotella intermedia and Campylobacter rectus. Human cells were exposed to a four log order range of concentrations of the SAM, or of Escherichia coli lipopolysaccharide, to provide full agonist dose responses in order to allow comparison of the potency and efficacy of each SAM. All SAMs demonstrated the capacity to stimulate human gingival fibroblasts (HGFs), human peripheral blood mononuclear cells (PBMCs) or the myelomonocytic cell line - Mono-Mac-6 to release one or all of the cytokines assayed. Activity was heat- and trypsin-sensitive suggesting that the active components were proteinaceous. However, there were substantial differences in the potency and efficacy of each SAM when compared on a concentration basis (w/v). The most active SAM was from A. actinomycetemcomitans with those from E. corrodens and P. gingivalis being slightly less active. The least active cytokine-stimulating SAMs were from C. rectus and Pr. intermedia. One major difference between the SAMs and E. coli LPS was the inability of the former to stimulate HGFs to release IL-1 beta or TNF alpha although they could stimulate PBMCs to release these cytokines. This may have relevance to the pathology of the periodontal diseases.

Aggregatibacter actinomycetemcomitans↗
PubMed1996

Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis.

Cytokines are a diverse group of proteins and glycoproteins which have potent and wide-ranging effects on eukaryotic cell function and are now recognized as important mediators of tissue pathology in infectious diseases. It is increasingly recognized that for many bacterial species, cytokine induction is a major virulence mechanism. Until recent years, the only bacterial component known to stimulate cytokine synthesis was lipopolysaccharide (LPS). It is only within the past decade that it has been clearly shown that many components associated with the bacterial cell wall, including proteins, glycoproteins, lipoproteins, carbohydrates, and lipids, have the capacity to stimulate mammalian cells to produce a diverse array of cytokines. It has been established that many of these cytokine-inducing molecules act by mechanisms distinct from that of LPS, and thus their activities are not due to LPS contamination. Bacteria produce a wide range of virulence factors which cause host tissue pathology, and these diverse factors have been grouped into four families: adhesins, aggressins, impedins, and invasins. We suggest that the array of bacterial cytokine-inducing molecules represents a new class of bacterial virulence factor, and, by analogy with the known virulence families, we suggest the term "modulin" to describe these molecules, because the action of cytokines is to modulate eukaryotic cell behavior. This review summarizes our current understanding of cytokine biology in relation to tissue homeostasis and disease and concisely reviews the current literature on the cytokine-inducing molecules produced by gram-negative and gram-positive bacteria, with an emphasis on the cellular mechanisms responsible for cytokine induction. We propose that modulins, by controlling the host immune and inflammatory responses, maintain the large commensal flora that all multicellular organisms support.

Animals↗
PubMed1996

Inhibition of tissue factor and cytokine release.

The effect of inhibitors of cytokine release and plasma coagulation on lipopolysaccharide (LPS)-induced tissue factor and interleukin-6 (IL-6) was investigated. Dexamethasone, an inhibitor of cytokine production, inhibited LPS-induced tissue factor and IL-6 release by mononuclear cells (MNC), but enhanced IL-1beta-evoked tissue factor activity. Clinical antithrombin (AT) concentrates inhibited, in a dose-dependent manner, tissue factor and IL-6 production by MNC and human umbilical vein endothelial cells (HUVEC). The three AT preparations tested, when compared using the same antithrombin unit, had different potencies. Activated protein C (APC) augmented LPS stimulation of HUVEC and further increased the production of tissue factor and IL-6. The same effect was not observed with MNC; LPS-induced tissue factor and IL-6 release were unaffected by APC. Truncated tissue factor pathway inhibitor (TFPI1-161) inhibited LPS-induced MNC tissue factor and IL-6 production, but was unable to prevent LPS stimulatory activity on HUVEC. These data suggest a complex interaction between the coagulation pathway and the cytokine network.

Blood Coagulation↗
PubMed1995

Surface-associated proteins from Staphylococcus aureus demonstrate potent bone resorbing activity.

Staphylococcus aureus infections are associated with rapid bone destruction in conditions such as osteomyelitis, bacterial arthritis, and infected orthopedic implant failure. How this bacterium induces bone destruction has not been defined. In studies of the role of oral Gram-negative bacteria in periodontal pathology, we have established that cell surface-associated proteins (SAPs) are potent stimulators of bone resorption. The surface-associated components from S. aureus have now been isolated and demonstrated to be extremely potent stimulators of bone resorption in the murine calvarial bone resorption assay. Bone resorption appears to be due to proteins, is not the result of contamination with lipoteichoic acid or muramyl dipeptide, and is potently inhibited by indomethacin and can be completely blocked by high concentrations of interleukin-1 receptor antagonist or TN3-19.12, a neutralizing monoclonal antibody to murine TNF. The SAP fraction can stimulate fibroblasts or monocytes to release osteolytic cytokines, but only at high concentrations. Fractionation of the SAPs by high performance liquid chromatography demonstrated that a number of fractions were osteolytically active. The most active contained a heterodimeric protein of molecular weight 32-36 kD. The presence of this osteolytically active surface-associated fraction may account for the bone resorption associated with local infection with S. aureus.

Animals↗
PubMed1995

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones.

Cells, Cultured↗
PubMed1995

Relative cytokine-stimulating activities of surface components of the oral periodontopathogenic bacterium Actinobacillus actinomycetemcomitans.

The purpose of this study was to determine whether bacterial surface components other than lipopolysaccharide (LPS) could stimulate pro-inflammatory cytokine synthesis by mesenchymal and myelomonocytic cells in vitro. LPS, lipid A-associated proteins (LAP) and saline-extractable surface-associated material (SAM) were isolated from the periodontopathogenic bacterium Actinobacillus actinomycetemcomitans and added to cultures of human gingival fibroblasts (HGFs), human PBMCs and the human myelomonocytic MonoMac-6 cell line. Pro-inflammatory cytokine release into culture supernatants was determined by two-site ELISAs. Contrary to expectation, the highly purified LPS extracted from this bacterium was significantly less potent than the other surface extracts in stimulating release of IL-1 beta, IL-6 and TNF-alpha by all three cell types. The SAM was the most potent cytokine-stimulating agent showing equivalent activity to highly purified E. coli LPS in stimulating IL-6 release by PBMCs. LAP also had cytokine-stimulating activity although it was generally significantly less potent than the SAM. Thus in the case of this organism, which is involved in the pathology of chronic inflammatory diseases the LPS does not appear to be the major cytokine-stimulating component.

Aggregatibacter actinomycetemcomitans↗
PubMed1995

Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10.

1. The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and carrageenin were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to bradykinin (1 micrograms) were inhibited in a dose-dependent manner by prior treatment with IL-10 (1-100 ng). 3. Hyperalgesic responses to TNF alpha (2.5 pg), IL-1 beta (0.5 pg) and IL-6 (1.0 ng) but not to IL-8 (0.1 ng) and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4. Hyperalgesic responses to carrageenin (100 micrograms) were inhibited by IL-10 (10 ng) when this cytokine was injected before but not after the carrageenin. 5. A monoclonal antibody to mouse IL-10 potentiated the hyperalgesic responses to carrageenin (10 micrograms) and TNF alpha (0.025 pg) but not that to IL-8 (0.01 ng). 6. In in vitro experiments in human peripheral blood mononuclear cells (MNCs), IL-10 (0.25-4.0 ng ml-1) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with IL-1 beta (1-64 ng ml-1) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-1) but evoked only small increases in IL-1ra production. 7. These data suggest that IL-10 limits the inflammatory hyperalgesia evoked by carrageenin and bradykinin by two mechanisms: inhibition of cytokine production and inhibition of IL-1 beta evoked PGE2 production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-Ira and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).

Animals↗
PubMed1995

Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia.

1. Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones. 2. To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene-related peptide (CGRP) in the L4 dorsal root ganglion 48 h post CFA injection. 3. The effects of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drug on the levels of NGF and IL-1 beta in inflamed tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones. 4. Systemic dexamethasone (120 micrograms kg-1 per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg-1 daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg-1 daily was required to reduce significantly mechanical and thermal hypersensitivity. 5. The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL-1 beta whereas indomethacin had an effect only at the higher dose. 6. The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes. 7. Intraplantar injections of IL-1 beta (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL-1 receptor antagonist (IL-1 ra) (0.625 microgram, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL-1 beta (1 ng) was prevented by administration of a polyclonal neutralizing anti-NGF serum. 8. IL-1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA-induced elevation in NGF levels. Anti-NGF pretreatment substantially reduced CFA-induced mechanical and thermal hyperalgesia without reducing the elevation in IL-1 beta. 9. Intraplantar NGF (0.02, 0.2 and 2 microg) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL-1beta levels in the hindpaw skin.10. Our results demonstrate that IL-1beta contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.

Animals↗
PubMed1995

Lipid A-associated proteins from periodontopathogenic bacteria induce interleukin-6 production by human gingival fibroblasts and monocytes.

The aim of this study was to determine whether lipid A-associated proteins (LAP) from two periodontopathogenic species of bacteria were able to stimulate interleukin-6 (IL-6) release from human gingival fibroblasts and myelomonocytic cells. LAP and lipopolysaccharide (LPS) were extracted from Porphyromonas gingivalis and Prevotella intermedia and added to cultures of human gingival fibroblasts and mono-mac-6 monocytic cells. Release of IL-6 into the culture supernatants was determined by ELISA. LAP and LPS from Por. gingivalis, but not from Prev. intermedia, stimulated IL-6 release from both cell types in a dose-dependent manner although LPS was less potent than LAP in inducing IL-6 release from the fibroblasts. IL-6 was detectable in cultures of both cell types following stimulation with LAP from Por. gingivalis at a concentration as low as 10 ng/ml. In response to LAP from Prev. intermedia, IL-6 was produced by mono-mac-6 cells but not by fibroblasts. Our results show that bacterial cell wall components other than LPS can induce IL-6 release from cells of the periodontium in vitro. The production of such potent immunomodulatory agents in vivo may contribute to the connective tissue breakdown characteristic of chronic periodontitis.

Bacterial Proteins↗
PubMed1995

Corticotrophin-releasing hormone (CRH)-binding protein interference with CRH antibody binding: implications for direct CRH immunoassay.

Direct immunoassay of plasma corticotrophin-releasing hormone (CRH) is potentially subject to interference from high levels of CRH-binding protein (CRH-BP) that exist in the human circulation. In this study, we tested the effect of CRH-free, native CRH-BP (6.4 nmol/l) purified from human plasma, CRH-BP diluent alone, normal human plasma (containing 5.8 nmol endogenous CRH-BP/l) and normal sheep plasma (containing no CRH-BP) on the binding of 125I-labelled CRH tracer to five N-terminal and four C-terminal CRH antibodies. All anti-(1-20)CRH N-terminal antibody dilution curves displayed marked inhibition of binding in the presence of purified CRH-BP and human plasma in comparison with the curves with the control diluent or sheep plasma. Almost no inhibition of binding was obtained with any of the C-terminal antibodies (all directed against epitopes within the last six amino acids of CRH) and the four dilution curves were nearly superimposable. Liquid-phase CRH IRMAs were then developed with different combinations of two of each of the N- and C-terminal antibodies, using radiolabelled IgG prepared from purified C-terminal antisera as tracer and raw N-terminal antisera as the link antibodies to the separating system. The addition of dilutions of purified CRH-BP over the range 1.25-20 nmol/l to the IRMA standard curve in assay buffer resulted in a dose-dependent reduction in the signal; with 5 nmol CRH-BP/l, a level commonly found in human plasma, the reduction in binding was 67% and 81% in two different IRMAs at a CRH concentration of 631 pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Antinociceptive activity of peptides related to interleukin-1 beta-(193-195), Lys-Pro-Thr.

A series of closely related peptide analogues of Lys-Pro-Thr [(interleukin-1 beta-(193-195)] have been investigated in two models of antinociception in mice (acetic acid-induced abdominal constrictions and formalin tests) and compared with morphine, aspirin and indomethacin. Formalin-induced nociceptive responses in the mouse showed early (0-5 min) and late (15-30 min) phases of peak activity. Lys-D-Pro, Lys-D-Pro-Thr, Lys-D-Pro-Arg, Lys-D-Pro-Val, morphine and aspirin, were antinociceptive in both phases after intraperitoneal (i.p.) and oral (p.o.) administrations. Lys-D-Pro-Leu inhibited the early phase response only after i.p. injection. Lys-D-Pro-Val-NH2, Lys-D-Pro-Gln, Lys-D-Pro-Tyr, Lys-D-Pro-Asn, Asp-Lys-D-Pro-Val and indomethacin were active only against the late phase (ED50 values of 64, 32, 44, 94, 67 and 25 mg/kg i.p., respectively). Several of the peptides showed good bio-availability, e.g. Lys-D-Pro-Asn (ED50: 10 mg/kg i.p.; 11.4 mg/kg p.o.) in the abdominal constrictions test, where two modes of action were apparent, non-opioid and opioid; non-opioid (naloxone-insensitive antinociception) mechanisms were illustrated by Lys-D-Pro-Thr and Lys-D-Pro-Asn; opioid (naloxone-sensitive antinociception) mechanisms by Lys-D-Pro-Val and Lys-D-Pro-Leu. These data identify orally active antinociceptive peptides in both antinociceptive tests with varied relative potency profiles to morphine, indomethacin and aspirin in the mouse formalin test.

Abdomen↗