bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenous opioids suppress activation of nociceptors by sub‐nanomolar nicotine
Authors: Miao Frederick J‐P , Benowitz Neal L , Levine Jon D 
Published: January 2005

Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of sub‐nanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla‐derived δ‐opioid receptor agonists.
While neurogenic plasma extravasation in the knee joint of the rat was not increased by intra‐articular perfusion of nicotine (10−8 M), perfusion of nicotine, at concentrations as low as 10−10 M, combined with naloxone to block opioid receptors (or naltrindole to block δ‐opioid receptors) was able to enhance bradykinin‐induced plasma extravasation. This pro‐inflammatory effect of intra‐articular nicotine was mimicked by subcutaneous nicotine which was abolished by intra‐articularly‐administered hexamethonium, a nicotinic receptor antagonist.
Following denervation of the adrenal medulla, intra‐articular nicotine, alone at 10−8 M, enhanced plasma extravasation, which was no longer enhanced by naloxone.
Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin‐1 receptor antagonist RP‐87,580 abolished the pro‐inflammatory effect of nicotine.
The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second‐hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids.

British Journal of Pharmacology (2001) 133, 23–28; doi:10.1038/sj.bjp.0704031
Mechanical effects of liriodenine on the left ventricular‐arterial coupling in Wistar rats: pressure‐stroke volume analysis
Authors: Chang Kuo‐Chu , Su Ming‐Jai , Peng Ying‐I , Shao Ching‐Chih , Wu Yang‐Chang , Tseng Yung‐Zu 
Published: January 2005

In a recent in vivo study, liriodenine, an aporphine alkaloid, has been identified as a prominent anti‐arrhythmic agent that can prevent rats' sudden deaths, even at the dose as low as 10−7 g kg−1. The aim of this study was to determine whether liriodenine at its effective anti‐arrhythmic dose of 10−7 g kg−1 had effects on the left ventricular (LV)‐arterial coupling in Wistar rats.
LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end‐systolic pressure‐stroke volume relationships to calculate LV end‐systolic elastance (Ees) and effective arterial volume elastance (Ea), respectively. The optimal afterload (Qload) determined by the ratio of Ea to Ees was used to measure the optimality of energy transmission from the left ventricle to the arterial system.
Liriodenine at the dose of 10−7 g kg−1 showed no significant changes in basal heart rate (HR), cardiac output (CO), LV end‐systolic pressure (Pes), Ea, Ees, and Qload.
By contrast, liriodenine at the dose of 10−6 g kg−1 produced a significant fall of 2.0% in HR and a significant rise of 5.8% in CO, but no significant change in Pes. Moreover, liriodenine administration of 10−6 g kg−1 to rats significantly decreased Ees by 8.5% and Ea by 10.6%, but did not change Qload.
We conclude that liriodenine at the dose of 10−7 g kg−1 has no effects on the mechanical properties of the heart and the vasculature and the matching condition for the left ventricle coupled to its vasculature in rats. Even at 10 times the effective anti‐arrhythmic dose, liriodenine shows no effects on the efficiency of energy transferred from the left ventricle to the arterial system.

British Journal of Pharmacology (2001) 133, 29–36; doi:10.1038/sj.bjp.0704036
Mutation screening of the muscarinic M2 and M3 receptor genes in normal and asthmatic subjects
Authors: Fenech A G , Ebejer M J , Felice A E , Ellul‐Micallef R , Hall I P 
Published: January 2005

Muscarinic receptors are important in the development of airway hyperresponsiveness, and dysfunction of these receptors has been suggested to be present in asthma.
The human muscarinic M2 and M3 receptor genes were screened for polymorphic variation using single‐stranded conformation polymorphism (SSCP) analysis, complemented by direct fluorescent sequencing. Forty‐six random DNA samples and 46 respiratory physician diagnosed asthmatic samples were used as a template for analysis.
Within the muscarinic M2 receptor gene, we identified two degenerate single base substitutions (1197T→C, Thr→Thr and 976A→C, Arg→Arg) in one random and one asthmatic sample respectively. Analysis of the 3′ UTR region revealed an additional ‘A’ at bp 1793 (c.f. ATG). This was present in all of 49 samples analysed by sequencing or BsmI digest, suggesting that the published sequence (GenBank Accession No. M16404) is incorrect. A common 3′ UTR polymorphism (T→A) was found at bp 1696 (c.f. ATG) (allelic frequency=65%, n=60), but this does not alter transcription factor recognition sites.
We were unable to identify any polymorphic variation within the muscarinic M3 coding region or the flanking regions investigated, using the methods described.
The coding regions for the human muscarinic M2 and M3 receptor genes are both highly conserved. These data suggest that polymorphic variation within these coding sequences is unlikely to account for inter‐individual variability in response to methacholine or anticholinergic therapy. The potential functional significance of the muscarinic M2 receptor 3′ UTR polymorphism (bp 1696) remains to be determined.

British Journal of Pharmacology (2001) 133, 43–48; doi:10.1038/sj.bjp.0704039
The biphasic immunoregulation of pyrimidylpiperazine (Y‐40138) is IL‐10 sensitive and requires NF‐κB targeting in the alveolar epithelium
Authors: Haddad J J E , Safieh‐Garabedian B , Saadé N E , Land S C 
Published: January 2005

Pyrimidylpiperazine (Y‐40138), a synthetic derivative of N‐[1‐(4‐{[4‐(pyrimidin‐2‐yl)piperazin‐1‐yl]methyl}phenyl)cyclopropyl] acetamide, is a novel dual regulator of pro‐ and anti‐inflammatory cytokines in vivo. The aim of the present study was to determine the signal transduction mechanisms implicated in vitro.
In alveolar epithelial cells, pre‐treatment (30 min) with Y‐40138 reduced LPS‐induced biosynthesis of IL‐1β, IL‐6 and TNF‐α, an effect paralleled by up‐regulating an anti‐inflammatory counter‐loop mediated through IL‐10.
This differential regulation of pro‐ and anti‐inflammatory signals was accompanied by an inhibition of the nuclear localization of selective NF‐κB subunits, particularly NF‐κB1 (p50), RelA (p65), the major transactivating member of the Rel family, RelB (p68) and c‐Rel (p75). In addition, Y‐40138 blockaded, in a dose‐dependent manner, the LPS‐induced nuclear activation of NF‐κB.
Analysis of the upstream pathway involved in Y‐40138‐dependent retardation of LPS‐induced NF‐κB translocation/activation revealed the involvement of an IκB‐α sensitive pathway. Pre‐treatment with Y‐40138 ameliorated LPS‐induced degradation of IκB‐α in the cytosolic compartment and retarded its phosphorylation, suggesting the involvement of an upstream kinase.
Recombinant IL‐10 (0 – 10 ng ml−1) blockaded, in a dose‐dependent manner, LPS‐induced biosynthesis of IL‐1β, IL‐6 and TNF‐α. Furthermore, rhIL‐10 reduced the DNA binding activity of NF‐κB. Immunoneutralization of endogenous IL‐10 by a polyclonal αIL‐10 (5 μg ml−1) reversed the inhibitory effect of Y‐40138 on pro‐inflammatory cytokines and partially restored the DNA binding activity of NF‐κB.
These results indicate that Y‐40138 mediated dual immunoregulation of pro‐ and anti‐inflammatory cytokines is IL‐10 sensitive and mediated through the IκB‐α/NF‐κB signal transduction pathway.

British Journal of Pharmacology (2001) 133, 49–60; doi:10.1038/sj.bjp.0704041
NK‐104, a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, reduces osteopontin expression by rat aortic smooth muscle cells
Authors: Takemoto Minoru , Kitahara Masaki , Yokote Koutaro , Asaumi Sunao , Take Ayako , Saito Yasushi , Mori Seijiro 
Published: January 2005

It has been suggested that osteopontin promotes the development of atherosclerosis, especially under diabetic conditions.
In the present study, we found that NK‐104, a new potent synthetic inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, reduced osteopontin expression both at protein and mRNA levels in cultured rat aortic smooth muscle cells.
The inhibitory effect of NK‐104 was almost completely reversed by mevalonate, suggesting that mevalonate or its metabolites play important roles in the regulation of osteopontin expression.
Furthermore, oral administration of NK‐104 (3 mg kg−1 day−1 for 7 days) effectively suppressed abnormally upregulated expression of osteopontin mRNA in the aorta and kidney of streptozotocin‐induced diabetic rats.
These data support a notion that NK‐104 is a suitable drug for the treatment of diabetic patients with hypercholesterolaemia.

British Journal of Pharmacology (2001) 133, 83–88; doi:10.1038/sj.bjp.0704046
Protection against β‐amyloid peptide toxicity in vivo with long‐term administration of ferulic acid
Authors: Yan Ji‐Jing , Cho Jae‐Young , Kim Hee‐Sung , Kim Kyoung‐Li , Jung Jun‐Sub , Huh Sung‐Oh , Suh Hong‐Won , Kim Yung‐Hi , Song Dong‐Keun 
Published: January 2005

β‐Amyloid peptide (Aβ), a 39 – 43 amino acid peptide, is believed to induce oxidative stress and inflammation in the brain, which are postulated to play important roles in the pathogenesis of Alzheimer's disease. Ferulic acid is an antioxidant and anti‐inflammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against Aβ toxicity in vivo was examined.
Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, Aβ1‐42 (410 pmol) was administered via intracerebroventricular injection.
Injection of control mice with Aβ1‐42 impaired performance on the passive avoidance test (35% decrease in step‐through latency), the Y‐maze test (19% decrease in alternation behaviour), and the water maze test (32% decrease in percentage time in platform‐quadrant). In contrast, mice treated with ferulic acid prior to Aβ1‐42 administration were protected from these changes (9% decrease in step‐through latency; no decrease in alternation behaviour; 14% decrease in percentage time in platform‐quadrant). Aβ1‐42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid.
In addition, Aβ1‐42 increased immunoreactivities of the astrocyte marker glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) in the hippocampus, effects also suppressed by pretreatment with ferulic acid.
Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL‐1β immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. A slight (8%) decrease in alternation behaviour was observed on day 14.
These results demonstrate that long‐term administration of ferulic acid induces resistance to Aβ1‐42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimer's disease.

British Journal of Pharmacology (2001) 133, 89–96; doi:10.1038/sj.bjp.0704047
Histamine H3 receptor‐mediated inhibition of depolarization‐induced, dopamine D1 receptor‐dependent release of [3H]‐γ‐aminobutyric acid from rat striatal slices
Authors: Arias‐Montaño J‐A , Floran B , Garcia M , Aceves J , Young J M 
Published: January 2005

A study was made of the regulation of [3H]‐γ‐aminobutyric acid ([3H]‐GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H3‐agonist. Depolarization‐induced release of [3H]‐GABA was Ca2+‐dependent and was increased in the presence of the dopamine D2 receptor family antagonist, sulpiride (10 μM). The sulpiride‐potentiated release of [3H]‐GABA was strongly inhibited by the dopamine D1 receptor family antagonist, SCH 23390 (1 μM). Neither antagonist altered basal release.
The 15 mM K+‐induced release of [3H]‐GABA in the presence of sulpiride was inhibited by 100 μM histamine (mean inhibition 78±3%) and by the histamine H3 receptor‐selective agonist, immepip, 1 μM (mean inhibition 81±5%). The IC50 values for histamine and immepip were 1.3±0.2 μM and 16±2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H3 receptor antagonist, thioperamide, 1 μM.
The inhibition of 15 mM K+‐induced [3H]‐GABA release by immepip was reversed by the H3 receptor antagonist, clobenpropit, Kd 0.11±0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [3H]‐GABA.
Elevated K+ caused little release of [3H]‐GABA from striatal slices from reserpinized rats, unless the D1 partial agonist, R(+)‐SKF 38393, 1 μM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 μM immepip to the level obtained in the absence of SKF 38393.
These observations demonstrate that histamine H3 receptor activation strongly inhibits the dopamine D1 receptor‐dependent release of [3H]‐GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

British Journal of Pharmacology (2001) 133, 165–171; doi:10.1038/sj.bjp.0704053
Enhancement of the effects of a complete inhibitor of enkephalin‐catabolizing enzymes, RB 101, by a cholecystokinin‐B receptor antagonist in diabetic rats
Authors: Coudoré‐Civiale Marie‐Ange , Méen Murielle , Fournié‐Zaluski Marie‐Claude , Boucher Michel , Roques Bernard P , Eschalier Alain 
Published: January 2005

RB 101, a complete inhibitor of enkephalin‐catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin‐B (CCK‐B) receptor antagonist has been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neuropathic pain. The type of opioid receptors (μ or δ) involved was determined using naloxone and naltrindole, respectively, and the interactions between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK‐B receptor antagonist CI‐988.
RB 101 suppressed mechanical hyperalgesia (paw pressure‐induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled by naloxone or naltrindole, suggesting that is requires the availability of μ‐ and/or δ‐opioid receptors.
The combination of an inactive dose of CI‐988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone.
The present study demonstrates that the antinociception generated by RB 101 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of CCK‐B receptors potentiated antinociceptive effects elicited by RB 101.

British Journal of Pharmacology (2001) 133, 179–185; doi:10.1038/sj.bjp.0704059
Effects of terbutaline on NGF formation in allergic inflammation of the rat
Authors: Amann Rainer , Peskar Bernhard A , Schuligoi Rufina 
Published: January 2005

The aim of this study was to determine the effects of the beta adrenergic agonist terbutaline on NGF increase caused by allergic inflammation in rats.
Intraplantar antigen injection in sensitized rats increased paw volume and stimulated NGF biosynthesis in the skin of the injected paw as determined 3 and 6 h after injection. Treatment of rats with terbutaline (0.1 – 0.3 mg kg−1, s.c.) had no significant effect on the NGF concentration in non‐inflamed skin, but reduced oedema, and at 0.3 mg kg−1 also NGF mRNA and immunoreactive NGF in the skin of the inflamed paw in a propranolol‐reversible manner. In carrageenan‐induced inflammation, terbutaline did not significantly reduce the inflammation‐induced increase of NGF in paw skin.
Exposure of sensitized rats to aerosolized antigen (twice, 24 h interval) increased protein content, eosinophil leukocytes, and immunoreactive NGF in the bronchoalveolar lavage fluid (BAL, obtained 16 h after the second antigen exposure). Treatment of rats with terbutaline (0.3 mg kg−1, s.c. 30 min before the second antigen challenge) suppressed antigen‐induced elevation of protein and eosinophil leukocytes, and reduced the concentration of NGF in BAL to values similar to those found in non‐sensitized rats.
The present results demonstrate anti‐allergic properties of terbutaline in rats that were accompanied by a marked reduction of antigen‐induced NGF increase in skin and BAL, respectively. These results are compatible with the assumption that terbutaline primarily suppressed the immune response to antigen thereby attenuating the release of vasoactive mediators and the stimulation of NGF biosynthesis.

British Journal of Pharmacology (2001) 133, 186–192; doi:10.1038/sj.bjp.0704060
Neuromodulatory effect of propentofylline on rat brain under acute and long‐term hypoperfusion
Authors: Plaschke Konstanze , Grant Masilo , Weigand Markus A , Züchner Janet , Martin Eike , Bardenheuer Hubert J 
Published: January 2005

The effects of propentofylline (PPF, 25 mg kg−1 body weight per day) on rat cerebral energy state and cytokine expression as well as on behaviour and histopathology were studied after acute and long‐term permanent bilateral common carotid artery occlusion (BCCAO).
In the absence of PPF, acute ischaemia led to a decrease in energy‐rich phosphates in parietotemporal cortex and hippocampus which correlated with an increase in AMP and adenosine concentrations measured by high‐performance liquid chromatography technique. The concentrations of cortical cytokines TNFα and IL1β were increased 12 and 19 fold, respectively.
PPF had a neuroprotective action after 20 min of BCCAO, reducing the deleterious effect of acute ischaemia on rat brain energy state and microglial reaction. Simultaneously, PPF treatment increased cyclic‐AMP 3 fold.
Three weeks of permanent BCCAO did not significantly disturb brain energy metabolism, microglial reaction or histopathology. However, a significant reduction of 30 – 50% in rat memory capacities and a locomotor hyperactivity were obtained.
Continuous PPF‐application, however, led to a marked increase in rat working memory and to reduced locomotor activity, which were returned nearly to control levels by 1 week after permanent BCCAO.
In summary, PPF showed a clear neuroprotective effect on cerebral energy state and pro‐inflammatory cytokines under conditions of acute global ischaemia. Continuous administration of PPF led to memory improvement during permanent BCCAO. These results underscore the benefit of treatment with PPF in clinical practice, particularly during stroke, but also in cerebrovascular and neurodegenerative disorders.

British Journal of Pharmacology (2001) 133, 107–116; doi:10.1038/sj.bjp.0704061
Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines
Authors: Tolomeo Manlio , Grimaudo Stefania , Milano Salvatore , La Rosa Marzia , Ferlazzo Viviana , Di Bella Gloria , Barbera Caterina , Simoni Daniele , D'Agostino Pietro , Cillari Enrico 
Published: January 2005

Recently discovered chemically modified tetracyclines (CMTs) have shown in vitro and in vivo anti‐proliferative and anti‐tumour activities. Here, we evaluated in vitro the anti‐proliferative and apoptotic activity of six different dedimethylamino chemically modified tetracyclines (CMT‐1, CMT‐3, CMT‐5, CMT‐6, CMT‐7 and CMT‐8) in sensitive and multidrug resistant myeloid leukaemia cells (HL60 and HL60R) in vitro.
Three of these compounds (CMT‐5, CMT‐6, CMT‐7) showed low cytotoxic activity both in sensitive and in resistant cells, CMT‐3 was endowed with a high anti‐proliferative activity only in sensitive cells and was moderately effective as apoptosis inducing agent, with an activity similar to that shown by doxycycline. On the contrary, CMT‐1 and CMT‐8 were very effective as programmed cell death inducing agents.
The apoptotic pathway activated by these compounds involved the activation of caspases, especially caspase‐9 and, for CMT‐1, also the activation of Fas.
Interestingly CMT‐8, but not CMT‐1, was able to induce apoptosis in multidrug resistant HL60R and in Fas‐ligand resistant HUT78B1 cell lines. These properties, together with others previously described (e.g. anti‐metastatic and anti‐osteolytic activities), suggest that CMT‐8 may have important applications in the clinical management of cancer.
The comparative analysis of structure‐activity relationship of CMT‐8 and doxycycline suggests that the C‐5 hydroxy moiety may play an important role in conferring activity in multidrug resistant cells. These findings appear to support the hypothesis that CMT‐8 may represent an interesting lead for the development of a new class of potent apoptosis inducer agents active in multidrug resistant and Fas‐ligand resistant malignancies.

British Journal of Pharmacology (2001) 133, 306–314; doi:10.1038/sj.bjp.0704068
Synthesis and characterization of a novel tritiated KATP channel opener with a benzopyran structure
Authors: Manley Paul W , Löffler‐Walz Cornelia , Russ Ulrich , Hambrock Annette , Moenius Thomas , Quast Ulrich 
Published: January 2005

The synthesis of a tritiated benzopyran‐type opener of the ATP‐dependent K+ channel (KATP channel), [3H]‐PKF217 – 744 {(3S,4R)‐N‐[3,4‐dihydro‐2,2‐dimethyl‐3‐hydroxy‐6‐(2‐methyl‐4‐pyridinyl)‐2H‐1‐benzopyran‐4‐yl]‐3‐[2,6‐3H]pyridinecarboxamide} with a specific activity of 50 Ci mmol−1 is described. Binding of the ligand was studied in membranes from human embryonic kidney cells transfected with the sulphonylurea receptor isoforms, SUR2B and SUR2A, respectively.
PKF217 – 744 was confirmed as being a KATP channel opener by its ability to open the Kir6.1/SUR2B channel, the recombinant form of the vascular KATP channel, and to inhibit binding of the pinacidil analogue, [3H]‐P1075, to SUR2B (Ki=26 nM).
The kinetics of [3H]‐PKF217 – 744 binding to SUR2B was described by rate constants of association and dissociation of 6.9×106 M−1 min−1 and 0.09 min−1, respectively.
Binding of [3H]‐PKF217 – 744 to SUR2B/2A was activated by MgATP (EC50∼3 μM) and inhibited (SUR2B) or enhanced (SUR2A) by MgADP.
Binding of [3H]‐PKF217 – 744 to SUR2B was inhibited by representatives of the different structural classes of openers and sulphonylureas. Ki values were identical with those obtained using the opener [3H]‐P1075 as the radioligand.
Glibenclamide accelerated dissociation of the SUR2B‐[3H]‐PKF217 – 744 complex.
The data show that the affinity of [3H]‐PKF217 – 744 binding to SUR2B is ∼6 times lower than that of [3H]‐P1075. This is due to a surprisingly slow association rate of the benzopyran‐type ligand, suggesting a complex mechanism of opener binding to SUR. The other pharmacological properties of the two opener radioligands are identical.

British Journal of Pharmacology (2001) 133, 275–285; doi:10.1038/sj.bjp.0704071