Opioid activation of toll-like receptor 4 contributes to drug reinforcement

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4−/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.M. R. Hutchinson... J. Thomas, K. van Steeg... A. A. Somogyi... et al

Implementing, monitoring and measuring a programme of relationship marketing

This single, embedded case study examined the marketing activities of Flensted Catering A/S, a Danish food company. The case is the first one in a series of case studies constituting a larger research project with the overall objective of understanding how to implement relationship marketing, how to monitor the outputs and how to measure the returns. In 1996, the company embarked on a three-phase programme directed at building relations with customers. As a prelude to the implementation, Flensted Catering A/S conducted focus groups and issued questionnaires to determine customer perceptions of how the company could meliorate its performance. Subsequently, the Danish firm established project teams, instituted customer-focused staff training and sought to improve communications with customers. Following the implementation, the monitoring revealed that Flensted Catering A/S was rated as a better supplier by 43 per cent of its customers and that customer retention had risen to 94 per cen

Susceptibility to Phytophthora ramorum in California bay laurel, a key foliar host of sudden oak death

Sudden oak death, caused by the water mold Phytophthora ramorum, is a plant disease responsible for the death of hundreds of thousands of oak and tanoak trees. Some foliar hosts play a major role in the epidemiology of this disease. Upon infection by P. ramorum, these foliar hosts express non-fatal leaf lesions from which large amounts of inoculum can be produced and spread to neighboring host individuals, including oak species. Umbellularia californica (California bay laurel) may be one of the most important foliar hosts of sudden oak death due its observed ability to produce inoculum and its high abundance in the woodlands of coastal California. While previous research on susceptibility to P. ramorum in U. californica has shown significant variability among trees, with more resistant individuals in northern areas of its range, little is known about the causes or extent of this variability. Here, we ask three research questions: (1) How does susceptibility vary among U. californica individuals and P. ramorum isolates? (2) Are U. californica phenotype and genotype related to susceptibility? (3) What factors influence disease expression in nature

Miscanthus combustion properties and variations with Miscanthus agronomy

A study of the interaction of agronomy and its effects on fuel quality has been carried out for Miscanthus x giganteus grown in the UK through the UK’s SUPERGEN Bioenergy Consortium activities. Work on Miscanthus yield responses to N, K and S fertilizer will be reported elsewhere, and this study is focused on how fertilisers affected Miscanthus fuel quality. Six different fertiliser treatments were chosen to give interesting contrasts from the field experiment investigating yield responses; nitrogen (ammonium nitrate) at 0, 100, 150 and 250 kg N ha 1 in combination with potassium (K as KCl) at 50 kg K ha 1 and 150 kg N ha 1 also with zero K, and with 50 kg K ha 1 (K as K2SO4). A total of 270 samples were taken at five time points over the autumn and winter harvest window in each of the two growth years, 2005 and 2006. Results show that Miscanthus stems have better fuel quality than leaves, with much lower ash, N and S contents, and slightly higher C concentrations and hence higher estimated calorific value. The treatment without any N added into fertiliser seems to give a better fuel quality than other treatments considered in the study, resulting in a fuel with lower N, ash content, and a lower propensity to fouling (as indicated by the indices calculated from its ash analysis), and also higher C concentrations. In general, the late harvested Miscanthus samples have better fuel quality, with lower N, Cl, ash contents, alkali index and slightly higher C contents

A comparison of the neutron response of CR-39 made by different manufacturers

CR-39 was obtained from American Acrylics and Plastics, Inc. (A.A), N. E. Technology, Ltd. (N.E), and Tech/Ops Landauer, Inc. (LT). The dosemeters were exposed to radioisotopic neutron sources at SLAC, and moderated {sup 252}Cf at ORNL. The A.A. and N.E. dosemeters were electrochemically etched (pre-etch in 6.5 N KOH at 60{degrees}C for 1 hour and 45 minutes, a 5 hour etch at 3000 V and 60 Hz, a 23 minute blow-up step at 2 kHz and a post-etch for 15 minutes). Track densities were determined with the Homann Track Size Image Analyzer. The LT dosemeters were chemically etched in 5.5 N NaOH at 70{degrees}C for 15.5 hours. Some A.A., N.E., and LT dosemeters were etched in 6.25 N NaOH at 70{degrees}C for 6 hours. A pre-etch step in 60% methanol and 40% NaOH at 70{degrees}C for 1 hour was added for some N.E. dosemeters. The results of these studies are reported in this paper. 3 refs., 2 figs., 2 tabs

The Psychic Distance Postulate Revised: From Market Selection to Speed of Market Penetration

In this paper we revise the psychic distance postulate of the Uppsala Model (Johanson and Vahlne, 1977, 1990) by injecting more recent findings (i.e., distinguishing between selection of foreign markets and time needed to achieve sufficient penetration in foreign markets and the role of social capital). The model we propose posits that a higher psychic distance decreases the speed of market penetration. On distant markets, internationalizing technology-based ventures need more time to establish a position in the foreign network and to obtaining positive cash flow. Our model presents social capital as a mean to overcome the psychic distance and to increase the speed of market penetration. We build our model on four case studies on technology-based new ventures internationalizing at very early ages. Copyright Springer Science + Business Media, Inc. 2005Uppsala model, psychic distance, speed of market penetration,