Toll-Like Receptors change morphine-induced antinociception, tolerance and dependence: studies using male and female TLR and Signalling gene KO mice

Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling po- tentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2 -/- mice. In silico docking simu- lations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [3H](-)-naloxone or [3H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR- opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.Jacob H.L. Thomas, Liang Lui, Andrew Abell, William Tieu, Andrew A. Somogyi, Juliana E. Bajic, Mark R. Hutchinso

The survival and growth of worker co-operatives: a comparison with small businesses

ALAN THOMAS AND CHRIS Cornforth are with the Co-operatives Research Unit at the Open University, England. There has been a good deal of theoretical debate and general speculation about the performance of worker co-operatives. However, there has been a shortage of good empirical work has been restricted to case studies or surveys of producer co-operatives formed during the early years of the century in Britain. This paper helps to rectify that situation. It draws upon a complete database of all worker co-operatives formed between 1946-86 in the UK to detail their spread and distribution, and goes on to analyse the survival rates of worker co-operatives, and briefly, their growth rates. Contrary to much of the speculation it concludes that co-operatives have similar survival rates and patterns of growth to those of other small businesses. However, co-operatives tend to be concentrated in certain sub-sectors and their survival rates also vary between sectors, tending to confirm those writers who suggest that despite good performance once set up, co-operatives will tend to have a limited role in the economy