Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury. Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived (...) from lipopolysaccharide. Additionally, -naltrexone, -naloxone, and -naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by -naloxone and -naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists -naloxone and -naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with -naloxone is of potential clinical relevance. This is because -naloxone is an antagonist that is inactive at the -opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that -opioid antagonists such as -naloxone may be useful clinically to suppress glial activation, yet -opioid agonists suppress pain. (shrink)

Purpose of the article is to partially describe underpinning economics for the circular economy. A circular economy is an advancement from the linear economy which behaves according to the hierarchy of 6R, preferring reuse, remanufacture or recycle solutions insead of disposal. This new approach is a trigger of new business models seeking many times vor various kinds of support from the side of government. However, governmental support is not neither the only option nor the most functional one. Underpinning economics for (...) the circular economy can be based also at market-based tools. What we have in mind under this term for the purspose of this paper is the game in the market being played between buyers and sellers. Methodology: We have analyzed this interaction using game theory tool. The scietific goal of our paper was to suggest a quick market-based solution how to support circular economy business models whilst helping to the society to solve certain social problems. Our findings have led to a newly proposed way, how the current game in pricing could be changed. An emphasis shall be placed on strategies how to rise prices of linear economy products whilst offering wider social benefits to small sellers of such products. The price increase of linear economy products is considered in this paper as a market-based incentive to support recycled, remanufactured ones, whilst circular economy products are becoming more economically feasible in comparison with more expensive linear economy products. (shrink)

This commentary on coderre & katz, wiesenfeld-hallin et al., and dickenson focuses on: (a) the brain as an under-recognized contributor to pain facilitation at the spinal cord; (b) these brain-to-spinal pathways being activated by learning or by body infection/inflammation; and (c) the resultant spinal release of anti-analgesic neuropeptides, activators of the NMDA-NO cascade, and activators of glia.