Jason Harrison

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.

The primary responsibility for global climate change responsiveness is usually attributed to nation states. This is reflected in the United Nations’ processes aimed at enrolling governments in mitigation and adaptation programmes. Such an approach begs the question of how global climate change (GCC) responsiveness might proceed if a national government is hostile to the issue, as appears likely to be the case in the USA. This paper addresses this concern by documenting the percentage of the population of the USA who are ‘covered’ by at least one of six examples of GCC responsiveness at sub-federal – state and municipality – levels. Of the population of the USA, 25.8% lives in states where all of the state-level initiatives surveyed are in effect, whereas only 4.4% are not covered by any of the six. This coverage has increased as compared to earlier surveys (Lutsey, N., and D. Sperling. 2008. “America’s Bottom-Up Climate Change Mitigation Policy.” Energy Policy 36: 673–685. doi:10.1016/j.enpol.2007.10.018). This finding suggests that there is more practical hope for GCC responsiveness than might be commonly appreciated and this also has ramifications for research in accounting.