Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Abstract Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

Navigating the future of roads – considering potential impacts of environmental and social trends on road infrastructure

Providing mobility corridors for communities, enabling freight networks to transport goods and services, and a pathway for emergency services and disaster relief operations, roads are a vital component of our societal system. In the coming decades, a number of modern issues will face road agencies as a result of climate change, resource scarcity and energy related challenges that will have implications for society. To date, these issues have been discussed on a case by case basis, leading to a fragmented approach by state and federal agencies in considering the future of roads – with potentially significant cost and risk implications. Within this context, this paper summarises part of a research project undertaken within the ‘Greening the Built Environment’ program of the Sustainable Built Environment National Research Centre (SBEnrc, Australia), which identified key factors or ‘trends’ affecting the future of roads and key strategies to ensure that road agencies can continue to deliver road infrastructure that meets societal needs in an environmentally appropriate manner. The research was conducted over two years, including a review of academic and state agency literature, four stakeholder workshops in Western Australia and Queensland, and industry consultation. The project was supported financially and through peer review and contribution, by Main Roads Western Australia, QLD Department of Transport and Main Roads, Parsons Brinckerhoff, John Holland Group, and the Australian Green Infrastructure Council (AGIC). The project highlighted several potential trends that are expected to affect road agencies in the future, including predicted resource and materials shortages, increases in energy and natural resources prices, increased costs related to greenhouse gas emissions, changing use and expectations of roads, and changes in the frequency and intensity of weather events. Exploring the implications of these potential futures, the study then developed a number of strategies in order to prepare transport agencies for the associated risks that such trends may present. An unintended outcome of the project was the development of a process for enquiring into future scenarios, which will be explored further in Stage 2 of the project (2013-2014). The study concluded that regardless of the type and scale of response by the agency, strategies must be holistic in approach, and remain dynamic and flexible.

Emerging issues for road construction and maintenance – A futuristic view

In the coming decades the design, construction and maintenance of roads will face a range of new issues and as such will require a number of new approaches. In particular, road authorities will be required to consider and respond to a range of issues related to climate change, and associated extreme weather events, such as the extensive flooding in January 2011 in Queensland, Australia Figure 1). Coupled with diminishing access to road construction supplies (such as aggregate), water scarcity, and the potential for increases in oil and electricity prices, this range of challenges bear little resemblance to those previously faced. In Australia, state and federal authorities face further pressures given the variety of needs resulting from the country's geographical and population diversity, expansive road networks, road freight requirements and relatively small population base.

Reducing environmental pressures of road building

Although road construction and use provides significant economic and social benefits its environmental impact is of growing concern. Roads are one of the greatest greenhouse gas contributors both directly through fossil energy consumed in mining, transporting, earthworks, and paving work, along with in-direct emissions from road use by vehicles. This discussion paper will outline opportunities within the Australian context for reducing environmental pressure in road building and consider the future environmental impacts of road projects.

Understanding pressures on the future of roads: A sustainable built environment National Research Centre Discussion Paper

According to the Australian Government, when combined with expected population growth and internal migration, expected changes in temperature and rainfall are expected to increase road maintenance costs by over 30 percent by 2100. This presents a significant future economic risk, in response, this paper will discuss the potential for roads to improve their resilience to the impacts of climate change and other key pressures. The paper will also highlight how such measures can inform state and national main road infrastructure planning and reduce future associated risks and costs.

The future of roads: How road agencies are facing a conflicted future

Although road construction and use provides significant economic and social benefits, its environmental impact is of growing concern. Roads are one of the greatest greenhouse gas contributors, both directly through fossil energy consumed in mining, transporting, earthworks and paving work, and through the emissions from road use by vehicles. Further,according to the Australian Government, when combined with expected population growth and internal migration,expected changes in temperature and rainfall are expected to increase road maintenance costs. This discussion paper will outline opportunities within the Australian context for reducing environmental and carbon pressure from road building, and provide a framework for considering the potential pressures that will affect the resilience of roads to the impacts of climate change and oil vulnerability.

The future of roads: Reducing environmental pressures and the management of carbon

Although road construction and use provides significant economic and social benefits, its environmental impact is of growing concern. Roads are one of the greatest greenhouse gas contributors, both directly through fossil energy consumed in mining, transporting, earthworks and paving work, plus the emissions from road use by vehicles. Further, according to the Australian Government, when combined with forecast population growth, internal migration and changes in temperature and rainfall, these are expected to increase road maintenance costs. This discussion paper outlines opportunities within the Australian context for reducing environmental and carbon pressure from road building, and provides a framework for considering the potential future pressures that will affect the resilience of roads to the impacts of climate change and oil vulnerability. Seven strategic areas are outlined for further investigation, including a guide to carbon management for road agencies covering planning, funding, procurement, delivery and maintenance of roads.

Reducing the environmental impact of road construction

The practice of road construction and maintenance is inherently lean and efficient; a result of the economic benefits that are gained by minimizing wasted resources. In this age of conservation and environmental management, the inbuilt sustainability of existing road construction practices is being developed and extended to produce variety of environmentally sustainable options. A new concept of a “sustainable road” has emerged through both academia and industry, and is defined to be a road that is: - constructed to reduce environmental impacts; - designed to optimise the alignment (vertical and horizontal including considerations of ecological constraints and operational use by vehicles); - resilient to future environmental and economic pressures (e.g. climate change and resource scarcity); - adaptable to changing uses including increased travel volumes, greater demand for public and active (cycling and walking) transport, and; - able to harvest the energy to power itself.

Scenario planning and emerging global trends for the future of roads and automobile transport

Roads and road infrastructure will be faced with multiple challenges over the coming decades – challenges that in many ways bear little resemblance to those previously faced - and as such will require new approaches. The opportunity exists to transform the way road infrastructure is conceived and constructed, as a key part of the process of assisting society to respond to climate change and reduce other environmental pressures. Innovations in road construction, use and management in order to manage these changes can now be seen. Scenario planning is one tool that can take into account emerging challenges, develop or adopt new approaches, and thus help this transformation to occur. The paper explores scenario planning methodologies, global innovations and trends in road construction and maintenance and the findings from stakeholder workshops in Brisbane and Perth. It highlights key opportunities for road agencies to use scenarios to enable planning that, in the face of future uncertainties, facilitates appropriate responses.

How will the future of roads be navigated?

In the coming decades the design, construction and maintenance of roads will face a range of new challenges - that in many ways will bear little resemblance to the challenges previously faced - and as such will require a number of new approaches. Such challenges will result from a growing number of interconnected environmental, social and economic factors, which are set to apply significant pressure on the future of roads. For instance, environmental pressures will include the impacts of climate change on rainfall patterns and temperature profiles; economic pressure will be affected by shifting global economic balances and flows, and will include materials and resources shortages, along with predicted increases in energy and resource prices globally,i and social pressures will include potential shifts to lighter vehicles, reduced use of cars due to higher fuel costs, and political pressure to respond to climate change.