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.

Assessing the concordance of health and child protection data for 'maltreated' and 'unintentionally injured' children

Objectives: To quantify the concordance of hospital child maltreatment data with child protection service (CPS) records and identify factors associated with linkage. Methods: Multivariable logistic regression analysis was conducted following retrospective medical record review and database linkage of 884 child records from 20 hospitals and the CPS in Queensland, Australia. Results: Nearly all children with hospital assigned maltreatment codes (93.1%) had a CPS record. Of these, 85.1% had a recent notification. 29% of the linked maltreatment group (n=113) were not known to CPS prior to the hospital presentation. Almost 1/3 of children with unintentional injury hospital codes were known to CPS. Just over 24% of the linked unintentional injury group (n=34) were not known to CPS prior to the hospital presentation but became known during or after discharge from hospital. These estimates are higher than the 2006/07 annual rate of 2.39% of children being notified to CPS. Rural children were more likely to link to CPS, and children were over 3 times more likely to link if the index injury documentation included additional diagnoses or factors affecting their health. Conclusions: The system for referring maltreatment cases to CPS is generally efficient, although up to 1 in 15 children had codes for maltreatment but could not be linked to CPS data. The high proportion of children with unintentional injury codes who linked to CPS suggests clinicians and hospital-based child protection staff should be supported by further education and training to ensure children at risk are being detected by the child protection system.

Microarray expression profiling in melanoma reveals a BRAF mutation signature

We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.

Stability and change

This special feature section of Journal of Management & Organization (Volume 17/1 - March 2011) sets out to widen understanding of the processes of stability and change in today's organizations, with a particular emphasis on the contribution of institutional approaches to organizational studies. Institutional perspectives on organization theory assume that rational, economic calculations, such as the maximization of profits or the optimization of resource allocation, are not sufficient to understand the behavior of organizations and their strategic choices. Institutionalists acknowledge the great uncertainty associated with the conduct of organizations and suggest that taken-for-granted values, beliefs and meanings within and outside organizations also play an important role in the determination of legitimate action.

Peer state assessment of TxDOT maintenance program and practices : workshop and road rally findings

In an effort to evaluate and improve their practices to ensure the future excellence of the Texas highway system, the Texas Department of Transportation (TxDOT) sought a forum in which experts from other state departments of transportation could share their expertise. Thus, the Peer State Review of TxDOT Maintenance Practices project was organized and conducted for TxDOT by the Center for Transportation Research (CTR) at The University of Texas at Austin. The goal of the project was to conduct a workshop at CTR and in the Austin District that would educate the visiting peers on TxDOT’s maintenance practices and invite their feedback. CTR and TxDOT arranged the participation of the following directors of maintenance: Steve Takigawa, CA; Roy Rissky, KS; Eric Pitts, GA; Jim Carney, MO; Jennifer Brandenburg, NC; and David Bierschbach, WA. One of the means used to capture the peer reviewers’ opinions was a carefully designed booklet of 15 questions. The peers provided TxDOT with written responses to these questions, and the oral comments made during the workshop were also captured. This information was then compiled and summarized in the following report. An examination of the peers’ comments suggests that TxDOT should use a more holistic, statewide approach to funding and planning rather than funding and planning for each district separately. Additionally, the peers stressed the importance of allocating funds based on the actual conditions of the roadways instead of on inventory. The visiting directors of maintenance also recommended continuing and proliferating programs that enhance communication, such as peer review workshops.

Integrating treatment for mental and physical disorders and substance misuse in Indigenous primary care settings

Objective: Australian Indigenous peoples in remote and rural settings continue to have limited access to treatment for mental illness. Comorbid disorders complicate presentations in primary care where Indigenous youths and perinatal women are at particular risk. Despite this high comorbidity there are few examples of successful models of integrated treatment. This paper outlines these challenges and provides recommendations for practice that derive from recent developments in the Northern Territory. Conclusions: There is a strong need to develop evidence for the effectiveness of integrated and culturally informed individual and service level interventions. We describe the Best practice in Early intervention Assessment and Treatment of depression and substance misuse study which seeks to address this need.