Mu opioid receptor activation enhances regulator of G protein signaling 4 association with the mu opioid receptor/G protein complex in a GTP-dependent manner.

The interaction of Regulator of G protein Signaling 4 (RGS4) with the rat mu opioid receptor (MOR)/G protein complex was investigated. Solubilized MOR from rat brain membranes was immunoprecipitated in the presence of RGS4 with antibodies against the N-terminus of MOR (anti-MOR10-70 ). Activation of MOR with [D-Ala(2) , N-Me-Phe(4) , Gly(5) -ol] enkephalin (DAMGO) during immunoprecipitation caused a 150% increase in Goα and a 50% increase in RGS4 in the pellet. When 10 µM GTP was included with DAMGO, there was an additional 72% increase in RGS4 co-immunoprecipitating with MOR (p = 0.003). Guanosine 5'-O-(3-thiotriphosphate) (GTPγS) increased the amount of co-precipitating RGS4 by 93% (compared to DAMGO alone, p = 0.008), and the inclusion of GTPγS caused the ratio of MOR to RGS4 to be 1 : 1 (31 fmoles : 28 fmoles, respectively). GTPγS also increased the association of endogenous RGS4 with MOR. In His6 RGS4/Ni(2+) -NTA agarose pull down experiments, 0.3 µM GTPγS tripled the binding of Goα to His6 RGS4, whereas the addition of 100 µM GDP blocked this effect. Importantly, activation of solubilized MOR with DAMGO in the presence of 100 µM GDP and 0.3 µM GTPγS increased Goα binding to His6 RGS4/Ni(2+) -NTA agarose (p = 0.001). Regulators of G protein Signaling (RGS) shorten the time that G proteins are active. Activation of the mu opioid receptor (MOR) causes GTP to bind to and to activate Go (αoßγ). RGS4 then binds to the activated αo-GTP/MOR complex and accelerates the intrinsic GTPase of αo. After αo dissociates from MOR, RGS4 remains bound to the C-terminal region of MOR.

Trends in Traumatic Brain Injury Among U.S. Service Members Deployed in Iraq and Afghanistan, 2002-2016.

INTRODUCTION: Traumatic brain injury (TBI) is a major health issue for service members deployed and is more common in recent conflicts; however, a thorough understanding of risk factors and trends is not well described. This study aims to characterize the epidemiology of TBI in U.S. service members and the potential impacts of changes in policy, care, equipment, and tactics over the 15 years studied. METHODS: Retrospective analysis of U.S. Department of Defense Trauma Registry data (2002-2016) was performed on service members treated for TBI at Role 3 medical treatment facilities in Iraq and Afghanistan. Risk factors and trends in TBI were examined in 2021 using Joinpoint regression and logistic regression. RESULTS: Nearly one third of 29,735 injured service members (32.4%) reaching Role 3 medical treatment facilities had TBI. The majority sustained mild (75.8%), followed by moderate (11.6%) and severe (10.6%) TBI. TBI proportion was higher in males than in females (32.6% vs 25.3%; p<0.001), in Afghanistan than in Iraq (43.8% vs 25.5%; p<0.001), and in battle than in nonbattle (38.6% vs 21.9%; p<0.001). Patients with moderate or severe TBI were more likely to have polytrauma (p<0.001). TBI proportion increased over time, primarily in mild TBI (p=0.02), slightly in moderate TBI (p=0.04), and most rapidly between 2005 and 2011, with a 2.48% annual increase. CONCLUSIONS: One third of injured service members at Role 3 medical treatment facilities experienced TBI. Findings suggest that additional preventive measures may decrease TBI frequency and severity. Clinical guidelines for field management of mild TBI may reduce the burden on evacuation and hospital systems. Additional capabilities may be needed for military field hospitals.

Saving the brain after mild-to-moderate traumatic injury: A report on new insights of the physiology underlying adequate maintenance of cerebral perfusion.

ABSTRACT: Traumatic brain injury (TBI) is associated with increased morbidity and mortality in civilian trauma and battlefield settings. It has been classified across a continuum of dysfunctions, with as much as 80% to 90% of cases diagnosed as mild to moderate in combat casualties. In this report, a framework is presented that focuses on the potential benefits for acute noninvasive treatment of reduced cerebral perfusion associated with mild TBI by harnessing the natural transfer of negative intrathoracic pressure during inspiration. This process is known as intrathoracic pressure regulation (IPR) therapy, which can be applied by having a patient breath against a small inspiratory resistance created by an impedance threshold device. Intrathoracic pressure regulation therapy leverages two fundamental principles for improving blood flow to the brain: (1) greater negative intrathoracic pressure enhances venous return, cardiac output, and arterial blood pressure; and (2) lowering of intracranial pressure provides less resistance to cerebral blood flow. These two effects work together to produce a greater pressure gradient that results in an improvement in cerebral perfusion pressure. In this way, IPR therapy has the potential to counter hypotension and hypoxia, potentially significant contributing factors to secondary brain injury, particularly in conditions of multiple injuries that include severe hemorrhage. By implementing IPR therapy in patients with mild-to-moderate TBI, a potential exists to provide early neuroprotection at the point of injury and a bridge to more definitive care, particularly in settings of prolonged delays in evacuation such as those anticipated in future multidomain operations. LEVEL OF EVIDENCE: Report.

The Biological Basis of Chronic Traumatic Encephalopathy following Blast Injury: A Literature Review.

The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.