Empowering Primary Care Nurse Practitioners: A Multilevel Approach to Combating the Opioid Crisis.

Aims: We offer a literature-driven, empirically informed, and highly warranted recommendation for a multilevel approach tailored to nurse practitioners. This approach aimed to drive change at the individual level (nurse practitioner), dyadic level (nurse-patient therapeutic relationship), and systems level (organisational culture, education, and policy) to strengthen nurse practitioners' capacity to deliver optimal opioid use disorder care.

Background: The opioid overdose epidemic is a global public health crisis, with the United States facing the most severe impact.

Predictors of Enrollment and Adherence in a Randomized Tobacco Cessation Clinical Trial.

Background: New therapeutic cessation approaches are being tested in clinical trials to engage and retain people who smoke. Our team is conducting a pragmatic randomized clinical trial (RCT) to evaluate a new treatment for tobacco dependence, but enrolling participants and ensuring adherence has been more challenging than in previous trials.

Objective: To determine the predictors of enrollment and adherence in the RCT.

The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance.

As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway.

K7 channel opener retigabine reduces self-administration of cocaine but not sucrose in rats.

The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviours that can be modelled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that K7/KCNQ channels may contribute to the transition from recreational to chronic drug use.

The unmet mental health needs of U.S. adults living with chronic pain.

Previous research suggests that individuals with mental health needs and chronic pain may be less likely to use mental health treatment compared with those with mental health needs only. Yet, few studies have investigated the existence of population-level differences in mental health treatment use. We analyzed data from the National Health Interview Survey (n = 31,997) to address this question.

The Impact of Nonpharmacological Interventions on Opioid Use for Chronic Noncancer Pain: A Scoping Review.

Despite the lack of evidence, opioids are still routinely used as a solution to long-term management for chronic noncancer pain (CNCP). Given the significant risks associated with long-term opioid use, including the increased number of unregulated opioid pills at large in the opioid ecosystem, opioid cessation or reduction may be the desired goal of the patient and clinician. Viable nonpharmacological interventions (NPIs) to complement and/or replace opioids for CNCP are needed.

The Role of Ryanodine Receptor 2 in Drug-Associated Learning.

Type-2 ryanodine receptor (RyR2) ion channels facilitate the release of Ca from stores and serve an important function in neuroplasticity. The role for RyR2 in hippocampal-dependent learning and memory is well established and chronic hyperphosphorylation of RyR2 (RyR2P) is associated with pathological calcium leakage and cognitive disorders, including Alzheimer's disease. By comparison, little is known about the role of RyR2 in the ventral medial prefrontal cortex (vmPFC) circuitry important for working memory, decision making, and reward seeking.

PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease.

Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements.

Co-occurrence of chronic pain and anxiety/depression symptoms in U.S. adults: prevalence, functional impacts, and opportunities.

Co-occurrence of chronic pain and clinically significant symptoms of anxiety and/or depression is regularly noted in the literature. Yet, little is known empirically about population prevalence of co-occurring symptoms, nor whether people with co-occurring symptoms constitute a distinct subpopulation within US adults living with chronic pain or US adults living with anxiety and/or depression symptoms (A/D). To address this gap, this study analyzes data from the 2019 National Health Interview Survey, a representative annual survey of self-reported health status and treatment use in the United States (n = 31,997).

Morphine-induced osteolysis and hypersensitivity is mediated through toll-like receptor-4 in a murine model of metastatic breast cancer.

The propensity for breast cancer to metastasize to bone is coupled to the most common complaint among breast cancer patients: bone pain. Classically, this type of pain is treated using escalating doses of opioids, which lack long-term efficacy due to analgesic tolerance, opioid-induced hypersensitivity, and have recently been linked to enhanced bone loss. To date, the molecular mechanisms underlying these adverse effects have not been fully explored.

K 7 Channel Opener Retigabine Reduces Self-Administration of Cocaine but Not Sucrose in Rats.

The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviors that can be modeled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that K 7/KCNQ channels may contribute in the transition from recreational to chronic drug use.

ABHD6 and MAGL control 2-AG levels in the PAG and allodynia in a CSD-induced periorbital model of headache.

Introduction: The high prevalence and severe symptoms of migraines in humans emphasizes the need to identify underlying mechanisms that can be targeted for therapeutic benefit. Clinical Endocannabinoid Deficiency (CED) posits that reduced endocannabinoid tone may contribute to migraine development and other neuropathic pain conditions. While strategies that increase levels of the endocannabinoid n-arachidonoylethanolamide have been tested, few studies have investigated targeting the levels of the more abundant endocannabinoid, 2-arachidonoylgycerol, as an effective migraine intervention.

The endocannabinoid system and breathing.

Recent changes in cannabis accessibility have provided adjunct therapies for patients across numerous disease states and highlights the urgency in understanding how cannabinoids and the endocannabinoid (EC) system interact with other physiological structures. The EC system plays a critical and modulatory role in respiratory homeostasis and pulmonary functionality. Respiratory control begins in the brainstem without peripheral input, and coordinates the preBötzinger complex, a component of the ventral respiratory group that interacts with the dorsal respiratory group to synchronize burstlet activity and drive inspiration.

Development and evaluation of a pre-clerkship spiral curriculum: data from three medical school classes.

Pre-clerkship curricula of most Liaison Committee on Medical Education (LCME)-accredited medical schools are divided into blocks by organ system, leaving a significant amount of information susceptible to loss due to prolonged nonuse. We describe the implementation of a formal Spiral Curriculum that periodically revisits material from previous blocks. Learners were surveyed on receptivity to the curriculum across three graduating classes at a single medical school.

Targeting 5-HT receptors and Kv7 channels in PFC to attenuate chronic neuropathic pain in rats using a spared nerve injury model.

Chronic pain remains a disabling disease with limited therapeutic options. Pyramidal neurons in the prefrontal cortex (PFC) express excitatory G-coupled 5-HT receptors (5-HTR) and their effector system, the inhibitory Kv7 ion channel. While recent publications show these cells innervate brainstem regions important for regulating pain, the cellular mechanisms underlying the transition to chronic pain are not well understood.

Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury.

Introduction: Traumatic brain injury (TBI) is a leading cause of disability in the US. Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR) to inhibit inflammatory mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed TBI.

Extracellular Alterations in pH and K+ Modify the Murine Brain Endothelial Cell Total and Phospho-Proteome.

Pathologies of the blood-brain barrier (BBB) have been linked to a multitude of central nervous system (CNS) disorders whose pathology is poorly understood. Cortical spreading depression (CSD) has long been postulated to be involved in the underlying mechanisms of these disease states, yet a complete understanding remains elusive. This study seeks to utilize an in vitro model of the blood-brain barrier (BBB) with brain endothelial cell (b.

β-spectrin as a stalk cell-intrinsic regulator of VEGF signaling.

Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report β-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific β-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina.

Brain Penetrant, but not Peripherally Restricted, Synthetic Cannabinoid 1 Receptor Agonists Promote Morphine-Mediated Respiratory Depression.

Cannabis acceptance and use continues to rise despite the gaps in knowledge regarding the mechanisms of cannabinoids and the endocannabinoid system in many physiological functions, including respiratory influence. With recent evidence of cannabinoid receptor 1 (CB1R) presence in the collection of respiratory neurons in the brainstem, as well as in the peripheral lung tissue, it is vital that the mechanisms involved in central and peripheral CB1R modulation of respiratory function be delineated. In this study we sought to define the roles of central versus peripheral CB1R activation on respiratory depression alone and in combination with morphine using whole body plethysmography.

Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents.

The voltage-gated sodium NaV1.7 channel, critical for sensing pain, has been actively targeted by drug developers; however, there are currently no effective and safe therapies targeting NaV1.7.

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats.

Background: Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors.

Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport.

Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission, a large cytoplasmic GTPase recruited to the mitochondrial surface via transmembrane adaptors to initiate scission. While Brownian motion likely accounts for the local interactions between Drp1 and the mitochondrial adaptors, how this essential enzyme is targeted from more distal regions like the cell periphery remains unknown. Based on proteomic interactome screening and cell-based studies, we report that GAIP/RGS19-interacting protein (GIPC) mediates the actin-based retrograde transport of Drp1 toward the perinuclear mitochondria to enhance fission.

Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression.

An escalating number of fatalities resulting from accidental opioid overdoses typically attributed to respiratory depression continue to define the opioid epidemic. Opioid respiratory depression results from a decrease in reflexive inspiration within the preBötzinger complex in the brainstem. Cannabinoid receptor agonism is reported to enhance opioid analgesia, yet whether cannabinoids enhance or inhibit opioid-induced respiratory depression is unknown.

The Effects of Repeated Morphine Treatment on the Endogenous Cannabinoid System in the Ventral Tegmental Area.

The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry.

Sex hormones regulate NHE1 functional expression and brain endothelial proteome to control paracellular integrity of the blood endothelial barrier.

Background: Sex hormones have been implicated in pH regulation of numerous physiological systems. One consistent factor of these studies is the sodium-hydrogen exchanger 1 (NHE1). NHE1 has been associated with pH homeostasis at epithelial barriers.