The role of pharmacists in opioid stewardship: A scoping review.

BACKGROUND: The opioid epidemic is an international public health concern. Pharmacists are in a strategic position to promote and implement effective opioid stewardship due to both their central role on health care teams and frequent interaction with patients. Despite this integral role, pharmacists do not have harmonized scopes of practice in opioid stewardship. OBJECTIVES: This scoping review was conducted to identify and critically review the role of pharmacists in opioid stewardship and identify future areas of study. METHODS: The scoping review was conducted according to the methodological framework proposed by Arksey and O'Malley, which was further modified by the Joanna Briggs Institute. Six databases were searched for original, peer-reviewed research; PubMed (MEDLINE), Ovid Embase, Ovid International Pharmaceutical Abstracts, Scopus, Cochrane Library, and APA PsycInfo. RESULTS: In 92% of the included studies (n = 77), opioid stewardship interventions led by either a pharmacist or in an interdisciplinary team resulted in improvements in at least one outcome measure, with education and medication therapy adjustments being the most predominant activities. Other areas supported by evidence include community stakeholder education, policy and guideline setting, and risk assessment. CONCLUSION: This scoping review provides valuable insight into the various roles pharmacists can have in opioid stewardship. The findings from this review identified opioid stewardship activities that can make significant contributions towards reducing the impact of the opioid crisis. This review informs future research and has the potential to influence pharmacy practice on a national and international scale.

Chronic early-life social isolation affects NMDA and TrkB receptor expression in a sex-specific manner.

Exposing mammals to adverse social environments early in life can affect brain development in ways that alter adult behaviour. For example, chronic, early-life social isolation (CELSI) has been found to cause novelty-induced hyperactivity, impaired pre-pulse inhibition, and enhanced anxiety-related behaviour. Although the molecular mechanism(s) underlying the embedding of CELSI have not been fully elucidated, evidence suggests changes in the level of excitatory neurotransmission and neurotrophic factor signalling may be quite important. Since much of the work in this area has focused upon mRNA-level analyses, and has shown variable responses across both brain region and animal sex, our study aimed to explore the impact of CELSI on the expression of two important plasticity-related proteins (Tropomyosin receptor kinase B and the GluN2B subunit of the NMDA receptor) in the pre-frontal cortex and hippocampus of both male and female rats. We observed that the expression of both proteins was clearly changed by CELSI, but that the effect occurred in a sex (but not region) specific manner. Our results support the growing view that early-life adversity can cause structural changes reasonably associated with adult behaviour, and emphasise that the study of such changes benefits from a sex-based analysis.

The role of pharmacists in opioid stewardship: Protocol.

BACKGROUND: The opioid crisis is a worldwide public health concern. In North America, evidence suggests that the increase in opioid prescriptions correlates with the observed increase in opioid-related mortality and morbidity. Pharmacists are in a strategic position to promote effective opioid stewardship as they have a central role on healthcare teams. However, in many contexts, pharmacists do not have a harmonized scope of practice and no standardized opioid stewardship approach has been implemented. OBJECTIVES: A scoping review will be conducted to identify and summarize evidence on the role of pharmacists in opioid stewardship and identify areas for future study. METHODS: The scoping review will be conducted according to the methodological framework proposed by Arksey and O'Malley, which was further modified by the Joanna Briggs Institute. Six databases will be searched which include PubMed, Embase, International Pharmaceutical Abstracts, Scopus, Cochrane Library, and APA PsycInfo. PROJECT IMPACT: The findings of this review will identify opioid stewardship activities that can contribute towards reducing the impact of the opioid crisis. Additionally, it will provide foundational strategies to promote policy level change and foster a harmonized scope of practice. This review has the potential to inform future research, impact pharmacy practice, and drive policy change.

Amyloid-ß Inhibits PDGFß Receptor Activation and Prevents PDGF-BBInduced Neuroprotection.

BACKGROUND: PDGFß receptors and their ligand, PDGF-BB, are upregulated in vivo after neuronal insults such as ischemia. When applied exogenously, PDGF-BB is neuroprotective against excitotoxicity and HIV proteins. OBJECTIVE: Given this growth factor's neuroprotective ability, we sought to determine if PDGF-BB would be neuroprotective against amyloid-ß (1-42), one of the pathological agents associated with Alzheimer's disease (AD). METHODS AND RESULTS: In both primary hippocampal neurons and the human-derived neuroblastoma cell line, SH-SY5Y, amyloid-ß treatment for 24 h decreased surviving cell number in a concentrationdependent manner. Pretreatment with PDGF-BB failed to provide any neuroprotection against amyloid-ß in primary neurons and only very limited protective effects in SH-SY5Y cells. In addition to its neuroprotective action, PDGF promotes cell growth and division in several systems, and the application of PDGFBB alone to serum-starved SH-SY5Y cells resulted in an increase in cell number. Amyloid-ß attenuated the mitogenic effects of PDGF-BB, inhibited PDGF-BB-induced PDGFß receptor phosphorylation, and attenuated the ability of PDGF-BB to protect neurons against NMDA-induced excitotoxicity. Despite the ability of amyloid-ß to inhibit PDGFß receptor activation, immunoprecipitation experiments failed to detect a physical interaction between amyloid-ß and PDGF-BB or the PDGFß receptor. However, G protein-coupled receptor transactivation of the PDGFß receptor (an exclusively intracellular signaling pathway) remained unaffected by the presence of amyloid-ß. CONCLUSIONS: As the PDGF system is upregulated upon neuronal damage, the ability of amyloid-ß to inhibit this endogenous neuroprotective system should be further investigated in the context of AD pathophysiology.

Fluoxetine-induced transactivation of the platelet-derived growth factor type ß receptor reveals a novel heterologous desensitization process.

Many G protein-coupled receptors (GPCRs), including serotonin (5-HT) receptors promote the activity of receptor tyrosine kinases (RTKs) via intracellular signaling pathways in a process termed transactivation. Although transactivation pathways are commonly initiated by a GPCR, a recent report demonstrated that serotonin-selective reuptake inhibitors (SSRIs) were able to block 5-HT-induced transactivation of the platelet-derived growth factor (PDGF) type ß receptor. We show that a 45 min pretreatment of SH-SY5Y cells with the SSRI fluoxetine indeed blocked 5-HT-induced transactivation of the PDGFß receptor. However, upon further examination, we discovered that during the pretreatment period, fluoxetine itself was transiently transactivating the PDGFß receptor via 5-HT2 receptor activation. After 45min, the increase in PDGFß receptor phosphorylation induced by fluoxetine had returned to baseline, but a subsequent transactivating stimulus (5-HT) failed to "re-transactivate" the PDGFß receptor. We further demonstrate that 45min, but not 3h, 5-HT pretreatment blocks dopamine-induced PDGFß receptor transactivation. This did not involve changes in PDGF receptor function, since ligand (PDGF)-induced PDGFß receptor activation was not inhibited by 5-HT pretreatment. To our knowledge this is the first demonstration of the heterologous desensitization of an RTK transactivation pathway and reveals a previously unknown short-term "blackout" period where no additional transactivation signaling is possible.

5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation.

The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.