Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis.

Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs.

Chronic and acute pain and pain management for patients in methadone maintenance treatment.

BACKGROUND AND OBJECTIVES: Many individuals receiving methadone maintenance treatment (MMT) for opioid addiction also require treatment for acute or chronic pain, and the presence of pain is known to have a negative impact on patient health and function. However, effective pain management in this population is complicated by many factors, including heightened pain sensitivity, high opioid tolerance, illicit substance use, and variable cross-tolerance to opioid pain medications. This article reviews the recent literature on acute and chronic pain among, and pain treatment of, patients receiving MMT for opioid addiction and discusses the implications for effective pain management. Acute pain management among women maintained on methadone during and after labor and delivery is also discussed, as well as common concerns held by patients and providers about appropriate pain management strategies in the context of methadone maintenance and addiction treatment. METHODS: One hundred nine articles were identified in a PubMed/MEDLINE electronic database search using the following search terms: methadone, methadone maintenance, methadone addiction, pain, pain management, chronic pain, and acute pain. Abstracts were reviewed for relevance, and additional studies were extracted from the reference lists of articles identified in the original search. RESULTS: The pain sensitivity and pain responses of MMT patients differ significantly from those of patients not maintained on opioids, and few data are available to guide patient care. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Rigorous studies are needed to identify and evaluate effective pain management approaches for this unique patient population and to improve patient treatment outcomes.