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American epidemic : reporting from the front lines of the opioid crisis
\"Just a few years ago, the opioid crisis could be referred to as a \"silent epidemic,\" but it is no longer possible to argue that the scourge of opiate addiction is overlooked. This is in large part thanks to the writings featured in this volume, which includes some of the most impactful reporting in the United States in recent years addressing the opiate addiction crisis. American Epidemic collects, for the first time, the key works of reportage and analysis that provide the best picture available of the origins, consequences, and human calamity associated with the epidemic.\"--Provided by publisher.
Book
Opioid therapy in the 21st century
Opioid Therapy in the 21st Century, Second Edition provides clinicians with up-to-date, evidence-based information about appropriate opioid use, including the potential benefits and adverse affects of the therapy.
eBook
Single-molecule characterization of opioid receptor heterodimers reveals soluble µ-δ dimer blocker peptide alleviates morphine tolerance
Heterodimerization of opioid receptors (ORs), MOR, KOR, and DOR, is implied in their functional regulation and diversification, and thus its understanding is crucial for developing better analgesic treatments. However, our knowledge on OR heterodimerization/heterodimers remains limited. Here, using single-molecule imaging and functional analysis, we find that MOR, the main morphine receptor, repeatedly forms
transient (≈250 ms) heterodimers
with DOR every 1-10 seconds, but not with KOR, whereas DOR and KOR also form transient heterodimers. We obtain all the heterodimer-monomer equilibrium constants and rate constants with/without agonists. We identify the critical heterodimer binding sites in the extracellular domains, in addition to the less-specific transmembrane domains, and develop soluble peptide blockers for MOR-DOR and DOR-KOR heterodimerization, using amino-acid sequences mimicking the extracellular binding sites. With these peptide blockers, we dissect the monomer/dimer roles in OR internalization and signaling. The soluble MOR-DOR heterodimer blocker reduces the development of long-term morphine tolerance in mice.
Development of morphine tolerance is a critical medical and social issue. Here, the authors use single-molecule imaging to identify interaction sites of opioid receptor heterodimers and demonstrate that a soluble µ-δ heterodimer blocker peptide reduces tolerance in mice.
Journal Article
Biased Opioid Ligands
Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.
Journal Article
The opioid crisis
\"Opioids are pain relievers that include legal drugs like morphine, fentanyl, and oxycodone and illegal drugs like heroin. In 2017, the US Department of Health and Human Services declared the opioid epidemic a public health crisis after 42,249 people in the United States died of opioid overdoses in 2016. Opioid prescription has been on the rise since the 1990s, when pharmaceutical companies asserted that the pain relievers were not addictive, though the tragic consequences have proven otherwise. This volume explores the history of the opioid crisis and solutions that have been proposed to fight this increasingly deadly epidemic.\"-- Provided by publisher.
Book
Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum
In this study, the authors show that there are multiple forms of opioid-induced long-term depression (OP-LTD) in the dorsal striatum, each mediated by the mu, delta or kappa opioid receptor. The mu and delta OP-LTD are presynaptic and can summate, but only mu OP-LTD occludes endocannabinoid-induced LTD. Furthermore, mu OP-LTP, but not kappa or delta OP-LTP, is blocked by the analgesic oxycodone.
As prescription opioid analgesic abuse rates rise, so does the need to understand the long-term effects of opioid exposure on brain function. The dorsal striatum is an important site for drug-induced neuronal plasticity. We found that exogenously applied and endogenously released opioids induced long-term depression (OP-LTD) of excitatory inputs to the dorsal striatum in mice and rats. Mu and delta OP-LTD, although both being presynaptically expressed, were dissociable in that they summated, differentially occluded endocannabinoid-LTD and inhibited different striatal inputs. Kappa OP-LTD showed a unique subregional expression in striatum. A single
in vivo
exposure to the opioid analgesic oxycodone disrupted mu OP-LTD and endocannabinoid-LTD, but not delta or kappa OP-LTD. These data reveal previously unknown opioid-mediated forms of long-term striatal plasticity that are differentially affected by opioid analgesic exposure and are likely important mediators of striatum-dependent learning and behavior.
Journal Article
Getting wrecked : women, incarceration, and the American opioid crisis
\"Getting Wrecked provides a rich ethnographic account of women battling addiction as they cycle through jail, prison, and community treatment programs in Massachusetts. Since incarceration has become a predominant American social policy for managing the problem of drug use, including the opioid epidemic, this book examines how prisons and jails have attempted concurrent programs of punishment and treatment to deal with inmates struggling with a diagnosis of substance use disorder. An addiction physician and a medical anthropologist, Kimberly Sue powerfully illustrates the impacts of incarceration on women's lives as they seek well-being and better health while confronting lives marked by structural violence, gender inequity, and ongoing trauma\"--Provided by publisher.
Book
Single-molecule methods for characterizing receptor dimers reveal metastable opioid receptor homodimers that induce functional modulation
Opioid receptors (ORs) are critical for endogenous and synthetic analgesics. OR homodimerization is considered important for their pharmacological diversity, but whether they form homodimers remains controversial. Here, we establish that the three classical ORs, μ-, κ-, and δ-ORs (MOR, KOR, and DOR, respectively) undergo repeated transient (120-180 ms) homodimerizations every few seconds. This is achieved by using single-molecule imaging and developing theories for analyzing single-molecule colocalization data, which provide key parameters, such as homodimer-monomer dissociation equilibrium constants and rate constants. Their 9-26 amino-acid C-terminal cytoplasmic domains, without sequence similarities, are involved in specific homodimerization, whereas the transmembrane domains provide less specific affinities. Using the membrane-permeable peptides mimicking the C-terminal homodimerization sequences which block homodimerizations, functions of monomers and homodimers were dissected. KOR and DOR homodimers, but not MOR homodimers, activate downstream G-proteins differently from monomers upon agonist addition, without influencing OR internalization. These findings guide strategies to enhance OR-based analgesia.
Receptor dimerization is central to many GPCRs signaling, but key rate and equilibrium constants are hard to measure. Here, the authors present single-molecule methods to obtain such constants and reveal transient opioid receptor homodimers modulating function.
Journal Article