Molecular Assays for Characterization of Alternatively Spliced Isoforms of the Mu Opioid Receptor (MOR)
Mu-opioid receptor (MOR) belongs to a family of heptahelical G-protein-coupled receptors (GPCRs). Studies in humans and rodents demonstrated that the OPRM1 gene coding for MOR undergoes extensive alternative splicing afforded by the genetic complexity of OPRM1. Evidence from rodent studies also demonstrates an important role of these alternatively spliced forms in mediating opiate analgesia via their differential signaling properties. MOR signaling is predominantly G(ia) coupled. Release of the alpha subunit from G-protein complex results in the inhibition of adenylyl cyclase/cAMP pathway, whereas release of the betagamma subunits activates G-protein-activated inwardly rectifying potassium channels and inhibits voltage-dependent calcium channels. These molecular events result in the suppression of cellular activities that diminish pain sensations. Recently, a new isoform of OPRM1, MOR3, has been identified that shows an increase in the production of nitric oxide (NO) upon stimulation with morphine. Hence, there is a need to describe molecular techniques that enable the functional characterization of MOR isoforms. In this review, we describe the methodologies used to assay key mediators of MOR activation including cellular assays for cAMP, free Ca(2+), and NO, all of which have been implicated in the pharmacological effects of MOR agonists.
Available from: George Anderson
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ABSTRACT: Schizophrenia and depression are two common and debilitating psychiatric conditions. Up to 61% of schizophrenic patients have comorbid clinical depression, often undiagnosed. Both share significant overlaps in underlying biological processes, which are relevant to the course and treatment of both conditions. Shared processes include changes in cell-mediated immune and inflammatory pathways, e.g. increased levels of pro-inflammatory cytokines and a Th1 response; activation of oxidative and nitrosative stress (O&NS) pathways, e.g. increased lipid peroxidation, damage to proteins and DNA; decreased antioxidant levels, e.g. lowered coenzyme Q10, vitamin E, glutathione and melatonin levels; autoimmune responses; and activation of the tryptophan catabolite (TRYCAT) pathway through induction of indoleamine-2,3-dioxygenase. Both show cognitive and neurostructural evidence of a neuroprogressive process. Here we review the interlinked nature of these biological processes, suggesting that schizophrenia is immunologically primed for an increased expression of depression. Such a conceptualization explains, and incorporates, many of the current perspectives on the nature of schizophrenia and depression, and has implications for the nature of classification and treatment of both disorders. An early developmental etiology to schizophrenia, driven by maternal infection, with subsequent impact on offspring immuno-inflammatory responses, creates alterations in the immune pathways, which although priming for depression, also differentiates the two disorders.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2012; 42. DOI:10.1016/j.pnpbp.2012.07.016 · 3.69 Impact Factor
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ABSTRACT: This paper is the thirty-fourth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2011 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).
Peptides 10/2012; 38(2). DOI:10.1016/j.peptides.2012.09.027 · 2.62 Impact Factor
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ABSTRACT: The hypothalamic–pituitary–adrenal (HPA) axis is a feedback loop that includes the hypothalamus, pituitary, and adrenal glands. The HPA axis has been shown to regulate immune responses. The main hormones involved in the HPA axis are corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids (GC), which are also called stress hormones. These hormones contribute to the regulation of immune responses and can also affect neuronal survival, neurogenesis, synaptic plasticity, and behavioral responses [1, 2]. The HPA axis is a three-tiered biological system that begins at the highest level with the release of CRH from the hypothalamic paraventricular nucleus (PVN). CRH-expressing neurons located in the PVN of the hypothalamus play a pivotal role in orchestrating the central stress response. CRH stimulates the release of ACTH from the anterior pituitary gland. In turn, ACTH acts on the adrenal cortex to increase the production and release of GC hormones. Proper functioning of all of these neurons is essential for maintaining a homeostatic state following a stressful event. Several neuronal pathways modulate HPA axis activity. For example, the hippocampus and prefrontal cortex inhibit the HPA axis, and the amygdala and monoaminergic input from the brainstem stimulate CRH production by PVN neurons. GC hormones exert negative feedback control of the HPA axis by binding to GC receptors on hippocampal and hypothalamic PVN neurons [3–5].
Neural-Immune Interactions in Brain Function and Alcohol Related Disorders, 01/2013: pages 477-508; , ISBN: 978-1-4614-4728-3
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