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Posttranscriptional Regulation of Mu Opioid Receptor (MOR-1): Implications of Alternative Splicing in the Neuropathogenesis of Morphine Tolerance

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Posttranscriptional Regulation of Mu Opioid Receptor (MOR-1): Implications of Alternative Splicing in the Neuropathogenesis of Morphine Tolerance Review Article J Anest & Inten Care Med Volume 9 Issue 4 - Octomber 2019 Copyright © All rights are reserved by Alrena V Lightbourn DOI: 10.19080/JAICM.2019.09.555767 Posttranscriptional Regulation of Mu Opioid Receptor (MOR-1): Implications of Alternative Splicing in the Neuropathogenesis of Morphine Tolerance. Literature Review and Research Approach Alrena V Lightbourn* Basic & Pharmaceutical Sciences Division, Florida A&M University, USA Submission: May 28, 2018; Published: October 10, 2019 *Corresponding author: Alrena V Lightbourn, Basic & Pharmaceutical Sciences Division, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences, Tallahassee, FL, USA Abstract It is no surprise that the progressive increase in the use, misuse and abuse of prototypical narcotic analgesic, morphine, has so heightened approachesawareness within investigating scientific cellular and clinicalchanges communities and receptor that binding researchers strategies, are the clamoring wealth of to genetic discover information new and comingdivergent from approaches the Human to Genome disrupt negative opioid receptor-mediated outcomes and to improve drug efficacy toward beneficial effects. Beyond the traditional pharmacologic Enthusiasm for the contributions of alternatively spliced variants has been slow, except for the widely accepted cytochrome P450 metabolic Project provokes deeper insight to be sought at the more significant, mechanistically relevant, posttranslational and posttranscriptional levels. greater demand on scientists to elucidate the signal transduction pathways and molecular mechanisms employing these variants. The hope of discoveringenzymes. Nonetheless, functional signaturesa steadily growingfor these repository variants is of increasing recently identifiedand it appears opioid that receptor their clinical alternatively utility splicedas new andvariants relevant (ASVs) molecular places an targets even for improving opioid pharmacotherapy may gain momentum. targetAs for the pain-mediating field of pharmacogenomics drugs, the chief grows, of which the iscentral morphine. role ofThe the medical mu opioid decision receptor to prescribe (MOR-1) morphine gene (OPRM1) for the managementand its variants of moderate- are being to-severeexplored inchronic greater pain depth. is complicated MOR-1 belongs by the to existencea family of of 7-transmembrane polymorphisms in (7TM) drug g-proteinresponse tocoupled opioid receptors pharmacotherapy. (GPCR). It Under serves acute as the or essential chronic conditions, morphine induces pharmacological tolerance, avoidable only by abstaining from its use. Over the past three decades, the enigmatic neuropeptide mechanisms, but none of these theories explain the sustained tolerance that progresses to physical dependence and in some cases, opioiddevelopment addiction. of morphine The current tolerance review hasadvances been surveysvariably existingattributed knowledge to reversible and peersmodifications ahead to inanticipate receptor a binding,role for alternativelysignal transduction spliced andmu opioid receptor variants in the development and termination of morphine tolerance, withdrawal and addiction. Keywords: Neuron; Neuroblastoma; SH-SY5Y Mu opioid receptor; MOR-1; Alternative splice variant; ASV; Morphine; Naloxone; Gene expression; Post-transcription; Tolerance; Abbreviations: Neuron; Neuroblastoma; SH-SY5Y Mu opioid receptor; MOR-1; Alternative splice variant; ASV; Morphine; Naloxone; Gene expression; Post-transcription; Tolerance; Introduction physiological changes in the brain over time may be accompanied The National Institute on Drug Addiction has recently by behavioral and emotional cue of the systematic degradation rendered drug addiction as ‘a chronic disease characterized by reward circuit in chronic users [2-4]. The predictability of despite harmful consequences’ [1]. Physical, biochemical and on brain function with ensuing modifications of the brain drug seeking and use that is compulsive, or difficult to control man’s responses to morphine intake is highly variable, giving J Anest & Inten Care Med 9(4): JAICM.MS.ID.555767 (2019) 0085 Journal of Anesthesia & Intensive Care Medicine rise to inter-individual and intra-individual differences whose context in the current opioid crisis is not clearly understood the 70-90% of cancer patients requiring individualized opioid variable responsiveness to opioids acting through MOR-1. Among [4-5]. Hence, it is important to adequately dissect the extent to therapy for intense chronic pain, their response to morphine is highly variable, necessitating dose escalation with an increased which mu opioid receptor (MOR-1) alternatively spliced variants mechanisms underlying the development of morphine tolerance, in the general population has been linked to common variants (ASVs) are involved in the biological processes and physiological risk of developing tolerance. Recently, variable pain sensitivity addiction and withdrawal [6-8]. It is also unclear to what extent ultimate source of genetic variation may lie in the differences of the μ-opioid receptor. As is true of all human pathologies, the individual differences in drug response. Close evaluation of the in DNA sequences and the proteins expressed. Central to these the multiplicity [9] of MOR-1 ASVs govern human inter- and intra- for further preclinical research and future clinical intervention. molecular influences of MOR-1 ASVs may reveal relevant targets molecular extremes is the RNA molecule, whose successful The current paper reviews existing information concerning the relevant genes and the production of functional proteins to meet posttranscriptional modification facilitates the expression of mu opioid receptor and alternative splicing at the intersection the body’s physiologic needs. It remains uncertain whether recent of much needed clinical interventions to curb the vast extent to which individuals become addicted or display maladaptive highly subjective variability in drug response, in the development findings of alternative splicing of hMOR-1 are implicated in the behaviors following chronic opioid use. of tolerance to opioid pharmacotherapy [10], or whether these Background alternatively spliced variants. Opioid class of pharmaceutical Agents: Opioids, one of most effects might be mitigated through manipulation of hMOR-1 frequently prescribed pain medications, accounted for roughly Methods 257 million prescriptions in 2009, up 48% from 2000. Nearly 4 The literature review was developed based upon electronic million long-acting or extended-release opioids are prescribed searches of digital scientific and public health databases, Central, Medscape, and Biomed Central Open Access. Using the every year (FDA 2010; CARES Alliance 2010). Therapeutic uses including: ScienceDirect, IUPHAR, PubMed (MEDLINE), PubMed and anti-diarrheal applications. Morphine, a mainstay of opioid terms such as: mu opioid receptor, alternative splicing, alternative of opioid drugs include analgesic, antitussive (cough suppressant) splice variant, tolerance, and gene expression, keyword searches were conducted with English language restrictions. Government pharmacotherapy, was recently identified on the 2008 list of ‘Top reports and relevant textbooks were also consulted. All resources 20 Molecules in U.S. Markets’ as having $277 million in sales (GPhA, were manually assessed for relevancy and adequacy in developing 2009). It is officially used in preoperative medical and short-term the manuscript. sedation procedures, and as an analgesic (WHO 2007). Morphine is listed as an essential medicine for adults (WHO 2009a) and its strong analgesic properties, morphine is the drug-of-choice for Discussion children (WHO 2009b) by the World Health Organization. Due to moderate-to-severe pain and is recommended for freedom from Significance of the Problem pain (e.g., cancer pain, pain of myocardial infarction, surgical pain) Pain is a universal phenomenon (WHO 1986; Tao 2010). consistent with the World Health Organization (WHO) patient bill of rehabilitation admissions for treatment of opioid pain reliever Due to its hemodynamic action’s morphine sulfate is also used Regrettably, in the United States, a 400% increase in the number of rights and its introduction of the ‘pain ladder’ (WHO 1986). abuse, misuse and addiction has also been observed between to relieve dyspnea of acute left ventricular failure and dyspnea of pulmonary edema. 2004 and 2008, the number of emergency room visits for non- Statement of the Problem: Morphine exerts its pain- 1998 and 2008 (SAMHSA 2010; CARES Alliance 2010). Between medical use of opioid analgesics soared by 111% (CDC 2010a; relieving effects primarily through the mu opioid receptor (MOR- peripheral nervous system. Maintenance of the specialized state CARES Alliance 2010). Nearly 40% of all poisoning deaths in 2006 1), which are ubiquitous throughout the central (chiefly) and of neurons through regulation of gene expression is essential were attributed to opioid analgesics (CDC 2010b; CARES Alliance 2010). More than 5 million persons >12 years old self-reported its euphoric effects, morphine is one of the most abused opiate personal non-medical use of morphine (USDHHS, 2009). Due to drugs. for achieving optimal efficacy of opioid response systems (e.g., responses, and their ability to function is compromised in disease. OPRM1). Neurons mediate normal cellular communication and History of Morphine: H NO Moreover, neuronal failure to recognize and respond to changes 17 19
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