\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"2663",leadTitle:null,fullTitle:"Child Abuse and Neglect - A Multidimensional Approach",title:"Child Abuse and Neglect",subtitle:"A Multidimensional Approach",reviewType:"peer-reviewed",abstract:"Child maltreatment constitutes a social problem that affects all societies of the world. 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The reader will find a selection of internationally recognized works addressing the issue of child maltreatment both from theoretical and applied view.",isbn:null,printIsbn:"978-953-51-0671-5",pdfIsbn:"978-953-51-5136-4",doi:"10.5772/3035",price:119,priceEur:129,priceUsd:155,slug:"child-abuse-and-neglect-a-multidimensional-approach",numberOfPages:196,isOpenForSubmission:!1,isInWos:1,hash:"9fa543105bd942a1db694c7e3755bfef",bookSignature:"Alexander Muela",publishedDate:"July 11th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2663.jpg",numberOfDownloads:25069,numberOfWosCitations:22,numberOfCrossrefCitations:9,numberOfDimensionsCitations:20,hasAltmetrics:1,numberOfTotalCitations:51,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 5th 2011",dateEndSecondStepPublish:"January 9th 2012",dateEndThirdStepPublish:"April 14th 2012",dateEndFourthStepPublish:"July 13th 2012",dateEndFifthStepPublish:"August 12th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"138437",title:"Dr.",name:"Alexander",middleName:null,surname:"Muela Aparicio",slug:"alexander-muela-aparicio",fullName:"Alexander Muela Aparicio",profilePictureURL:"https://mts.intechopen.com/storage/users/138437/images/3480_n.jpg",biography:"Alexander Muela is a Professor and a Researcher of Psychology at the University of Mondragon, Spain. 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\r\n\tFast detection and measurement of anomalies in personal and community health status is paramount in ensuring their health. Accuracy and speed of medical diagnosis and intervention ensure the efficacy of those procedures for any anomalies that happen within individuals, their communities, and their environments.
\r\n\r\n\tDemands for the more comfortable, faster, cheaper, more reliable, and more accurate way for medical diagnosis and intervention has been pushing the shift of researcher's interest from conventional medical procedures that based on biochemical and immunological methods to proposed medical procedures based on physical methods.
\r\n\r\n\tThis book mainly aims to discus on physical aspects of medical technology, procedures, or devices. This book welcomes topics on how physical methods substitute conventional methods for medical diagnosis and intervention and also proposed methods and their clinical trial reports as evidence of their performance.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"fff3e6fb155e4ef69838bcc1f79d83ae",bookSignature:"Dr. Husein Irzaman and Dr. Renan Prasta Jenie",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8528.jpg",keywords:"Spectrophotometry,Optics, Photonics, Mechanics, Medical Condition, Health Physical Marker, Machine Learning, Regression, Anamnesis, Diagnosis Enforcement, Treatment, Procedure",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 4th 2019",dateEndSecondStepPublish:"February 25th 2019",dateEndThirdStepPublish:"April 26th 2019",dateEndFourthStepPublish:"July 15th 2019",dateEndFifthStepPublish:"September 13th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"193016",title:"Dr.",name:"Husein",middleName:null,surname:"Irzaman",slug:"husein-irzaman",fullName:"Husein Irzaman",profilePictureURL:"https://mts.intechopen.com/storage/users/193016/images/system/193016.jpg",biography:"Irzaman was born in Jakarta, Indonesia, in 1963. He received the B.S. in agro-meteorology from Bogor Agricultural University, in 1988, M.S. degrees in physics from University of Indonesia, in 1998, and Ph.D. degree in physics from Bandung Technology University, Bandung, in 2005.\n\nSince 1997, he is a resident lecturer of Physics Physics Department, Bogor Agricultural University. From 2007 to 2011, He is Physics Head of Department, Bogor Agricultural University. From 2011, He is Head of Material Physics Laboratory, Physics Department, Bogor Agricultural University. He is the author of 16 Scopus indexed journal articles and a book chapter. His research interests include sensors engineering, semiconductor device physics and new material characterization, and ferroelectrics. From 2012, He is a technical member of Alternative Energy Division, Ministry of Energy and Mineral Resources, Indonesia.",institutionString:"Bogor Agricultural University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Bogor Agricultural University",institutionURL:null,country:{name:"Indonesia"}}}],coeditorOne:{id:"235853",title:"Dr.",name:"Renan Prasta",middleName:null,surname:"Jenie",slug:"renan-prasta-jenie",fullName:"Renan Prasta Jenie",profilePictureURL:"https://mts.intechopen.com/storage/users/235853/images/system/235853.png",biography:"Renan Prasta Jenie was born in Jakarta, Indonesia, in 1983. He received B.S. degree in agriculture engineering from Bogor Agricultural University in 2005, M.S. degree in software engineering from Bandung Technology University in 2008, and Ph.D. Degree in human nutrition from Bogor Agricultural University 2018.\nFrom 2008 to 2013, he was a researcher in Binus Foundation. Since 2013, He is an IT Consultant for Child Growth and Development Cohort Study, Bogor, West Java, Indonesia, and Researcher for Physics Department, Bogor Agricultural University. He is the author of 4 Scopus indexed proceedings articles and a book chapter, and editorial assistant for a book. His research interests include software engineering, artificial intelligence, sensoring, and human and nutrition telemetry.",institutionString:"Bogor Agricultural University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"288104",firstName:"Ivana",lastName:"Spajic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/288104/images/8497_n.jpg",email:"ivana.s@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6801",title:"Ferroelectrics and Their Applications",subtitle:null,isOpenForSubmission:!1,hash:"ce5ff2c700cc6d73c62c2f6541226248",slug:"ferroelectrics-and-their-applications",bookSignature:"Husein Irzaman",coverURL:"https://cdn.intechopen.com/books/images_new/6801.jpg",editedByType:"Edited by",editors:[{id:"193016",title:"Dr.",name:"Husein",surname:"Irzaman",slug:"husein-irzaman",fullName:"Husein Irzaman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"66080",title:"Excitability of Vascular Smooth Muscle",doi:"10.5772/intechopen.85053",slug:"excitability-of-vascular-smooth-muscle",body:'\nRegulation of pressure and local blood flow occurs at the level of resistance arteries and arterioles. Once blood exits the heart, it first flows into large elastic arteries, followed by smaller distributing arteries, which branch further into small resistance arteries and, finally, arterioles. The branching and reduction in vessel diameter actually results in the increase in total cross-sectional area of circulation. Because of their small diameter, resistance arteries and arterioles are the place of the largest pressure drop.
\nResistance arteries and arterioles typically exhibit a state of partial constriction termed myogenic tone [1]. Myogenic tone is related to the level of the intraluminal pressure and provides a level of tone that vasodilators can act upon [2]. When the intraluminal pressure increases, resistance arteries and arterioles first dilate due to their elastic properties and then constrict to the new steady-state level. Myogenic tone is an intrinsic property of arteriolar smooth muscle cells and does not require endothelium [3, 4]. Resistance to blood flow is actively controlled by contraction or relaxation of arteriolar smooth muscle cells wrapped around the vessel so that their tone regulates the vessel diameter [2]. Arterial walls are made up of three layers: the tunica intima, tunica media and tunica adventitia. While the tunica intima contains endothelial cells and a thin layer of connective tissue, the tunica media supplies mechanical strength and contractile power. It is composed of several layers of spindle-shaped smooth muscle cells arranged helically in a matrix of elastin and collagen fibers. In some places, endothelial cells make contacts with smooth muscle cells to transmit signals between the intima and media. The tunica adventitia is mostly a connective tissue sheath with no distinct outer border. Its role is to tether the vessel loosely to the surrounding tissue [5]. Arterioles, the smallest resistance arteries placed right before capillaries, have a single layer of spindle-shaped smooth muscle cells [6]. Endothelial cells frame the lumen of arterioles. The shape and orientation within the vessels help to distinguish between these two distinct cells types (Figure 1).
\n4th order skeletal muscle arteriole loaded with 10 mM Fluo-4. A single layer of spindle-like vascular smooth muscle cells (VSMC) runs perpendicular to the vessel’s length (left panel). Long endothelial cells (EC) frame the lumen of skeletal muscle arteriole (right panel, adapted from [6]). Scale bar = 50 μm.
Development of the tone is associated with depolarization of smooth muscle cells. While the mechanisms underlying depolarization are not completely understood, it is known that development of myogenic tone depends on extracellular Ca2+. At 0 Ca2+, pressurized resistance arteries and arterioles are fully dilated. Adding Ca2+ up to ≈ 2 mM to the extracellular space causes maximal tone [7]. In addition to the development of basal tone, the myogenic mechanism is believed to underlie the response to acute changes in pressure and contribute to spontaneous vasomotor activity [7].
\nMyogenic tone is controlled by intrinsic as well as extrinsic mechanisms. Intrinsic mechanisms include constriction of arterioles in response to pressure increase (Bayliss effect), endothelial secretions (nitric oxide, EDHF, prostacyclin, endothelin), vasoactive metabolites (e.g. adenosine in exercising muscle), autacoids (local vasoactive paracrine secretions such as histamine), and temperature. Important physiological responses mediated entirely by intrinsic regulation include the autoregulation of flow, and functional and reactive hyperemia. Intrinsic regulation also contributes to pathological responses such as inflammation and arterial vasospasm. Extrinsic regulation is brought about by factors originating outside the organ, namely the vasomotor nerves (sympathetic, parasympathetic and others) and circulating hormones such as adrenaline, vasopressin and insulin (for review, see [8]).
\nSkeletal muscle is the largest organ in the body that receives about 20% of cardiac output at rest and up to 80% during exercise. In skeletal muscle, the local blood flow is regulated over a 20× range to meet the demands of exercise. Therefore, vascular resistance of skeletal muscle is a critical determinant of total peripheral resistance and blood pressure. Arterioles of skeletal muscle have a high myogenic tone at rest as they are subject to major hyperemia (increased blood flow) during exercise [8]. In case of orthostatic hypotension, a potential contributor to cardiovascular adaptation to prolonged periods of bed rest or microgravity, skeletal muscle arterioles may develop functional or structural adaptations. Despite the physiological importance of skeletal muscle arterioles, little is known about ionic mechanisms underlying their excitability. Even within the same skeletal muscle, arterioles might respond differently to pressure changes. For instance, the first-order arterioles isolated from fast-twitch (e.g., white gastrocnemius) skeletal muscle fiber demonstrated both functional and structural changes such as reduced myogenic tone, decreased contractile responsiveness, and reduced wall thickness with no change in luminal diameter [9, 10]. In contrast, arterioles isolated from slow-twitch (e.g., soleus) fibers show no difference in myogenic tone or contractile responsiveness but rather a structural remodeling resulting in a decreased arteriole diameter [11].
\nAfter development of isolated vessel techniques, the electrophysiology of smooth muscle cells was extensively studied in small arteries isolated from various vascular beds [12].
\nBoth slow changes (myogenic tone) and fast spikes in the membrane potential have been observed in arteriolar smooth muscle cells. Arteriolar smooth muscle cells can generate rhythmical contractions (vasomotion) over an extended period of time. Vasomotion occurs spontaneously or in response to vasoactive stimulation with a frequency of 3–20 per minute. The exact physiological role of vasomotion is not clear. In cases of ischemia and hypertension, it serves as a protective mechanism. Vasomotion is not a consequence of heartbeat, respiration, or neuronal input. It is generated within arteriolar smooth muscle cells by an endogenous pacemaker mechanism driven by a cytosolic Ca2+ oscillator. The cytosolic Ca2+ oscillator depends on Ca2+ entry and is regulated by transmitters and hormones, which increase the formation of InsP3 and diacylglycerol (DAG) and promote oscillatory activity (for review, see [13]).
\nFrom the early studies, it has been appreciated that an increase in intraluminal pressure leads to depolarization and consequent contraction of vascular smooth muscle cell (electromechanical coupling). Mechanisms of depolarization are still not well understood. Depolarization increases Ca2+ concentration inside the cell, which leads to activation of myosin light chain kinase by Ca2+/calmodulin and consequent contraction. Propagation of depolarization is achieved through gap junctions between neighboring smooth muscle cells. The signaling between endothelial and smooth muscle cells via gap junctions is essential for normal vascular function. Gap junctions in arteriolar smooth muscle cells and endothelial cells are formed by connexins Cx37, Cx40, and Cx43. Coupling between arteriolar smooth muscle cells appears to be essential for the maintenance of oscillations in membrane potential, the intracellular [Ca2+], and vasomotion.
\nThe exact signaling mechanisms that underlie detection of the mechanical stimulus and membrane depolarization are not completely understood (for review, see [7, 14]). Depolarization of vascular smooth muscle’s membrane activates various voltage-gated ion channels, pumps and exchangers, including voltage-gated Ca2+ and K+ channels, Ca2+-activated BKCa and ClCa channels, Na+/Ca2+ exchanger, Ca2+-ATP pump and N+/K+-ATPase, ATP-sensitive P2X receptor, and transient receptor potential (TRP) ion channels. Voltage-gated L-type Ca2+ channels are activated upon depolarization and increase Ca2+ concentration inside the cell. BKCa K+ channels hyperpolarize smooth muscle cell back to its resting potential [15, 16]. Some vascular myocytes, particularly in large vessels, contract via pathways that appear to be unrelated to significant changes in the membrane potential (pharmacomechanical coupling).
\nMembrane potential of arteriolar smooth muscle cells is difficult to measure because of the changes in the intraluminal pressure and active vasomotor responses. Resting membrane potentials range from approximately −60 to −35 mV for physiological pressures (for review, see [17, 18]). Resting membrane potentials between −80 to −60 mV were previously reported for un-pressurized mice mesenteric artery [19], submucosal arterioles [20], and cerebral arterioles [21, 22]. A range of membrane potentials was reported for un-pressurized mice skeletal muscle arterioles (Figure 2). The average resting potential was reported to be around −68 mV (Figure 2, adapted from [6]). However, it’s significantly more negative than −55 mV previously reported for un-pressurized arterioles in rat cremaster muscle [23]. Resting membrane potential in vascular smooth muscle cells is determined to a large extent by K+ conductance [18]. Intracellular [Cl−] in vascular smooth muscle cells is around 55 mM, which is unusually high and mediated probably through Cl−▬HCO3− exchanger. A small influx of Ca2+ and efflux of Cl− ions at rest reduce the membrane potential from the Nernst equilibrium for K+ [24].
\nResting membrane potential of un-pressurized 4th order arterioles isolated from mice skeletal muscle. Distribution of the resting membrane potential values was fitted by a single Gaussian function peaking at −77 ± 2 mV (n = 81, smooth line). The average resting potential was Vrest = −68 ± 2 mV (n = 81). Adapted from [6].
Most of the arteriolar smooth muscle cells are quiescent. In some cases, a drop in the intraluminal pressure (during trauma to a vessel) that leads to hyperpolarization and dilation generates membrane action potentials. Physiological role of membrane action potentials in arteriolar smooth muscle is unclear, as relatively small changes in the membrane potential (between −55 and − 35 mV) are sufficient to control Ca2+ entry and to initiate contraction in response to stimulation by mechanical stress of the blood flow [14]. Spontaneous action potentials could be associated either with rhythmic vasomotor activity [23]; follow K+-induced hyperpolarization and dilation [25], or precede injury-induced constriction [26].
\nOnly a few recordings of action potentials in skeletal muscle arterioles were made so far [6, 23, 25, 27]. Spontaneous action potential spikes could be observed in pressurized small arteries [23, 25], as well as in un-pressurized arterioles as shown in Figure 3 [6, 21].
\nSpontaneous action potentials were observed in un-pressurized skeletal muscle arterioles (2 mM Ca bath solution). Smooth muscle cells were current-clamped using gramicidin-perforated configuration, with intracellular solution containing 150 KCl. Adapted from [6].
Unlike in many other excitable tissues, action potentials in smooth muscle cells of arteries [28] and arterioles [21] are thought to be independent of voltage-gated Na+ channels, as they could not be blocked by the application of voltage-gated Na+ channel blocker tetrodotoxin (TTX). Depolarization of smooth muscle cells induced by the change in intraluminal pressure and/or tissue-stretch produces an increase in the intracellular [Ca2+], consequent myosin light chain phosphorylation and contraction (for review, see [14]). Since specific blockers of L-type voltage-gated Ca2+ channels suppress both the upstroke and the after-depolarizing components of action potentials, these channels are thought to be the main pathway for the depolarizing current. Nevertheless, several groups have demonstrated that voltage-gated Na+ channels are present in arterial beds and are activated upon membrane depolarization [6, 29].
\nVoltage-gated Ca2+ channels mediate influx of Ca2+ ions in response to membrane depolarization and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression in many different cell types. Their activity is essential to couple electrical signals in the cell surface to physiological events in cells. Voltage-gated Ca2+ channels are comprised of the pore-forming α1 subunit in complex with auxiliary subunits. A transmembrane disulfide-linked α2δ, an intracellular β, and a γ subunit are components of most types of calcium channels. The α1 subunit contains four repeats of a domain with six transmembrane segments, the fourth of which is the voltage-sensing S4 segment. The pore loop between transmembrane segments S5 and S6 in each domain determines ion conductance and selectivity (for review, see [30]). Ten distinct genes encode mammalian α1 subunits of three subfamilies of voltage-gated Ca2+ channels. The amino acid sequences of these α1 subunits are more than 70% identical within a subfamily but less than 40% identical among subfamilies. Voltage-gated Ca2+ channels are named using the chemical symbol of the principal permeating ion with the principal physiological regulator (voltage) indicated as a subscript according to the nomenclature developed for voltage-gated K+ channels [31]. The CaV1 subfamily (CaV1.1–CaV1.4) represents high-voltage activated L-type Ca2+ channels, the CaV2 subfamily (CaV2.1–CaV2.3) represents neuronal N-, P/Q-, and R-types Ca2+ channels, and CaV3 subfamily (CaV3.1–CaV3.3) represents low-voltage activated T-type Ca2+ channels.
\nThe pharmacology and biophysics of Ca2+ channels subfamilies are quite distinct. L-type Ca2+ calcium channels typically require a strong depolarization for activation and do not inactivate at positive potentials. They are the main pathway for Ca2+ currents recorded in muscle cells, where they initiate contraction and secretion. The CaV1 subfamily is the molecular target of the organic Ca2+ channel blockers used widely in the therapy of cardiovascular diseases. L-type Ca2+ channels are blocked by the organic antagonists, including dihydropyridines (e.g., nifedipine), phenylalkylamines, and benzothiazepines. Dihydropyridines can be channel activators or inhibitors and therefore are thought to act allosterically to shift the channel toward the open or closed state rather than by occluding the pore. T-type Ca2+ channels are activated by weak depolarization and are transient at sustained depolarization. They are expressed in a wide variety of cell types, where they are involved in shaping the action potential and controlling patterns of repetitive firing. The CaV3 subfamily of voltage-gated Ca2+ channels is insensitive to both the dihydropyridines that block CaV1 channels and the spider and cone snail toxins that block the CaV2 channels. There are no widely useful pharmacological agents that block T-type Ca2+ currents specifically. Mibefradil blocks both T-type Ca2+ channels and with less potency L-type Ca2+ channels. Currents through expressed CaV3.2 channels could be selectively blocked by application of 40 μM of Ni2+ [32].
\nCurrents through dihydropyridine-sensitive Ca2+ channels were recorded in arteries of various vascular beds [21, 33, 34, 35, 36], including from smooth muscle cells of skeletal muscle arterioles (Figure 4, left panel). CaV1.2 considered to be the principal sub-type of voltage-gated Ca2+ channels involved in excitation-contraction coupling of vascular smooth muscle cells [37]. Since L-type Ca2+ blocker nifedipine did not eliminate basal tone in skeletal muscle arterioles, other Ca2+ entry mechanisms are believed to contribute to myogenic tone along with L-type Ca2+ channels [38]. In addition to L-type, vascular smooth muscle cells also express T-type Ca2+ channels (for review, see [30, 39]). Currents through T-type Ca2+ channels have been found in smooth muscle cells of arteries and arterioles of cerebral [21], mesenteric [40], renal [41], coronary [35], and skeletal [6] vascular beds as shown in Figure 4 (right panel). Although the messenger RNAs for both, CaV3.1 and CaV3.2 T-type Ca2+ channels were found in rat cremaster arterioles [42], only L-type Ca2+ currents were recorded in single smooth muscle cells isolated from resistance arteries of hamster cremaster muscle [43]. The pressure/stretch stimulus initiates a depolarization that causes Ca2+ influx through voltage-gated L-type Ca2+ channels and initiates Ca2+ sparklets [44, 45, 46]. Both, Ca2+ sparklets and Ca2+ sparks (Ca2+ release from intracellular stores) signaling events, activate negative feedback mechanisms via Ca2+-dependent K+ currents thus preventing unrestrained depolarization [47, 48, 49]. While Ca2+ influx through L-type Ca2+ channels are believed to be involved in contraction of vascular smooth muscle, T-type Ca2+ channels, particularly CaV3.2 appear to be mostly involved in relaxation of coronary arteries, acting through activation of BKCa channels [40, 41, 42, 43, 50, 51].
\nVoltage-gated T-type and L-type Ca2+ channels are present in arteriolar smooth muscle. Whole-cell Ba2+ currents were recorded in the presence of 1 μM tetrodotoxin (TTX), voltage-gated Na+ channel blocker as described in more detail in [6]. Two kinetically different components were observed: while voltage steps from −30 up to −10 mV produced fast inactivating T-type Ca2+ current (left panel), further depolarization activated slowly inactivating L-type Ca2+ current (right panel). Adapted from [6].
In addition to voltage-gated Ca2+ channels, significant TTX-sensitive Na+ currents were found in smooth muscle cells from rabbit main pulmonary artery [52], human aorta [53], murine mesenteric arteries [29], and skeletal muscle arterioles [6] as shown in Figure 5. The above observations suggest that more complex mechanisms are likely to generate action potential in vascular smooth muscle cells. When voltage-gated Ca2+ and Na+ channels coexist in the same cell, Na+ conductance is thought to be responsible for generation and propagation of action potential in excitable cells such as neurons, striated muscle, and neuroendocrine cells. It has lower threshold and faster rise time than Ca2+ conductance. After Na+ channels rapidly inactivate, L-type voltage-gated Ca2+ channels open and further depolarize the cell, thus prolonging the plateau of an action potential. In contrast, T-type voltage-gated Ca2+ channels may open at resting potential and produce depolarizing current that brings the cell to threshold for Na+ spike [54, 55].
\nTTX-sensitive voltage-gated Na+ channels are present in arteriolar smooth muscle. In arteriolar smooth muscle of skeletal muscle arterioles, voltage steps produced inward currents with at least two kinetically distinct components in 2 mM Ca solution (left panel). The fast component was through voltage-gated Na+ channels as it was blocked by application of 1 μM TTX (right panel). Adapted from [6].
Voltage-gated Na+ channels consist of the subunit associated with auxiliary subunits. The pore-forming subunit is sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the subunits. These auxiliary subunits are involved in channel localization and interaction with cell adhesion molecules, extracellular matrix, and intracellular cytoskeleton. Similar to the voltage-gated Ca2+ channels, the subunits of Na+ channels are organized in four homologous domains, each composed of six transmembrane segments. S4 segment is a voltage sensor, and a pore loop located between the S5 and S6 segments determines ion conductance and selectivity (for review, see [56]). According to the nomenclature, the NaV1 superfamily (NaV1.1–NaV1.9) represents voltage-gated Na+ channels. Unlike the different classes of voltage-gated Ca2+ channels, the functional properties of Na+ channels are relatively similar. Amino acid sequences of the nine mammalian Na+ channel isoforms are more than 50% identical to each other, but separate families are difficult to define. By this criterion, nine isoforms are considered to be members of one NaV1 gene subfamily. Some voltage-gated Na+ channels (NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.6, and NaV1.7) could be blocked by tetrodotoxin that binds to the extracellular side of the pore.
\nSeveral isoforms of TTX-sensitive voltage-gated channels have been found previously smooth muscle cells of in vasa recta (NaV1.3), portal vein (NaV1.6 and NaV1.8), and vas deference (NaV1.6) [57, 58, 59]. The activity of these voltage-gated Na+ channels may be tightly controlled by elevations of intracellular Ca2+, potentially suppressing activity of Na+ channels [6]. For instance, Ca2+/CaM binding was shown to down-regulates skeletal muscle isoform NaV1.4 by shifting its steady-state inactivation curve in the hyperpolarizing direction [60]. NaV1.3 channels in descending vasa recta are suppressed by calmodulin inhibitors, while elevation of the intracellular [Ca2+] shifts the voltage-dependence of their activation to more positive voltages [57]. In addition, Ca2+-dependent down-regulation of Na+ channels can also occur via the PKC pathway since activation of PKC decreases peak sodium currents through brain NaV1.2 and skeletal muscle NaV1.4 channels by up to 80% [61, 62].
\nL-type voltage-gated Ca2+ channels are involved in excitation-contraction coupling of vascular smooth muscle cells. In addition, T-type Ca2+ channels were detected in arteriolar smooth muscle cells. These two types of voltage-gated Ca2+ channels together play an important role in the constriction/relaxation of smooth muscle cells by regulating Ca2+ signaling during myogenic tone. However, there are indications that other type of voltage-gated channels, specifically Na+ channels are present in various vascular beds. While the role of voltage-gated Ca2+ channels is well established, contribution of voltage-gated Na+ channel remains to be determined.
\nI would like to thank Dr. Roman E. Shirokov for invaluable discussion related to this work.
\nConflict of interest
The author declares no conflict of interest.
Abbreviations
Addiction is a chronic and multifactorial disorder characterized by compulsive drug seeking and use, despite its harmful consequences. Chronic opioid use induces profound molecular and behavioral changes, inducing long-lasting changes in brain plasticity [1]. During the use of the drug, reward and motivation circuits are modified, and new learning and memories are created in relation to the pleasurable effects of the drug and the context in which it is consumed [2]. These memories will later be responsible for the vulnerability to relapse even after a long period of withdrawal. In order to restructure these memories and avoid relapse and craving to opioids, the first recommended approach currently consists in combining psychotherapy with pharmacological substitution therapy [3]. Opioid addiction is currently a major medical and social problem, and its abuse and recreational use have been declared an epidemic in the USA [4, 5], with more than 90 people dying from an opioid overdose every day [6].
Opioids are highly addictive because they induce euphoria (positive reinforcement) and the cessation of a chronic use produces dysphoria [7]. The non-medical opioid use is a major public health challenge, making opioids the second most used illicit drug in the USA [8].
The use of opioids has increased 10- to 14-fold in the last 20 years, including those taken under supervision and recreational use [9].
In relation to this, opioids are one of the most commonly misused medications. Although it is usually prescribed to treat pain, its abuse has serious medical consequences. According to NIDA (National Institute on Drug Abuse, NIH), misuse of prescription drugs is defined as taking a medication in a manner or dose different than has been prescribed, either for a medical complaint, such as pain, or to feel euphoria [2]. The number of opioid prescriptions has increased significantly since the early 1990s [10], with this easier access to the drug being one of the reasons for the high prevalence of opioid misuse [9]. However, other factors can contribute to the problem, such as the lack of information about the addictive properties of prescription opioids, which are perceived as less harmful than illicit opioids [11, 12]. Regardless of the primary causes, there has been a dramatic increase in the number of treatment admissions for addictive disorders related to prescription opioids, as well as the associated overdose deaths in the past 15 years [8, 13, 14].
Pharmacological treatments are essential for initiating and sustaining effective patient-, public health, and system-level interventions to reduce opioid-related morbidity and mortality [15]. In the specific case of opioid use disorders, pharmacotherapy is strongly recommended as a part of an integrated approach, also including psychosocial interventions, psychotherapy, or relapse prevention programs [16]. Until the 1960s, the opioid addiction treatment was only oriented towards abstinence, but then the potential action of methadone as a maintenance treatment for opioid addiction was evaluated [17]. Currently, although complete abstinence continues to be the best possible outcome, the most common option is life-long substitution therapy. While the currently approved medications improve the outcomes, relapse rates are still high, and pharmacotherapy is not effective in all patients [18].
The final goal of the treatment is to reduce the risk of illicit opioid use, overdose or infections, as well as the general improvement of the individuals’ quality of life [15]. The available pharmacological interventions prevent the appearance of withdrawal symptoms and reduce craving, also increasing adherence to the psychotherapy. First, we will address the three different approved drugs on the market [19]. Although the rate of success, measured by maintenance of abstinence, has been greatly improved with the existing treatments, there is still room for further improvement. In a second part of this chapter, we will also refer to new treatments under development, both in preclinical models and in clinical trials. These new drugs are focused on different neurotransmission systems, which are altered by the neuroadaptive changes induced during the addictive process.
The great percentage of withdrawn patients who relapse into drug use [20] makes opioid maintenance therapy the first-line treatment in most cases. Ideal agents for substitution maintenance therapy are those with a high affinity for μ-type opioid receptors showing long-term action. Methadone and buprenorphine, as potent and long-acting opioid agonists, are usually prescribed for opioid substitution therapy, and both constitute the most effective treatments for opioid dependence [21].
Methadone is a safe, efficient, and effective treatment for heroin addiction [22]. This μ-opioid receptor agonist was introduced in the USA by Eli Lilly and Company as an opioid analgesic in 1947. Methadone maintenance treatment began at the Rockefeller Hospital (1965) with the aim to develop an effective and long action pharmacotherapy that targeted opioid receptors. In these initial clinical trials, patients received safe doses (20–40 mg) once a day, and over time, the dose was adjusted to avoid withdrawal symptoms and reduce craving [17]. Since 1964, a great number of studies have documented the safety, efficacy, and effectiveness of methadone pharmacotherapy for heroin addiction [22].
The National Institutes of Health (NIH) at the end of the 1990s supported methadone maintenance pharmacotherapy for heroin addiction. Nowadays, half of the problematic opiate users are under maintenance treatment, with more than 60% receiving methadone [23]. Elevated retention rates with a noteworthy decrease of illicit opiate use have been observed under methadone maintenance treatment [24, 25, 26, 27]. In addition, there are reductions of other associated problems such as intravenous drug use, crime [28, 29, 30], and improvement of social functioning [31]. Later studies reported that prolonged methadone maintenance normalized the immune system function in heroin addicts [32], as well as the altered stress response [33]. Methadone is also well suited with performance of complex cognitive tasks [34]. Regarding its efficacy, according to a recent Cochrane meta-analysis, methadone and buprenorphine appear to be equally effective [35].
Regardless of the positive effects of methadone, one of the main difficulties of methadone maintenance treatment is the stigma accompanying the methadone clinics. In order to solve this, maintenance programs aim to rehabilitate patients by reassigning addicts from a traditional clinic to a medical office for ongoing treatment. The concept of medical maintenance carefully emulates the treatment of chronic diseases, such as insulin-dependent diabetes [32].
On the other hand, there are specific drug interactions of methadone [36], for example, the antituberculosis agent rifampin or the anticonvulsant phenytoin [37, 38, 39]. Methadone can also inhibit gonadotropin-releasing hormones, lowering testosterone levels [40, 41]. Finally, another recognized effect of methadone is the QT prolongation [42]. Patients who undergo prolonged QT intervals must switch to a treatment with buprenorphine, which does not affect it [43]. Several countries, including Germany and Austria, have alternative treatments for opioid maintenance, such as Levomethadone (purified methadone) [44], which exerts its pharmacologic effects mainly via agonism of μ-opioid receptor.
Buprenorphine and the combination buprenorphine-naloxone were also introduced as a possible treatment for opioid use disorder. This medication is characterized by a better side effect profile, lower abuse potential, and good availability when compared to methadone [3]. Buprenorphine is a μ-receptor partial agonist that can reduce opiate cravings, prevent opiate withdrawal, but at the same time blocks the effects of other more powerful opiates [45]. As partial agonist, buprenorphine presents a safety profile with respect to other μ-opioid-receptor agonists and can be more easily adjusted to the desired effect [46]. Although buprenorphine can be the first-line medication over methadone to treat opioid addiction, as it has considerable less abuse potential, its efficacy is limited when treating severe opioid use disorders. Due to the displacement of a stronger opioid by a weaker one, buprenorphine can precipitate withdrawal symptoms [33, 47]. To increase the adherence to this treatment, patients should be at least in mild withdrawal [48].
To avoid diversion, buprenorphine is usually combined with the specific opioid antagonist, naloxone. In 2006, it was introduced in the European market as a sublingual combination tablet. Several works have established the efficacy of buprenorphine-naloxone as a maintenance medication [49, 50, 51] not only for prescription opioids but also for heroin addiction [52, 53]. Numerous meta-analyses have determined that buprenorphine produces successful results in heroin dependence, with no deficiency with respect to being abstinent of illicit opioid use [54, 55]. However, methadone was found to be superior to buprenorphine in overall treatment retention [56]. Buprenorphine therapy not only improves the overall individuals’ quality of life but also decreases overcrowding in emergency departments [57, 58].
From a pharmacological point of view, buprenorphine has important advantages over methadone besides the lower risk of overdose [41, 59]. It is preferable for treatment of opioid dependence in those patients with HIV/AIDS [60, 61] and for pregnant opioid users [62]. On the other hand, when buprenorphine is combined with respiratory depressants, such as alcohol or benzodiazepines, it results in sedation, coma, or even death [63]. Furthermore, patients who do not know about the pharmacology of buprenorphine and use additional opioids seeking a “high” are at risk of an overdose when the effects of buprenorphine wear off [55, 64, 65].
The antagonist therapy blocks or reduces a biological response by binding to and blocking a receptor rather than activating it like an agonist. Naloxone and naltrexone, the opioid antagonist treatments most accepted and commonly used, prevent and reverse opioid effects by mainly blocking the μ-opioid receptor. Both are employed for quick detoxification if there is an overdose and to prevent relapse [66]. Naloxone is a short-acting non-selective opioid antagonist that reverses an opioid overdose. Overdose is a common event for those who use opioids and is the leading cause of death in this population [67, 68]. It quickly crosses the blood-brain barrier and can reverse morphine-induced respiratory depression within 1–2 min [69].
Different studies support the effectiveness of community-based naloxone training and distribution programs in reducing overdose deaths [24, 70, 71]. Naloxone is considered a safe drug to use with little probability of complications, since it has no agonistic activity at the μ-opioid receptor [23]. Since opioid abuse has been declared an epidemic in the USA [4], naloxone has been made more accessible to the relatives of opioid users, which decreases potentially fatal overdoses around 30–40% [72, 73].
Naltrexone is an opioid receptor antagonist that blocks the euphoric and reinforcing effects of opioids consumption, being mainly used for detoxification programs [74, 75, 76, 77]. However, the main disadvantage of the use of this antagonist is the low rate of adherence to this treatment, since less than 20% of patients continue opioid antagonist treatments after several months [78]. Nevertheless, with highly motivated patients or dependent people who cannot be included in the methadone program, naltrexone maintenance therapy can be proposed as a successful approach for treating opioid addiction [79]. Furthermore, it has the advantage of not generating tolerance and/or dependency [80]. In the last years, a new intra-muscular depot formulation of naltrexone has been approved, being useful in reducing the days-of-heroin-use and relapse rate compared with a placebo [81, 82]. This depot naltrexone is taken once monthly, and several studies have shown good outcomes compared to placebo in decreasing craving in naltrexone-treated patients [83]. These extended-release naltrexone formulations address the compliance problems that are often found with oral administration [84]. However, a recent comparative study shows that the extended-release naltrexone presents more difficulties in terms of induction and ongoing care with respect to other buprenorphine products, such as the sublingual film of buprenorphine-naloxone [85].
Nevertheless, to date, the extended-release naltrexone is, together with methadone and buprenorphine, the most recommended pharmacotherapy for opioid use disorders, as it has shown superiority with respect to placebo treatment and counseling [83, 86, 87].
Drug addiction induces significant changes in numerous neurotransmission systems [1], which became new therapeutic targets to treat opioid addiction. Therefore, new pharmacological targets are constantly being developed to improve opiate addiction treatment. This second part of the review will offer an overview of the most promising agents under development and we will also discuss the recent advances in neuroinflammation and the pharmacogenetics field.
With the aim of increasing the efficacy and adherence of treatments, numerous studies are testing new approaches to the currently approved medications. For example, the newest buprenorphine subdermal implant called probuphine [88], which was approved by the FDA in May 2016, is prescribed to those patients who have achieved a sustained clinical stability with low-to-moderate doses of a transmucosal buprenorphine-containing product.This implant guarantees non-fluctuating blood levels of buprenorphine continuously for 6 months improving patient compliance [89].
There is growing interest in the slow-release oral morphine (SROM), as a potential effective candidate for maintenance treatment [90, 91, 92]. This medication is given once daily, and it suits those individuals who cannot tolerate methadone, respond poorly to other available treatments, or show a prolonged QT [93, 94, 95]. However, the last Cochrane meta-analysis reported that there is not enough evidence to confirm the effectiveness of SROM for opioid maintenance, as only three inconclusive studies exist [96].
Tramadol, a reuptake inhibitor of serotonin and norepinephrine, produces a metabolite that moderately acts as a μ-opioid receptor agonist [97]. Recent clinical trials have demonstrated for tramadol the same level of treatment retention and opioid withdrawal symptom suppression as buprenorphine, suggesting that this is a promising and valuable medication [98, 99]. However, although it has been used in the management of acute withdrawal, its use for maintenance treatment as a harm reduction approach has not been assessed systematically. A recent pilot study of tramadol on long-term maintenance in patients with opioid use disorders showed that most of them were able to achieve and maintain abstinence for at least 6 months [100].
It is well known that dopamine (DA) neurotransmission is a common mechanism of drugs of abuse, although the use of DA compounds has not been successful [22]. Numerous preclinical studies have tested the efficacy of different DA antagonists. Acute administration of the DA D3 receptor antagonist SB277011 reduces the reinforcing effects of different drugs of abuse and diminishes opiate withdrawal syndrome [101]. The well-known antipsychotics, aripiprazole (partial DAD2 and 5HT1A agonist and a 5HT2A antagonist) and risperidone (atypical antipsychotic), block context-dependent induced relapse. Risperidone also inhibits reinstatement into heroin seeking due to environmental cues but fails to block relapse induced by priming doses [102]. In the same line, aripiprazole inhibits the conditioned place preference (CPP) induced by morphine [103]. An ongoing clinical trial is evaluating aripiprazole effects to prevent relapse to cocaine use in patients being treated with methadone, as they could return to cocaine consumption, even when they are involved in a drug treatment program [104].
Preclinical studies show that reinstatement of morphine CPP is mainly mediated through glutamatergic neurotransmission [105]. NMDA receptors modulate nociceptive signals in conjunction with opioid receptors, and after continuous morphine treatment, both receptors suffer a desensitization, which mediate analgesic tolerance [22]. Therefore, NMDA receptor antagonists can prevent the development of morphine tolerance. Ifenprodil, an NMDA antagonist, prevents the development, maintenance, and reinstatement of morphine-induced CPP, as well as reinstatement of heroin-seeking self-administration [106].
Another well-known NMDA antagonist is memantine. Animal and human studies have shown positive results in reducing opiate withdrawal and preventing relapse [107, 108, 109]. However, clinical trials have not found significant differences in treatment retention, heroin consumption, or craving with respect to placebo [110]. Although memantine administered in combination with naltrexone can improve the emerging symptoms during the early phase of treatment, this combination did not induce significant improvement in preventing relapse [111].
The nitric oxide synthase (NOS) is a neural retrograde messenger molecule involved in several opioid effects. It has been reported that NOS upregulation takes place during the development of opioid dependence [112] and its inhibition blocks opioid dependence [113, 114]. In addition, administration of NOS inhibitors diminishes the development of morphine-induced CPP [106].
Baclofen is a GABA-B receptor agonist approved for spasticity treatment, and early preclinical studies suggested that it could promote abstinence from a variety of drugs of abuse [115], such as cocaine, ethanol, nicotine, and methamphetamine [116, 117, 118, 119]. Baclofen also reduces morphine withdrawal signs in morphine-dependent animals [120, 121] and disrupts reconsolidation of conditioned reward, facilitating the extinction of the morphine-induced CPP [122]. Assadi and coworkers [123] performed a clinical trial to evaluate the possible benefit of baclofen in the maintenance treatment of opioid addicts and found that the baclofen group presented increased treatment retention being superior to placebo in terms of opiate withdrawal syndrome and depressive symptoms.
An effective add-on therapy combined with methadone or buprenorphine is pregabalin and gabapentin, which are approved for treatment of epilepsy, neuropathic pain, or fibromyalgia [124]. These medications do not act directly on GABA receptors or transporters [125] but modulate the α2-delta subunit of calcium channels, preventing the release of neurotransmitters like glutamate [126]. Both medications prevent opioid tolerance and dependence and reduce withdrawal symptoms in humans and preclinical models [127, 128, 129].
Numerous studies have demonstrated that the cholinergic system is also implicated in opioid addiction, as chronic morphine administration is associated with changes in gene expression in the cholinergic system, and it increases cholinergic neurons in the laterodorsal tegmental nucleus. Administration of nicotinic antagonists reduces withdrawal symptoms in rodents [130], which suggests that nicotine receptors might be a potential pharmacotherapeutic target for opioid detoxification. Furthermore, a relatively recent study evaluated the role of the α4β2 nicotinic receptors as a potential therapeutic target to treat morphine dependence [131]. A recent clinical trial has evaluated the effects of varenicline, a α4β2 partial agonist and α7 full agonist, usually employed for smoking cessation. Varenicline was effective in opioid detoxification patients, as opioid withdrawal scores decrease with respect to those patients receiving a placebo [131].
Cholinesterase inhibitors, currently used to treat Alzheimer’s disease, including donepezil, rivastigmine, and galantamine, increase cholinergic activity and can be potential therapeutic targets in opioid abuse and dependence treatments [132]. Preclinical models have demonstrated that these cholinesterase inhibitors prevented morphine tolerance and attenuated the acquisition and expression of morphine CPP [133].
There are many studies suggesting the potential action of the endocannabinoid system in opioid dependence [134, 135]. Cannabidiol is a natural active metabolite of the Cannabis sativa plant, which is currently being explored for its potential anti-addiction properties [135]. It is the second most abundant cannabinoid present in the plant [136], and interestingly, it does not bind directly to cannabinoid receptors but acts as an inverse agonist at both types CB1 and CB2 [137]. Regarding this, cannabidiol has been shown to attenuate the cue-induced reinstatement of heroin seeking [138] and reduces the rewarding properties of morphine in rodents [139]. There is currently a clinical trial examining the effects of cannabidiol on drug craving in abstinent heroin-dependent subjects (ClinicalTrial.Gov identifier: NCT02539823). In addition, cannabidiol, when combined with a potent opioid like fentanyl, is well tolerated, confirming that cannabidiol would be safe in the case of a relapse in abstinent heroin abusers [140].
The neuroimmune response is an important but relatively poorly understood process in the development of drug addiction. Research is now setting up opportunities for the development of new pharmacotherapies targeting neuroimmune dysfunction. Opioids induce direct and indirect adaptations in the peripheral and central immune systems [141] with a clear relationship between opioid dependence and inflammatory processes [142]. Opioids, such as morphine and heroin, act directly on macrophages and lymphocytes, which produce changes in the CNS, resulting in neurotoxicity [143, 144, 145]. Preclinical models show that chronic morphine treatment increases proinflammatory cytokine levels and overactivates the glia [146, 147]. The consequences include dendrite atrophy, abnormal neurogenesis, and neurodegeneration [148]. To sum up, opioids act to generate the release of proinflammatory cytokines, which induce the activation of the inflammatory response, and finally, this response induces changes in the architecture and functioning of the brain. Neuroinflammation derived from opioid consumption is implicated in tolerance and dependence processes based on results obtained in animal models [149, 150, 151]. Anti-inflammatory cytokines, such as the IL-10, which are well tolerated and safe in other inflammatory diseases, could be used as pharmacotherapy in addiction [152]. For example, gabapentin upregulates the anti-inflammatory cytokine IL-10 in rats [128], thus reducing inflammation. Ibudilast prevents glial cell activation, inhibiting production of proinflammatory cytokines (IL1β, IL-6, TNF-α), and increases the secretion of anti-inflammatory mediators like IL-10 [153]. Clinical trials are currently evaluating if this medication, or other glial activation inhibitors, can prevent opioid withdrawal symptoms [154].
On the other hand, peroxisome proliferator-activated receptors (PPARs) mediate anti-inflammatory and neuroprotective processes [155]. Specifically, PPARγ is strongly implicated in reward processing and motivation [156], as they are located in VTA DA neurons and modulate DA release [157], which suggests its potential role in addiction. Currently, preclinical studies have tested the PPAR-γ agonist pioglitazone, an anti-inflammatory medication, as a treatment for opioid dependence, attenuating morphine withdrawal syndrome in rats [158].
Pharmacogenetics focuses on selecting the most adequate treatment for specific patients, based on their genetic profile and thereby increasing the therapeutic action of the medication. Its goal is the discovery of gene interactions that increase the success rate of treatments [22]. There are variants of gene-encoding proteins implicated in opioid pharmacokinetics and pharmacodynamics that make the patient respond better or worse to a specific treatment. Most studies focus on genes related to the therapeutic response to methadone and buprenorphine [159]. For example, two gene interactions are determinant for the response to methadone. First, there is the ABCB1, the gene encoding the P-glycoprotein efflux transporter, of which methadone is a substrate. People with variants of this gene (subjects with a wild-type and 61A haplotype combination or homozygous for the 61A) show lower methadone requirements. On the other hand, people with the variant 118A/A in μ-opioid receptor 1 gene (MOR1) show higher methadone requirements [160]. Regarding buprenorphine, the frequency of the gene polymorphism (SLC6A3/DAT1) allele 10 in the DA transporter is much higher in non-responder individuals [161]. These studies reveal the relevance of considering genetic variants when considering treatments with methadone or buprenorphine.
Currently, it is known that it is not only the polymorphisms that we inherit but also how they are expressed, what really matters in genetics. Epigenetics studies the reversible modifications to chromatin and their potent effects on gene expression regulation. Biochemical modifications, such as DNA methylation, histone modification, or micro-RNA expression, can change the pattern of the cell’s gene expression [162]. Consequently, such epigenetic changes can modify drug efficacy and its adverse effects, being necessary to take them into account in clinical pharmacology [163]. Currently, the role of epigenetics in personalized pharmacotherapy has been under-explored [164]. This field of research has increased scientific interest in the last years, as changes in DNA methylation or histone modifications alter gene expression, which affects reward, craving, and relapse [165]. For example, in opiate addiction, several changes have been reported in the μ-opioid receptor 1 (OPRM1) gene expression due to the hypermethylation of this gene’s promoter [166, 167]. Increased DNA methylation can be a predisposing factor for the vulnerability to heroin addiction or it can be a consequence of it. This is a new and exciting unexplored field that could offer promising results in future years.
Opioid addiction is a chronic relapsing brain disease, being a major medical and social problem. In the past 12 years, several countries are suffering a rise in opioid consumption, not only in its recreative use but also in opioid prescriptions and related misuse and abuse [5]. The high rate of relapse observed in opioid addicts forces the use of maintenance therapy with substitution opiates to reduce damage and to avoid the consumption of illegal opioids, such as heroin. Although the currently approved pharmacotherapies for opioid addiction are effective and encourage patients to stay in treatment, there is still much room for improvement [168]. Methadone, buprenorphine, and extended-release naltrexone are currently the most effective treatments to attenuate the illicit intake of opioids and, together with psychosocial therapy, constitute the best combination to succeed in the treatment [18]. The number of new pharmacological targets is constantly increasing, but frequently, initially promising preclinical studies result in failure in the clinical trials. However, we should be optimistic, since great advances have been made in recent years, but much remains to be improved in a disease as important and complex as opiate addiction.
This work was supported by Ministerio de Economía y Competitividad (MINECO), Dirección General de Investigación PSI2014-51847-R and PSI2017-83023-R. Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) RD12/0028/0005 y RD16/0017/0007 and Unión Europea, Fondos FEDER “una manera de hacer Europa.” We wish to thank Guillermo Chulia for his English language editing.
None.
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