The discovery of stem and progenitor cells capable of ongoing neurogenesis in the adult mammalian brain has raised hope that we will one day be able to harness their intrinsic regenerative capacity following injury. Development of such therapeutic strategies relies on a comprehensive understanding of the underlying regulation of the neurogenic process. To this end, I show, in this thesis, that cultured post-natal hippocampal neural progenitor cells (NPCs) express a specific repertoire of connexins (Cx), a family of channel forming proteins critical for communication prior to the development of functional chemical synapses. I show that this pattern of Cx expression, specifically Cx43 and Cx45, is modulated by interaction with the extracellular matrix component laminin providing evidence of extracellular matrix-cell interaction in the regulation of intrinsic Cx expression and function in postnatal NPCs. In adult brain, I show, for the first time, that Cx45 localizes to all cell types of the neuronal lineage with the exception of the type 3 doublecortin (DCX)-positive NPCs. Using a loss of function approach, I show that this expression is required for the normal proliferation of type 1 nestin and glial fibrillary acidic protein-positive stem like NPCs but not for the differentiation or survival of their progeny in the adult hippocampus. With respect to exogenous pharmacological cues that influence hippocampal neurogenesis, this thesis also demonstrates that chronic treatment with a sub-set of selective serotonin reuptake inhibitor antidepressants, fluoxetine and escitalopram, increases the proliferation but not the survival of adult NPCs in healthy, non-depressed mice. Further, standard post-operative analgesia with the opiate buprenorphine inhibits the proliferation of DCX-positive adult NPCs and increases the survival of their progeny. Finally, over the course of the research for this thesis, it became clear that exposing research animals to even very subtle environmental changes can influence the basal neurogenic process. Ultimately this work further highlights the exquisite sensitivity of the regulation of what is already recognized to be a highly dynamic process and provides important insight into the neurogenic process that can be used to inform future therapeutic development and application.

Endomorphin (Endo) 1 and 2, two tetrapeptides isolated from the bovine and human brain, have been proposed to be the endogenous ligand for the μ- opiate receptor. A multi-disciplinary study was undertaken to address the issues of localization, release and biological action of Endo with respect to the rat dorsal horn. First, immunohistochemical studies showed that Endo-1- or Endo-2-like immunoreactivity (Endo-1- or Endo-2-LI) is selectively expressed in fiber-like elements occupying the superficial layers of the rat dorsal horn, which also exhibit a high level of μ-opiate receptor immunoreactivity. Second, release of immunoreactive Endo-2-like substances (irEndo) from the in vitro rat spinal cords upon electrical stimulation of dorsal root afferent fibers was detected by the immobilized antibody microprobe technique. The site of release corresponded to laminae I and II where the highest density of Endo-2-LI fibers was localized. Lastly, whole- cell patch clamp recordings from substantia gelatinosa (SG) neurons of rat lumbar spinal cord slices revealed two distinct actions of exogenous Endo-1 and Endo-2: (1) depression of excitatory and/or inhibitory postsynaptic potentials evoked by stimulation of dorsal root entry zone, and (2) hyperpolarization of SG neurons. These two effects were prevented by the selective μ-opiate receptor antagonist β-funaltrexamine. The localization of endomorphin-positive fibers in superficial layers of the dorsal horn and the release of irEndo upon stimulation of dorsal root afferents together with the observation that Endo inhibits the activity of SG neurons by interacting with μ-opiate receptors provide additional support of a role of Endo as the endogenous ligand for the μ-opiate receptor in the rat dorsal horn.

We examined internal consistency and test-retest reliability of a measure of dispositional optimism, the Life Orientation Test-Revised, in 121 opiate-dependent patients seeking methadone treatment. Internal consistency was adequate at baseline (α=.69) and follow-up (α=.72). Low socioeconomic status and being on disability were significantly associated with reduced internal consistency; ethnic and educational differences approached significance. Test-retest reliability was good (ICC=.72), varying across gender, race, ethnicity, education, employment and income (ICC Range=.24-.85). Criterion validity was strong; the LOT-R was significantly negatively correlated with hopelessness (r=-.65, p<.001) and depression (r=-.60, p<.001). Findings support the use of this measure of optimism and pessimism to assess positive cognitive and emotional attributes and improve treatment strategies for opiate-dependent individuals. Future research should address the measurement and significance of optimism in minority, low socioeconomic status and poorly-educated individuals.

Bakgrund: Opiattillgängligheten är ett växande problem världen över. Således kan personer som är beroende eller missbrukare av opiater komma att söka sig till hälso- och sjukvården på grund av smärta. Personer som sjuksköterskan inom ramen för sitt omvårdnadsansvar kan behöva skatta avseende smärtintensitet och administrera smärtstillande läkemedel till. Syfte: Syftet med studien är att kartlägga sjuksköterskors upplevelser av att smärtlindra personer beroende av opiater.Metod: Studien genomfördes som en litteraturstudie med kvalitativ ansats. Resultat: Kartläggning resulterade fyra huvudteman: Likvärdigt bemötande, där en del sjuksköterskor visade empati medan andra inte gjorde det, handlingsberedskap via erfarenhet som hjälpte sjuksköterskors bemötande av personer med beroendeproblematik. Det tredje temat var misstänksamhet begränsar, där sjuksköterskor hade en misstänksamhet och deras syn på personer var att personerna bara ville ha smärtstillande läkemedel. Sjuksköterskor uttryckte även smärtbedömningens komplexitet vid bedömning av personens smärta.Konklusion: Sjuksköterskor ställs inför många komplexa situationer relaterat till smärta och beroende där varje person och situation är unik. Utifrån studiens fynd behöver sjuksköterskor implementera hela sin skicklighet, i mötet med personer beroende av opiater, vilket görs genom att de arbetar personcentrerat och holistiskt. Då antalet studier med kvalitativ ansats är få inom detta område behövs vidare forskning från såväl sjuksköterskans perspektiv som från personen beroende av opiater. / Background: Opiate availability is a growing problem worldwide. These people who are addicted or addicted to opiates may seek medical care because of pain. Persons to whom the nurses within the scope of their nursing responsibilities may need to assess pain intensity and administer additional painkillers. Aim: The purpose of the study is to survey nurses experiences of relief pain from persons with opiate addiction. Method: The study was conducted as a literature review with a qualitative approach. Results: Four main themes during the data-analysis. The four main themes were first; equal treatment, towards the person they care for, second; action readiness through experience, which helped nurses in dealing with people with addiction problems. Third; suspicion limiting, where nurses had a suspicion and their view was that individuals only wanted painkillers. Last; nurses expressed the complexity of pain assessment. Conclusion: Nurses are faced with many complex situations related to pain and dependence where each person and situation is unique. Based on the findings of this study, nurses need to implement all their skills in the meeting with the opioid-dependent person. This was done by working through person-centered care and with a holistic approach. As the number of studies with a qualitative approach is few in this area, further research is needed from both the nurse's perspective and from the person dependent on opiate.Keywords: Addiction, experiences, nurse, opiate, pain.

Through changes in the code of statutes, SOSFS 2009:27 (M), opioid addicts are excluded since March 1 2010 from possibilities to be accepted for substitution treatment. Opiate addicts are solitary admitted for substitution treatment from that date. Opioid addicts are excluded admission for treatment regardless of the fact that they fulfil the ICD-10 diagnosis F.11.2, i.e. opioid/opiate addictive criteria. The alteration in the statutes was carried out in reference to the fact that evidence for this kind of treatment intended for opioid addicts was missing. Both groups i.e. opiate – and opioid addicts, are nevertheless experienced in clinical work , to have extensive problems with addiction, health, social situation along with the risk of premature death.     The purpose with this study is to identify what differences and/or similarities there are in background varieties and the severity of the problems  between the groups. This is conducted with the use of a population (n=127) with comparable background material, e.g. collected Addictions Severe Index- interviews, scientifically survey and compare background factors and the severity of the problems.      The main discovery in this study is that one can demonstrate great similarities between the groups regarding background as well as the severity of the problems. It is therefore of great interest, on a individual as well as a social oriented level, that pursued studies regarding diagnostic safety and on processes in substitution program are needed to generate further knowledge as a foundation for development of future care and changes in the code of statutes.

Eine langdauernde Vorinkubation des GPI bzw. des MVD mit Morphin-haltiger Nährlösung (unter in vitro-Bedingungen wird anstelle von Morphin häufig Normorphin verwendet) führte zur Entwicklung von Toleranz und im Falle des GPI zu einer zusätzlichen Abhängigkeits-ähnlichen Reaktion. Die Toleranz manifestierte sich als verminderte Ansprechbarkeit gegenüber dem in Anwesenheit des Morphins akut applizierten Normorphin, während die Gewebeabhängigkeit sich als starke Naloxon-induzierte Kontraktion bemerkbar machte. Diese Kontraktion beruhte auf einer massiven Ausschüttung von Acetylcholin aus den postganglionär parasympathischen Nervenendigungen. Als Erklärung wurde hinzugezogen, dass Naloxon das Morphin von seinen Rezeptoren verdrängt und eine entzugsähnliche Reaktion auslöst. Da nicht nur eine in vitro-Vorinkubation mit Morphin in den beiden Präparaten zur Empfindlichkeitsabnahme gegenüber Morphin/Normorphin führte sondern auch die mehrtägige, subkutane Implantation eines Morphin-Pellets oder einer Opioid-Lösung enthaltenden osmotischen Minipumpe, haben wir über den letzteren Weg selektive Toleranz gegenüber μ- (Morphin, Fentanyl), δ- (DADLE) und κ-Agonisten (Ethylketocyclazocin, MR 2034, MRZ) hervorgerufen. Nach in vivo-Behandlung mit den genannten Substanzen wurde das GPI präpariert, in einer Nährlösung, die den jeweiligen Agonisten in der ungefähr 80-fachen Toleranz-induzierenden Kon-zentration enthielt, aufgehängt und mit Feldelektroden elektrisch stimuliert. Die Reizparameter wurden so gewählt (supramaximale Spannung, 0.5 ms Reizbreite, 0.1 Hz Frequenz), dass ausschließlich das neuronale Gewebe stimuliert wurde, nicht aber der Glattmuskel. In vorhergehenden Experimenten konnte die Rezeptorausstattung des GPI nicht eindeutig identifiziert werden. Mit der Erzeugung der selektiven Toleranz an µ-Rezeptoren wurde die akute Wirkung von sowohl μ- als auch δ-Rezeptor-Agonisten wesentlich vermindert. Demgegenüber, übten κ-Rezeptor-Agonisten ihre Wirkung in unveränderter Intensität aus. Die vollständige Kreuz-Toleranz zwischen Morphin und DADLE schloss das Vorhandensein eines δ-Rezeptors aus, während die fehlende Kreuz-Toleranz zwischen Normorphin/DADLE einerseits und Ethylketocyclazocin andererseits das Vorhandensein eines κ-Rezeptors belegte. Es bedarf einer Erklärung, weshalb die in vivo-Behandlung mit Fentanyl nur geringe Toleranz gegenüber Normorphin auslöste und vice versa (wenig Kreuz-Toleranz), obwohl sich eine hochgradige Toleranz gegenüber derselben Substanz entwickelte. Es wurde geschlussfolgert, dass es verschiedene Subtypen von μ-Rezeptoren gibt, eines mit Empfindlichkeit gegenüber Morphin/Normorphin und ein anderes gegenüber Fentanyl.

National rates of chronic non-cancer pain (CNCP) are rising alongside increasing reports of prescription opioid abuse and mortality. Associations between the rise in CNCP and in opioid abuse seem logical, yet research on CNCP among individuals with opioid dependence is currently limited due to the complicated nature of comorbid conditions in research and treatment. This study aims to expand the CNCP knowledge base by responding to the question: Do individuals with CNCP participating in an opiate treatment program have better or worse treatment outcomes than individuals without CNCP? This study used a secondary dataset including 483 adults from Kentucky’s Opiate Recovery Treatment Outcome Study. Individuals in the sample met DSM-IV-TR criteria for opioid dependence and were in treatment at a licensed opiate treatment program (OTP). Analysis compared cases with and without CNCP on national treatment outcome measures including substance use, recovery support, education, employment, mental health symptoms, and criminal justice system involvement. Results indicated no differences at follow-up between the CNCP (n=163) and non-CNCP (n=320) individuals on substance abstinence, recovery supports, education level, or criminal justice system involvement. At baseline and follow-up there were more unemployed individuals and individuals receiving disability benefits in the CNCP group than the non-CNCP group. Reported anxiety and depression symptoms increased at follow-up, while use of prescription medicine for mental health symptoms declined for both groups (non-significant differences). The only predictors for CNCP cases in this sample were tobacco use and presence of a chronic medical condition. Recommendations include expansion of smoking cessation programs in substance abuse treatment settings. Future research might examine integrated treatment and medical home health models to better address biopsychosocial components of clients with comorbid conditions like opioid dependence and CNCP.

Opiate addiction is now a major public health problem. Pregnant women continue to use opiates during gestation; up to 5.4% of pregnant women report using illicit drugs during pregnancy. Previous studies have shown that perinatal insults and exposure to opiates such as morphine in utero can affect the development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring and are associated with higher risk of developing neurobehavioral problems. Oxycodone, a semisynthetic putative kappa opioid receptor and partial mu opioid receptor agonist is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters the development and functions of the HPA-axis, the related stress axis and neurobehavioral outcomes of the offspring. Data from these experiments have provided novel evidence that POE indeed is associated with sex-specific changes in the HPA-axis in response to stress that persist beyond the neonatal period. 1) POE is associated with an increased adrenocorticotropic hormone (ACTH) response to corticotropin-releasing hormone (CRH), but not the corticosterone (CORT) response to CRH stimulation in late adolescent male offspring. 2) POE is associated with increased CORT, but not ACTH response to restraint stress test in adult female offspring. These changes in the HPA-axis response to stress may be partially explained by 1) an increase in the subpopulation of CRH neurons that also contain estrogen receptor-beta immunoreactivity following POE which then can exaggerate the stimulation of the HPA-axis, and 2) a decrease in mineralocorticoid receptor-mRNA expression in the hippocampus which may be associated with impaired negative feedback control of the HPA-axis by the limbic system. POE is also associated with cardiovascular changes in response to stress during a classical conditioning paradigm; adolescent male POE rats have a larger blood pressure increase than the control group. Although POE male rats can properly discriminate the stress versus non-stress cues in the conditioning paradigm, they do not retain this memory when retested during adulthood. When tested for learning and memory in a water maze, however, we did not find any differences between control rats and rats exposed to high dose oxycodone in utero. In addition, we demonstrated that exposure to the lower dose of oxycodone in utero is associated with hyperactivity in adult rats when tested in an open field. Our results make a significant contribution to the literature because they extend our knowledge about the effects of oxycodone on the developing brain and the resulting outcomes in animal models that are actually relevant to a current major public health problem in humans and will provide a platform for us to further study the underlying mechanisms and interventions that may mitigate these effects.

Investigators have suggested that opiate peptide hormones released during exercise stress may play an important role in athletic performance or perceived effort. Their enzymatic inactivation in the periphery is of considerable interest since the opiate peptides may be regulated by enkephalin hydrolyzing enzyme (EHA). In this study, the relationship between maximal aerobic capacity (VO_2max) and EHA activity was examined in two distinct fitness groups. When the metabolic capacity was evaluated in whole blood, the unfit subjects metabolized the peptides significantly faster than their fit counterparts. Since the total enzyme activity of the two groups is similar, the difference in metabolism must result from circulating factors in the trained athletes, which slow the rate of peptide inactivation.

Introduction: Opioid poisoning has been rapidly increasing in the past decade, and has been driven in large part due to increases in opioid prescribing. This has been accompanied by intervention efforts aimed at preventing and reversing opioid poisoning through naloxone prescription programs. Current literature have not quantified the economic burden of opioid poisoning. Understanding this information can help inform these efforts and bring light to this growing problem. In addition understanding various determinants of increased costs can help to identify the types of populations more likely to have greater costs. Main Objectives: The objectives are 1) to quantify the economic burden of opioid poisoning, 2) to evaluate differences in costs, LOS, and in-hospital mortality depending on opioid type, 3) to identify opioids most likely to result in hospitalization for opioid-related ED visits and 4) to determine differences in the odds of admission to various hospital admission categories with respect to opioid type. Methods: A cost-of-illness approach was used to estimate the economic burden of opioid poisoning. Direct costs and prevalence estimates were obtained from nationally representative databases. Other sources of direct costs were obtained from the literature. Indirect costs were measured using the human capital method. Differences in costs, LOS, and in-hospital mortality were measured through generalized linear models using the National Inpatient Sample in 2009 from the Healthcare Cost and Utilization Project. The Drug Abuse Warning Network database was used to evaluate opioids most likely to result in hospitalization and to evaluate the likelihood of different opioids to cause admission into different types of hospital settings. Results: Opioid poisoning resulted in an economic burden approximately $20.4 billion dollars in 2009. Productivity losses were associated with 89% of this total. Direct medical costs were associated with $2.2 billion. Methadone was associated with the greatest inpatient costs and LOS, while heroin was associated with a greater likelihood of in-patient mortality compared to prescription opioids. Heroin, methadone, and morphine were associated with the greatest odds of hospitalization. Among admitted patients, methadone, morphine, and fentanyl were each associated with the greatest odds of ICU admission compared with other opioids. Conclusions: Opioid poisoning results in a significant economic burden to society. Costs, length of stay, in-patient mortality and the odds of hospitalization and admission type depend on the type of opioid involved. The results from this study can be used to inform policy efforts in providing interventions to reduce opioid poisoning and help focus efforts on populations at highest risk for increased costs.