Because endorphin receptor activation alters the function of the central noradrenergic system, opiates may change the regenerative sprouting of neurons in response to adrenergic neurotoxins. To test this hypothesis, newborn rats were treated with several opioids and 6-hydroxydopa (6-OHDOPA) and the development of the noradrenergic system was evaluated. In combination with 6-OHDOPA morphine and naloxone potentiated the development of norepinephrine (NE) levels in the pons-medulla and cerebellum by four weeks of age. β-Endorphin, Leu- and Met-enkephalin and d-Ala2-enkephalinamide produced a similar effect in the pons-medulla. The effect of morphine was partially attenuated by naloxone. Increased cerebellar noradrenergic histofluorescent staining was observed with the morphine + 6-OHDOPA and naloxone + 6-OHDOPA treatments. Both naloxone and morphine decreased NE levels in the pons-medulla of adult rats treated with 6-OHDOPA. These results suggest that opiates and endorphins may enhance sprouting of noradrenergic neurons following neonatal treatment with 6-OHDOPA, by increasing the toxicity of this neurotoxin.

Human immunodeficiency virus (HIV) infected patients with a history of injection opiate abuse have higher incidences of acquired immunodeficiency syndrome (AIDS) and neurological dysfunction. The use of combined anti-retroviral therapy has significantly reduced the prevalence of mortality and progression to AIDS. Due to extended life expectancy, these patients are still at a great risk for HIV-associated neurological disorders and impairment in their later life. Neural progenitor cells (NPCs) play critical roles in brain growth and repair after injury and insult. Pediatric HIV patients whose glial populations are still developing are especially at risk for central nervous system (CNS) damage. Our previous reports suggest that HIV-1 transactivator of transcription (Tat) can directly cause pathology in neural progenitors and oligodendroglia (OLs) (Hauser et al. 2009). Thus, we have hypothesized that NPCs and/or glial progenitors may be targets of HIV proteins ± opiates drugs of abuse. To determine whether progenitors are targets of HIV-1, a multi-plex assay was performed to assess chemokine/cytokine expression after treatment with viral proteins Tat or glycoprotein 120 (gp120) with/without morphine. Murine striatal progenitors released increased amount of the beta-chemokines CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES), CCL3/macrophage inflammatory protein-1α (MIP-1α), and CCL4/macrophage inflammatory protein-1β (MIP-1β) after 12 h exposure to HIV-1 Tat, but no to gp120. Secreted factors from Tat-treated progenitors were chemoattractive towards microglia, an effect blocked by 2D7 anti- C-C chemokine receptor type 5 (CCR5) antibody pre-treatment. Tat and opiates have interactive effects on astroglial chemokine secretion, but this interaction did not occur in progenitors. We also examined effects of Tat and morphine on proliferation and lineage progression of NPCs in vitro and in vivo. In vitro, Tat and morphine independently reduced the proliferation and population of Sox2+ and Olig2+ cells in the absence of cell death. The interactive effects of morphine and either Tat or supernatant from HIV-1SF162 infected monocytes varied depending on outcome measure and time of exposure, but interactive effects occurred primarily on proliferation. In rare instances, viable human progenitors were associated with p24 immunolabeling suggesting that progenitors may be infected, a concept that is still controversial. To investigate effects of Tat and morphine on NPCs in vivo, we used a mouse model in which HIV-1 Tat1-86 is conditionally expressed in astroglia. In vivo results in neonatal striata were similar to those in cell cultures. We extended the experiments into adult mice with inducing Tat expression for 3 month and the effect of sexes was examined in these animals. Intriguingly, males showed more Tat-induced impairment in behavioral tests (rotarod, grip strength, light-dark box) than females. Tat+ males also showed a greater reduction in the proportion of NeuN+ cells and NeuN immunoreactivity in the striatum, accompanied by greater microglial activation (3-nitrotyrosine+/Iba-1+). Unbiased stereological estimation in Nissl staining revealed that the depletion of NeuN immunoreactivity in these mice was not due to neuron cell death or loss, because the total neuron number in striatum and total striatal volume were not affected by long-term Tat induction. Tat exposure appears to selectively reduce levels of NeuN in living neurons, although the reason is not known. Therefore, both the enhanced microglial reactivity and depletion of NeuN levels in males may help to explain sex-specific behavioral outcomes. Sox2+ and Olig2+ cells showed equivalent reduction in their population in both sexes. Overall, our findings show that CNS progenitors, including both undifferentiated NPCs and glial progenitors, are vulnerable to individual or combined effects of HIV-1 or Tat and opiates. Changes in progenitor dynamics may alter the balance of cell populations in both the developing and adult CNS. We speculate that such changes may contribute to the behavioral abnormalities that we observed in Tat+ mice and which appear to model aspects of motor, cognitive and anxiety deficits in HIV-infected patients.

Human immunodeficiency virus type 1 (HIV-1) is known to cause a spectrum of neurological, behavioral and motor deficits collectively termed as HIV-1 associated neurocognitive impairments (HAND). Opiates augment HIV-related CNS complications through both direct and indirect mechanisms that disrupt glial and neuronal function. All CNS macroglia and neurons derive from neural progenitor cells (NPCs) during development, and NPCs in the adult brain contribute to repair processes. Since disruptions in NPC function are known to impact CNS populations and brain function in a number of disease/injury conditions, we determined whether HIV ± opiate exposure affected the maturation and fate of human NPCs (hNPCs). As hNPC infection by HIV has occasionally been reported, we also reexamined this question, and parsed between effects due directly to hNPC infection by HIV, or to hNPC dysfunction caused by the infective milieu. Multiple approaches confirmed the infection of hNPCs by R5 tropic (CCR5 utilizing) HIVBaL, and demonstrated that active infection could be sequentially transferred to naïve hNPCs. Exposure to supernatant from HIVBaL-infected cells (HIVsup) reduced hNPC proliferation and led to premature differentiation into astrocytes and neurons. Morphine co-exposure prolonged hNPC infection and exacerbated functional effects of HIVsup. Neither purified virions nor UV-inactivated HIVsup altered proliferation, indicating that this effect did not require infection. Gene array analysis and RT-qPCR with immunoblot validation suggested that Cdk5 signaling was involved in HIV-morphine interactions. siRNA-mediated knockdown of Cdk5 expression attenuated the effect of HIV-1 and morphine on hNPC proliferation and MAP2 differentiation, but also increased hNPC death. Furthermore, in an attempt to understand the role of mu-opioid receptor (MOR) splice variants on the interactive effect of HIV-1 and morphine on hNPCs, we found that both MOR-1 and MOR-1K are differentially regulated by HIV-1 in these cells. This suggests that these splice variants may have differential actions in the response of hNPCs to HIV-1 and morphine co-exposure. Given the overlap of Cdk5 and MOR signaling, it is likely that MOR-1K and/or MOR-1 converge with Cdk5 in the mechanism underlying HIV-1 and morphine interaction in hNPCs. Overall, dysregulation of hNPC functions by the infectious environment may create cell population imbalances that contribute to CNS deficits in both adult and pediatric patients. Additionally, infected hNPCs may pass virus to their progeny, and serve as an unappreciated viral reservoir. The recent epidemic of opiate/heroin abuse highlights the clinical importance of HIV and opiate interactions.

The thesis deals with a substance treatment of opiate addiction and determines drug abuse problems. The paper defines free and regulated market and describes drug prohibition compared with alcohol prohibition. The next part considers the theory of substitute and complement which is a basis for determination of a substance treatment. The goal of thesis is evaluating the effectiveness of substance treatment in the Czech Republic by force of cost-benefits analysis with current information. The empiric part is based upon the information about costs of substance treatment and about lost productivity. The effectiveness of substance treatment is confirmed, the amount gives after deductions for expenses an affirmative value. The next conclusion is positive appraisal of effectiveness of partial financing of Subutex, that is paid by consumer presently.

A infusão intratecal de fármacos analgésicos é método considerado útil no tratamento da dor decorrente do câncer. Entretanto, estudos sobre eficácia no tratamento prolongado da dor crônica não decorrente de câncer são escassos. Este trabalho objetivou analisar prospectivamente o resultado do tratamento de 80 doentes com dor crônica não decorrente de câncer com infusão intratecal de morfina. Os resultados foram avaliados quanto à intensidade, características e etiologias da dor, qualidade de vida e complicações dos procedimentos; 42 doentes eram do sexo masculino, a média das idades foi de 48,4 anos e a duração média da condição álgica foi de 53 meses. A dor decorreu de mielopatia em 26,3% dos doentes, de síndrome dolorosa miofascial em 6,3%, de síndrome dolorosa pós-laminectomia em 23,8%, de síndrome complexa de dor regional em 8,8%, de síndrome fibromiálgica em 13,8% e de neuralgia pós herpética em 5,0%. Apresentavam dor neuropática 49 (61,2%), nociceptiva 19 (23,8%) e mista 12 (15%) pacientes. Foram implantadas 62 bombas de acionamento digital para infusão em bolo e 18 bombas de infusão contínua (gás) ou programável. As médias das intensidades da dor reduziram-se de 9,5 para 4,6 segundo a escala visual analógica (EVA) ao final do acompanhamento que variou de 18 a 98 meses (média = 46,7 meses); houve melhora significativa da dor nos doentes com dor neuropática (p < 0,001), nociceptiva (p < 0,001) ou mista (p = 0,005). Apesar da melhora da qualidade de vida de acordo com SF-36 (30,8 para 49,6) e nas dimensões do Questionário \"Treatment of Pain Survey\" (TOPS), não houve alteração na capacidade objetiva para o trabalho. Não houve diferença significativa entre infusão contínua e em bolo quanto à melhora da dor (p = 0,597). O consumo de morfina estabilizou-se após o sexto mês de tratamento na maioria dos casos. Não houve diferença significativa quanto à melhora em relação à localização da extremidade do cateter subaracnóideo (p = 0,227). Ocorreu agravamento da dor de 4,9 para 8,9 (p < 0,001) durante o período de uso de medicação placebo. Alguns efeitos adversos ocorreram inicialmente e geralmente foram toleráveis. Conclui-se que a infusão intratecal de opióides é método adequado e seguro para o tratamento da dor crônica rebelde não decorrente do câncer. / Implantable pumps for intrathecal delivery of opiates are efficient for treatment of cancer pain. However, studies of nonmalignant pain with long term follow-up are few. The present study use prospective analysis of the result of the long term treatment of 80 patients presenting nonmalignant pain with intrathecal infusion of morphine. The nature and etiology of the pain, quantitative and qualitative expressions of pain and the quality of the life before and at the end of the treatment and complications of procedures were evaluated; were male 42 (52%) patients, the average of the ages was 48.4 years and the mean duration of previous pain, 53 months. Pain was due to mielopathy in 26.3% of the cases, myofascial pain syndrome in 6.3%, failed back pain in 23.8%, complex regional pain syndrome in 8.8%, fibromyalgia in 13.8% and post-herpetic neuralgia in 5.0%. Presented as neuropathic pain 49 (61.2%) patients, as nociceptive pain 19 (23.8%) patients and as mixed pain 12 (15%) patients. In 62 patients pumps for self-administration bolus of morphine was implanted and in 18 constant-flow(gas) or programable pumps. The mean intensity of pain according the visual analogical scale (VAS) reduced from 9.5 to 4.6 at the end of 46.7 months (18 to 98 months) mean follow-up; there was significant improvement of the results in neuropathic(p < 0.001), nociceptive(p < 0.001) and mixed pain(p = 0.005). There was improvement of the quality of life measured by SF-36(30.8 to 49.6) and in all dimensions of the Questionnaire \"Treatment of Pain Survey\" (TOPS), except in working capacity. There was no significant difference of the results for patients treated with bolus or constant flow pumps (p = 0.597). The daily dose of morphine became constant after six month of treatment in the majority of the cases. The position of the tip of the cateter did not influenced improvement in pain intensity (p = 0.277). Patients treated with placebo had increasing of pain intensity from 4.9 to 8.9 according the VAS (p < 0,001). Side effects were more frequent at the beginning of the treatment and few were intolerable. Concluded that intrathecal infusion of morphine is a suitable and safe method for treatment of chronic nonmalignant pain.

Adults with an opiate addiction have a higher rate of noncompliance with treatment, which limits its effectiveness and increases the burden of care for society. Effective treatment decreases emergency room visits, and overdoses. The tristate area of Kentucky, West Virginia, and Ohio has experienced increased opiate-related arrests and deaths. This study sought to measure the extent to which treatment type (medical treatment (MS) or faith-based component of service (FBS)) predicts compliance when measured by number of clean urine drug screens (UDSs) and number of kept pill count, over and above dual diagnosis, college education, and income. The on-site records of voluntary enrollees in an outpatient facility that used either MT alone or MT with FBS were reviewed. Spearman's rho and multiple stepwise regression revealed that, with respect to clean UDSs or kept pill count, the association between dual diagnosis and college education was not found to be statistically significant. Rather, income explained about 5% of the variance in clean UDSs with a significant f change of .019, while type of treatment did not significantly impact clean UDSs. Dual diagnosis, income, and college education were not found to be significantly associated with the number of kept pill count. According to this study, type of treatment did not significantly impact compliance in the tristate area of Appalachia as measured by clean UDSs or kept pill count. Since MT and FBS are so similar in their relationship to compliance, attendance and participation in treatment may be areas for future study.

In the last few years, the prevalence of legal party pills in New Zealand has risen dramatically. These pills contain new piperazine designer drugs, two of the more common being 1-benzylpiperazine (BZP) and m-trifluoromethylphenylpiperazine (TFMPP). This thesis describes an optimised LC-MS/MS method for the detection of BZP and TFMPP in whole blood, using an automated solid phase extraction (SPE) for sample clean-up. The method was validated on three different days using five replicate samples each day. The standard curve was linear from 7 - 7000 ng/mL for BZP and 10 - 10,000 ng/mL for TFMPP, with coefficients of variation (CV) below 10%, and accuracy greater than 90% for both drugs. The method was used to quantitate samples provided by the Medical Research Institute of New Zealand. Blood levels were used to show concentrations in the blood over time, and relate these to performance of subjects on a driving simulator. The study was stopped after 41% of the participants who received BZP and TFMPP had adverse reactions to the pills, including vomiting and migraines. The LC-MS/MS method was also used to detect and quantitate methamphetamine, amphetamine, methylenedioxymethamphetamine, methylenedioxyamphetamine, morphine, codeine and 6-monoacetylmorphine in hair. The drugs were extracted from 20 mg of hair using hydrochloric acid in a water bath overnight, then purified using SPE. Validation on three days with five replicate samples gave coefficients of variation (CV) below 12% and acceptable accuracy for all drugs. The method was tested on three samples, previously reported by Environmental Science and Research (ESR) using gas chromatography mass spectrometry (GC-MS) giving results in good agreement. This thesis describes a sensitive, accurate, reproducible LC-MS/MS method easily adapted to analyse drugs of abuse in different biological matrices. It demonstrates the versatility of LC-MS/MS and its applications in forensic work.

Studiens syfte är att undersöka hur behandlingspersonal vid en opiatmottagning i en stor stad i Sverige ser på substitutionsbehandling och vilken betydelse behandlingsformen har för klientgruppen. Studien baseras på fyra kvalitativa semistrukturerade intervjuer med personal som har olika professioner (kurator, sjuksköterska, läkare samt psykolog) vid en för studien relevant behandlingsenhet. För att analysera det inkomna materialet har följande fem teorier använts: biologiska teorier, systemteorier, stämplingsteori, behavioristiska teorier samt psykodynamiska teorier/anknytningsteori. Resultaten visar att personalen överlag har en liknande syn på bakgrunden till ett drogmissbruk då samtliga anser att orsaken beror på både genetiska och sociala faktorer. Personalen anser även att behandlingsenhetens klienter är i behov av kemiskt framställda opiater (buprenorfin eller metadon) för att kunna bryta med sitt drogmissbruk, detta då det bidrar till att klienterna kan börja fokusera på andra livsområden utöver droganvändandet. Vidare visar resultaten att personalen anser att behandlingens längd varierar från individ till individ. Gruppen opiatberoende anses vara en resurskrävande grupp och önskemål finns gällande bättre samarbete med – för klienten – relevanta myndigheter. Sammanfattningsvis anser personalen att klienterna – genom behandlingen – får hjälp att uppnå ett drogfritt liv, bli en del av samhället, känna sig tillfreds med sig själva; genom detta får klienterna ett bättre och mer stabilt liv. / The purpose of this study is to examine how personnel working at a opiate substitution treatment clinic in a large city in Sweden view the treatment method and how important they reckon that the treatment is for the clientele. The study is based on four qualitative semi-structured interviews with a professional team that consists of counsellor, nurse, doctor and psychologist. To analyze the data the following five theories have been used: biological theories, system theories, labeling theory, behavioristic theories and psychodynamic theories/attachment theory. The results show that the professional team generally have a similar view on the background variables of drug addiction as they generally believe it depends on genetic and social factors. The main consensus of the team is that the clients are in need of chemically manufactured opiates (buprenorphine or methadone) to end their drug addiction because it helps the clients to focus on other areas, besides drugs, in their lives. The results also show that the team believe that the length of the treatment varies from individual to individual. Opiate addicts are considered to be a resource-demanding group and the team would like a better co-operation with relevant authorities. In conclusion the personnel believe that the clients – with help from the treatment method – can reach a life without drugs, become a part of the society and feel satisfied with themselves; with this the clients get a better and more stabile life.

The thesis research the frequency of illegal drugs use by student sof Univerzity of South Bohemia in the Czech Budějovice. In the theoretical part are characterized by drugs, illegal drugs and the effects of drug use on health, describes the emergence of drug addiction and its types and developmental stages of drug use. Furthermore, illegal drugs are divided into categories according to their effects and further described. The main aim of the practical part is the analysis of illegal drug use by students of the University of South Bohemia. On the basis of a questionnaire compiled data was found and it was statistically analyzed by the method, compares and conclusions were drawn. Over the past year have used an illegal drug 37.83% of respondents, that 2.91% of the respondents use illegal drugs daily. Earlier experience with illegal drugs has 18.78% of students of the University of South Bohemia. Past experience with drugs is more common in women, while use in the last year is much more common in men. The most commonly used substances are cannabinoids, as well as hallucinogens, opiates and finally stimulanci.

A infusão intratecal de fármacos analgésicos é método considerado útil no tratamento da dor decorrente do câncer. Entretanto, estudos sobre eficácia no tratamento prolongado da dor crônica não decorrente de câncer são escassos. Este trabalho objetivou analisar prospectivamente o resultado do tratamento de 80 doentes com dor crônica não decorrente de câncer com infusão intratecal de morfina. Os resultados foram avaliados quanto à intensidade, características e etiologias da dor, qualidade de vida e complicações dos procedimentos; 42 doentes eram do sexo masculino, a média das idades foi de 48,4 anos e a duração média da condição álgica foi de 53 meses. A dor decorreu de mielopatia em 26,3% dos doentes, de síndrome dolorosa miofascial em 6,3%, de síndrome dolorosa pós-laminectomia em 23,8%, de síndrome complexa de dor regional em 8,8%, de síndrome fibromiálgica em 13,8% e de neuralgia pós herpética em 5,0%. Apresentavam dor neuropática 49 (61,2%), nociceptiva 19 (23,8%) e mista 12 (15%) pacientes. Foram implantadas 62 bombas de acionamento digital para infusão em bolo e 18 bombas de infusão contínua (gás) ou programável. As médias das intensidades da dor reduziram-se de 9,5 para 4,6 segundo a escala visual analógica (EVA) ao final do acompanhamento que variou de 18 a 98 meses (média = 46,7 meses); houve melhora significativa da dor nos doentes com dor neuropática (p < 0,001), nociceptiva (p < 0,001) ou mista (p = 0,005). Apesar da melhora da qualidade de vida de acordo com SF-36 (30,8 para 49,6) e nas dimensões do Questionário \"Treatment of Pain Survey\" (TOPS), não houve alteração na capacidade objetiva para o trabalho. Não houve diferença significativa entre infusão contínua e em bolo quanto à melhora da dor (p = 0,597). O consumo de morfina estabilizou-se após o sexto mês de tratamento na maioria dos casos. Não houve diferença significativa quanto à melhora em relação à localização da extremidade do cateter subaracnóideo (p = 0,227). Ocorreu agravamento da dor de 4,9 para 8,9 (p < 0,001) durante o período de uso de medicação placebo. Alguns efeitos adversos ocorreram inicialmente e geralmente foram toleráveis. Conclui-se que a infusão intratecal de opióides é método adequado e seguro para o tratamento da dor crônica rebelde não decorrente do câncer. / Implantable pumps for intrathecal delivery of opiates are efficient for treatment of cancer pain. However, studies of nonmalignant pain with long term follow-up are few. The present study use prospective analysis of the result of the long term treatment of 80 patients presenting nonmalignant pain with intrathecal infusion of morphine. The nature and etiology of the pain, quantitative and qualitative expressions of pain and the quality of the life before and at the end of the treatment and complications of procedures were evaluated; were male 42 (52%) patients, the average of the ages was 48.4 years and the mean duration of previous pain, 53 months. Pain was due to mielopathy in 26.3% of the cases, myofascial pain syndrome in 6.3%, failed back pain in 23.8%, complex regional pain syndrome in 8.8%, fibromyalgia in 13.8% and post-herpetic neuralgia in 5.0%. Presented as neuropathic pain 49 (61.2%) patients, as nociceptive pain 19 (23.8%) patients and as mixed pain 12 (15%) patients. In 62 patients pumps for self-administration bolus of morphine was implanted and in 18 constant-flow(gas) or programable pumps. The mean intensity of pain according the visual analogical scale (VAS) reduced from 9.5 to 4.6 at the end of 46.7 months (18 to 98 months) mean follow-up; there was significant improvement of the results in neuropathic(p < 0.001), nociceptive(p < 0.001) and mixed pain(p = 0.005). There was improvement of the quality of life measured by SF-36(30.8 to 49.6) and in all dimensions of the Questionnaire \"Treatment of Pain Survey\" (TOPS), except in working capacity. There was no significant difference of the results for patients treated with bolus or constant flow pumps (p = 0.597). The daily dose of morphine became constant after six month of treatment in the majority of the cases. The position of the tip of the cateter did not influenced improvement in pain intensity (p = 0.277). Patients treated with placebo had increasing of pain intensity from 4.9 to 8.9 according the VAS (p < 0,001). Side effects were more frequent at the beginning of the treatment and few were intolerable. Concluded that intrathecal infusion of morphine is a suitable and safe method for treatment of chronic nonmalignant pain.