9 resultados para alcohol tolerance

em Duke University


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Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously that mice lacking (beta)arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the (beta)arr2-muOR interaction in other neuronal systems, we have, in the present study, tested (beta)arr2 knock-out ((beta)arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the (beta)arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the (beta)arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the muOR is differentially regulated in diverse regions of the CNS. Furthermore, although (beta)arr2 appears to be the most prominent and proximal determinant of muOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.

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Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.

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The highest rates of fetal alcohol syndrome worldwide can be found in South Africa. Particularly in impoverished townships in the Western Cape, pregnant women live in environments where alcohol intake during pregnancy has become normalized and interpersonal violence (IPV) is reported at high rates. For the current study we sought to examine how pregnancy, for both men and women, is related to alcohol use behaviors and IPV. We surveyed 2,120 men and women attending drinking establishments in a township located in the Western Cape of South Africa. Among women 13.3% reported being pregnant, and among men 12.0% reported their partner pregnant. For pregnant women, 61% reported attending the bar that evening to drink alcohol and 26% reported both alcohol use and currently experiencing IPV. Daily or almost daily binge drinking was reported twice as often among pregnant women than non-pregnant women (8.4% vs. 4.2%). Men with pregnant partners reported the highest rates of hitting sex partners, forcing a partner to have sex, and being forced to have sex. High rates of alcohol frequency, consumption, binge drinking, consumption and binge drinking were reported across the entire sample. In general, experiencing and perpetrating IPV were associated with alcohol use among all participants except for men with pregnant partners. Alcohol use among pregnant women attending shebeens is alarmingly high. Moreover, alcohol use appears to be an important factor in understanding the relationship between IPV and pregnancy. Intensive, targeted, and effective interventions for both men and women are urgently needed to address high rates of drinking alcohol among pregnant women who attend drinking establishments.

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BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection have high rates of alcohol consumption, which is associated with progression of fibrosis and lower response rates to HCV treatment. AIMS: This prospective cohort study examined the feasibility of a 24-week integrated alcohol and medical treatment to HCV-infected patients. METHODS: Patients were recruited from a hepatology clinic if they had an Alcohol Use Disorders Identification Test score >4 for women and >8 for men, suggesting hazardous alcohol consumption. The integrated model included patients receiving medical care and alcohol treatment within the same clinic. Alcohol treatment consisted of 6 months of group and individual therapy from an addictions specialist and consultation from a study team psychiatrist as needed. RESULTS: Sixty patients were initially enrolled, and 53 patients participated in treatment. The primary endpoint was the Addiction Severity Index (ASI) alcohol composite scores, which significantly decreased by 0.105 (41.7% reduction) between 0 and 3 months (P < 0.01) and by 0.128 (50.6% reduction) between 0 and 6 months (P < 0.01) after adjusting for covariates. Alcohol abstinence was reported by 40% of patients at 3 months and 44% at 6 months. Patients who did not become alcohol abstinent had reductions in their ASI alcohol composite scores from 0.298 at baseline to 0.219 (26.8% reduction) at 6 months (P = 0.08). CONCLUSION: This study demonstrated that an integrated model of alcohol treatment and medical care could be successfully implemented in a hepatology clinic with significant favorable impact on alcohol use and abstinence among patients with chronic HCV.

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Understanding immune tolerance mechanisms is a major goal of immunology research, but mechanistic studies have generally required the use of mouse models carrying untargeted or targeted antigen receptor transgenes, which distort lymphocyte development and therefore preclude analysis of a truly normal immune system. Here we demonstrate an advance in in vivo analysis of immune tolerance that overcomes these shortcomings. We show that custom superantigens generated by single chain antibody technology permit the study of tolerance in a normal, polyclonal immune system. In the present study we generated a membrane-tethered anti-Igkappa-reactive single chain antibody chimeric gene and expressed it as a transgene in mice. B cell tolerance was directly characterized in the transgenic mice and in radiation bone marrow chimeras in which ligand-bearing mice served as recipients of nontransgenic cells. We find that the ubiquitously expressed, Igkappa-reactive ligand induces efficient B cell tolerance primarily or exclusively by receptor editing. We also demonstrate the unique advantages of our model in the genetic and cellular analysis of immune tolerance.

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Opioids are efficacious and cost-effective analgesics, but tolerance limits their effectiveness. This paper does not present any new clinical or experimental data but demonstrates that there exist ascending sensory pathways that contain few opioid receptors. These pathways are located by brain PET scans and spinal cord autoradiography. These nonopioid ascending pathways include portions of the ventral spinal thalamic tract originating in Rexed layers VI-VIII, thalamocortical fibers that project to the primary somatosensory cortex (S1), and possibly a midline dorsal column visceral pathway. One hypothesis is that opioid tolerance and opioid-induced hyperalgesia may be caused by homeostatic upregulation during opioid exposure of nonopioid-dependent ascending pain pathways. Upregulation of sensory pathways is not a new concept and has been demonstrated in individuals impaired with deafness or blindness. A second hypothesis is that adjuvant nonopioid therapies may inhibit ascending nonopioid-dependent pathways and support the clinical observations that monotherapy with opioids usually fails. The uniqueness of opioid tolerance compared to tolerance associated with other central nervous system medications and lack of tolerance from excess hormone production is discussed. Experimental work that could prove or disprove the concepts as well as flaws in the concepts is discussed.

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OBJECTIVES: To examine patterns of onset and abuse/dependence episodes of prescription opioid (PO) and heroin use disorders in a national sample of adults, and to explore differences by gender and substance abuse treatment status. METHODS: Analyses of data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). RESULTS: Of all respondents, 5% (n = 1815) reported a history of nonmedical PO use (NMPOU) and 0.3% (n = 150) a history of heroin use. Abuse was more prevalent than dependence among NMPOUs (PO abuse, 29%; dependence, 7%) and heroin users (heroin abuse, 63%; dependence, 28%). Heroin users reported a short mean interval from first use to onset of abuse (1.5 years) or dependence (2.0 years), and a lengthy mean duration for the longest episode of abuse (66 months) or dependence (59 months); the corresponding mean estimates for PO abuse and dependence among NMPOUs were 2.6 and 2.9 years, respectively, and 31 and 49 months, respectively. The mean number of years from first use to remission from the most recent episode was 6.9 years for PO abuse and 8.1 years for dependence; the mean number of years from first heroin use to remission from the most recent episode was 8.5 years for heroin abuse and 9.7 years for dependence. Most individuals with PO or heroin use disorders were remitted from the most recent episode. Treated individuals, whether their problem was heroin or POs, tended to have a longer mean duration of an episode than untreated individuals. CONCLUSION: Periodic remissions from opioid or heroin abuse or dependence episodes occur commonly but take a long time. Timely and effective use of treatment services are needed to mitigate the many adverse consequences from opioid/heroin abuse and dependence.

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Introduction and Aims: In recent years, unprecedented levels of Internet access and the widespread growth of emergent communication technologies have resulted in significantly greater population access for substance use researchers. Despite the research potential of such technologies, the use of the Internet to recruit individuals for participation in event-level research has been limited. The purpose of this paper is to provide a brief account of the methods and results from an online daily diary study of alcohol use. Design and Methods: Participants were recruited using Amazon's Mechanical Turk. Eligible participants completed a brief screener assessing demographics and health behaviours, with a subset of individuals subsequently recruited to participate in a 2 week daily diary study of alcohol use. Results: Multilevel models of the daily alcohol data derived from the Mechanical Turk sample (n=369) replicated several findings commonly reported in daily diary studies of alcohol use. Discussion and Conclusions: Results demonstrate that online participant recruitment and survey administration can be a fruitful method for conducting daily diary alcohol research. © 2014 Australasian Professional Society on Alcohol and other Drugs.