Browsing by Subject "Drug Tolerance"
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Item Open Access Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.(J Neurosci, 2002-12-01) Bohn, Laura M; Lefkowitz, Robert J; Caron, Marc GMorphine 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.Item Open Access Heterogeneity of stimulant dependence: a national drug abuse treatment clinical trials network study.(The American journal on addictions, 2009-05) Wu, Li-Tzy; Blazer, Dan G; Patkar, Ashwin A; Stitzer, Maxine L; Wakim, Paul G; Brooner, Robert KWe investigated the presence of DSM-IV subtyping for dependence on cocaine and amphetamines (with versus without physical dependence) among outpatient stimulant users enrolled in a multisite study of the Clinical Trials Network (CTN). Three mutually exclusive groups were identified: primary cocaine users (n = 287), primary amphetamine users (n = 99), and dual users (cocaine and amphetamines; n = 29). Distinct subtypes were examined with latent class and logistic regression procedures. Cocaine users were distinct from amphetamine users in age and race/ethnicity. There were four distinct classes of primary cocaine users: non-dependence (15%), compulsive use (14%), tolerance and compulsive use (15%), and physiological dependence (tolerance, withdrawal, and compulsive use; 56%). Three distinct classes of primary amphetamine users were identified: non-dependence (11%), intermediate physiological dependence (31%), and physiological dependence (58%). Regardless of stimulants used, most female users were in the most severe or the physiological dependence group. These results lend support for subtyping dependence in the emerging DSM-V.Item Open Access Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.(Proc Natl Acad Sci U S A, 1989-05) Lohse, MJ; Lefkowitz, RJ; Caron, MG; Benovic, JLHomologous (agonist-specific) desensitization of beta-adrenergic receptors (beta ARs) is accompanied by and appears to require phosphorylation of the receptors. We have recently described a novel protein kinase, beta AR kinase, which phosphorylates beta ARs in vitro in an agonist-dependent manner. This kinase is inhibited by two classes of compounds, polyanions and synthetic peptides derived from the beta 2-adrenergic receptor (beta 2AR). In this report we describe the effects of these inhibitors on the process of homologous desensitization induced by the beta-adrenergic agonist isoproterenol. Permeabilization of human epidermoid carcinoma A431 cells with digitonin was used to permit access of the charged inhibitors to the cytosol; this procedure did not interfere with the pattern of isoproterenol-induced homologous desensitization of beta 2AR-stimulated adenylyl cyclase. Inhibitors of beta AR kinase markedly inhibited homologous desensitization of beta 2ARs in the permeabilized cells. Inhibition of desensitization by heparin, the most potent of the polyanion inhibitors of beta AR kinase, occurred over the same concentration range (5-50 nM) as inhibition of purified beta AR kinase assessed in a reconstituted system. Inhibition of desensitization by heparin was accompanied by a marked reduction of receptor phosphorylation in the permeabilized cells. Whereas inhibitors of beta AR kinase inhibited homologous desensitization, inhibitors of protein kinase C and of cyclic-nucleotide-dependent protein kinases were ineffective. These data establish that phosphorylation of beta ARs by beta AR kinase is an essential step in homologous desensitization of the receptors. They further suggest a potential therapeutic value of inhibitors of beta AR kinase in inhibiting agonist-induced desensitization.Item Open Access Meta-analysis of Placebo-Controlled Randomized Controlled Trials on the Prevalence of Statin Intolerance.(Am J Cardiol, 2017-09-01) Riaz, Haris; Khan, Abdur Rahman; Khan, Muhammad Shahzeb; Rehman, Karim Abdur; Alansari, Shehab Ahmad Redha; Gheyath, Bashaer; Raza, Sajjad; Barakat, Amr; Luni, Faraz Khan; Ahmed, Haitham; Krasuski, Richard AThe prevalence of intolerance varies widely. Stopping statin therapy is associated with worse outcomes in patients with cardiovascular disease. Despite extensive studies, the benefits and risks of statins continue to be debated by clinicians and the lay public. We searched the PubMed, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for all randomized controlled trials of statins compared with placebo. Studies were included if they had ≥1,000 participants, had patients who were followed up for ≥1 year, and reported rates of drug discontinuation. Studies were pooled as per the random effects model. A total of 22 studies (statins = 66,024, placebo = 63,656) met the inclusion criteria. The pooled analysis showed that, over a mean follow-up of 4.1 years, the rates of discontinuation were 13.3% (8,872 patients) for statin-treated patients and 13.9% (8,898 patients) for placebo-treated patients. The random effects model showed no significant difference between the placebo and statin arms (odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.93 to 1.06). The results were similar for both primary prevention (OR = 0.98, 95% CI = 0.92 to 1.05, p = 0.39) and secondary prevention (OR = 0.92, 95% CI = 0.83 to 1.05, p = 0.43) studies. The pooled analysis suggested that the rates of myopathy were also similar between the statins and placebos (OR = 1.2, 95% CI = 0.88 to 1.62, p = 0.25). In conclusion, this meta-analysis of >125,000 patients suggests that the rate of drug discontinuation and myopathy does not significantly differ between statin- and placebo-treated patients in randomized controlled trials. These findings are limited by the heterogeneity of results, the variable duration of follow-up, and the lower doses of statins compared with contemporary clinical practice.Item Open Access Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.(J Neurosci, 2004-05-12) Xu, Mei; Petraschka, Michael; McLaughlin, Jay P; Westenbroek, Ruth E; Caron, Marc G; Lefkowitz, Robert J; Czyzyk, Traci A; Pintar, John E; Terman, Gregory W; Chavkin, CharlesRelease 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.Item Open Access The role of mitogen-activated protein kinase (MAPK) in morphine tolerance and dependence.(Mol Neurobiol, 2009-10) Chen, Yong; Sommer, ClaudiaDespite the existence of a large body of information on the subject, the mechanisms of morphine tolerance and dependence are not yet fully understood. There is substantial evidence indicating that mitogen-activated protein kinase (MAPK), a family including extracellular signal-regulated protein kinase, p38 MAPK, and c-Jun N-terminal kinase, can be activated by chronic morphine treatment in the central and peripheral nervous systems and that application of a MAPK inhibitor reduces morphine tolerance and dependence. While the exact mechanism is not completely understood, recent evidence suggests that the activation of MAPK induced by long-term morphine exposure may participate in tolerance and dependence by regulating the downstream targets, such as calcitonin gene-related peptide, substance P, nitric oxide, transient receptor potential vanilloid 1, and proinflammatory cytokines. In this review, we focus on the current understanding of the role of MAPK signaling pathways in morphine tolerance and dependence.