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Chihshung Wong - One of the best experts on this subject based on the ideXlab platform.
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Resveratrol reverses Morphine-induced neuroinflammation in Morphine-tolerant rats by reversal HDAC1 expression
Elsevier, 2016Co-Authors: Ru-yin Tsai, Chihshung Wong, Juei-chii Wang, Kuang-yi Chou, Chen-hwan CherngAbstract:We previously showed that subsequent intrathecal (i.t.) injection of resveratrol (30 μg) significantly reverses Morphine-evoked neuroinflammation in Morphine-tolerant rats. The present study examined the underlying mechanism. Methods: Male Wistar rats were implanted with two i.t. catheters, one of which was connected to a miniosmotic pump and used for Morphine (15 μg/h) or saline infusion for 120 hours. To examine the effects on spinal cord expression of histone deacetylase 1 (HDAC1), the inflammatory cytokine tumor necrosis factor-α (TNF-α), and TNF receptor (TNFR) 1 and TNFR2 during tolerance induction, a tail-flick test was performed prior to infusion and after 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours of infusion. Results: Resveratrol treatment prior to Morphine challenge restored the antinociceptive effect of Morphine in Morphine-tolerant rats and reversed the Morphine infusion-induced increase in HDAC1, TNF-α, and TNFR1 expression. Moreover, chronic Morphine infusion increased TNFR1-specific expression in neuron in Morphine-tolerant rat spinal cords, and this effect was almost completely inhibited by resveratrol treatment prior to Morphine challenge. Conclusion: Resveratrol restores the antinociceptive effect of Morphine by reversing Morphine infusion-induced spinal cord neuroinflammation and increase in TNFR1 expression. The reversal of the Morphine-induced increase in TNFR1 expression by resveratrol is partially due to reversal of the Morphine infusion-induced increase in HDAC1 expression. Resveratrol pretreatment can be used as an adjuvant in clinical pain management for patients who need long-term Morphine treatment or with neuropathic pain
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n methyl d aspartate receptor antagonist mk 801 suppresses glial pro inflammatory cytokine expression in Morphine tolerant rats
Pharmacology Biochemistry and Behavior, 2011Co-Authors: Chinghang Liu, Chenhwen Cherng, Shinnlong Lin, Chunchang Yeh, Yuehhua Tai, Chihshung WongAbstract:Abstract Chronic opioid therapy induces tolerance and hyperalgesia, which hinders the efficacy of opioid treatment. Previous studies have shown that inhibition of neuroinflammation and glutamatergic receptor activation prevents the development of Morphine tolerance. The aim of the present study was to examine whether N-Methyl- d -aspartate receptors are involved in the regulation of chronic Morphine-induced neuroinflammation in Morphine-tolerant rats. Morphine tolerance was induced in male Wistar rats by intrathecal infusion of Morphine (15 μg/h) for 5 days. Tail-flick latency was measured to estimate the antinociceptive effect of Morphine. Morphine challenge (15 μg, intrathecally) on day 5 at 3 h after discontinuation of Morphine infusion produced a significant antinociceptive effect in saline-infused rats, but not in Morphine-tolerant rats. Pretreatment with MK-801 (20 μg, intrathecally) 30 min before Morphine challenge preserved its antinociceptive effect in Morphine-tolerant rats. Morphine-tolerant rats expressed high levels of the pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α and the increase in interleukin-1β and interleukin-6, and tumor necrosis factor-α levels was prevented by MK-801 pre-treatment at both the protein and mRNA levels. The results show that a single dose of MK-801 reduces the increase in pro-inflammatory cytokines in the spinal cord, thus re-sensitizing neurons to the antinociceptive effect of Morphine in Morphine-tolerant rats. This study provides a piece of theoretical evidence that NMDA antagonist can be a therapeutic adjuvant in treating Morphine tolerant patients for pain relief.
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dexamethasone modulates the development of Morphine tolerance and expression of glutamate transporters in rats
Neuroscience, 2005Co-Authors: G J Wu, Yichen Chang, J J Wang, Chihshung WongAbstract:Abstract We recently demonstrated an increase in spinal cerebrospinal fluid (CSF) excitatory amino acids (EAAs) in Morphine-tolerant rats after Morphine challenge. The present study examined whether co-infusion of the glucocorticoid dexamethasone (DEX) co-infusion inhibited Morphine tolerance and the Morphine challenge-induced EAAs increase after long-term Morphine infusion. Intrathecal (i.t.) catheters and one microdialysis probe were implanted to male Wistar rats. Rats were divided into four groups: i.t. Morphine (15μg/h), saline (1μl/h), DEX (2μg/h), or DEX (2μg/h) plus Morphine (15μg/h) infusion for 5 days. Tail-flick responses were examined before drug infusion and daily after the start of infusion for 5 days. Moreover, on day 5 after Morphine challenge (50μg, i.t.), CSF EAAs was also measured. Rat spinal cords were removed on day 5, and prepared for Western blot analysis of different glutamate transporters (GTs). The AD 50 (analgesic dose) on day 5 was 1.33μg in saline-infused rats, 83.84μg in Morphine-tolerant rats, and 10.15μg in DEX plus Morphine co-infused rats. Single DEX (2μg, i.t.) injection did not enhance Morphine’s antinociceptive effect in either naive or Morphine-tolerant rats. No difference in CSF EAA level was observed in all groups between baseline (before drug infusion) and on day 5 after tolerance developed. Surprisingly, on day 5, after Morphine challenge, an increase in glutamate and aspartate (284±47% and 201±18% of basal) concentration was observed, and Morphine lost its antinociceptive effect (maximum percent effect, MPE=41±12%), whereas DEX/Morphine co-infusion inhibited Morphine-evoked EAA increase with a MPE=97±2%. DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier). Upregulation of GLT-1 was also observed (204±20% of basal). DEX co-infusion inhibits the Morphine-challenge induced EAA increase and prevents the loss of Morphine’s antinociceptive effect after long-term Morphine infusion.
Gavril W Pasternak - One of the best experts on this subject based on the ideXlab platform.
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novel receptor mechanisms for heroin and Morphine 6β glucuronide analgesia
Neuroscience Letters, 1996Co-Authors: Grace C Rossi, Gavril W Pasternak, George P Brown, Liza Leventhal, Ke YangAbstract:The rapid metabolism of heroin to 6-acetylMorphine and its slower conversion to Morphine has led many to believe that heroin and Morphine act through the same receptors and that the differences between them are due to their pharmacokinetics. We now present evidence strongly implying that heroin and two potent mu drugs, fentanyl and etonitazine, act through a unique receptor mechanism similar to Morphine-6 beta-glucuronide which is readily distinguished from Morphine. Heroin, 6-acetylMorphine and Morphine-6 beta-glucuronide show no analgesic cross tolerance to Morphine in a daily administration paradigm, implying distinct receptors. Strains also reveal analgesic differences among the drugs. CXBK mice, which are insensitive to Morphine, retain their analgesic sensitivity to heroin, 6-acetylMorphine, Morphine-6 beta-glucuronide, fentanyl and etonitazine. Antisense mapping of the mu opioid receptor MOR-1 reveals that oligodeoxynucleotide probes against exon 2, which are inactive against Morphine analgesia, block Morphine-6 beta-glucuronide, heroin, fentanyl and etonitazine analgesia. Finally, an antisense probe targeting Gi alpha 1 blocks both heroin and Morphine-6 beta-glucuronide, but not Morphine, analgesia. These results indicate that heroin, 6-acetylMorphine, fentanyl and etonitazine all can produce analgesia through a novel mu analgesic system which is similar to that activated by Morphine-6 beta-glucuronide.
Gerd Geisslinger - One of the best experts on this subject based on the ideXlab platform.
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analgesic effects of Morphine and Morphine 6 glucuronide in a transcutaneous electrical pain model in healthy volunteers
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Carsten Skarke, Gerd Geisslinger, Jutta Darimont, Helmut Schmidt, Jörn LötschAbstract:Objective Our objective was to quantify the extent and time course of the effects of Morphine-6-glucuronide and Morphine on pain threshold, pain tolerance, pupil diameter, and side effects. Methods In a double-blind, placebo-controlled, randomized, 3-way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of Morphine-6-glucuronide or 26 to 66 mg of Morphine as an intravenous bolus, followed by an infusion of the same medication for 1.8 to 6.4 hours. Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0–9.99 mA). Pupil diameter and side effects were recorded concomitantly. Results At the administered doses, Morphine-6-glucuronide and Morphine had comparable effects on pain tolerance, pupil diameter, and side effects. The delay between the time course of the plasma concentrations and the time course of the effects was longer for Morphine-6-glucuronide than for Morphine (transfer half-life, 8.2 hours versus 2.6 hours for pain tolerance and 7.7 hours versus 2.8 hours for pupil diameter). The slope of the linear concentration versus effect relationship for pain tolerance was flatter for Morphine-6-glucuronide than for Morphine (0.05% versus 0.6% increase in pain tolerance per nanomole per liter of Morphine-6-glucuronide and Morphine at effect site, respectively). Morphine-6-glucuronide was less potent than Morphine in producing pupil constriction (mean concentration at half-maximum effect, 745 nmol/L versus 26.4 nmol/L for Morphine-6-glucuronide and Morphine, respectively). In carriers of the mutated G118 allele of the μ-opioid receptor, the potency of the pupil-constricting effects of Morphine-6-glucuronide and Morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of Morphine-6-glucuronide. Conclusions Morphine-6-glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic Morphine-6-glucuronide needed to produce the same effects as Morphine suggest that Morphine-6-glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of Morphine. Clinical Pharmacology & Therapeutics (2003) 73, 107–121; doi: 10.1067/mcp.2003.5
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pharmacokinetics of Morphine 6 glucuronide and its formation from Morphine after intravenous administration
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Gerd Geisslinger, Jörn Lötsch, Michael Weiss, G KobalAbstract:Background Morphine-6-β-glucuronide is a primary Morphine metabolite with potent opioid action. However, its low and slow brain permeability eventually prevents its central opioid effects after short-term intravenous administration. Research is needed to establish whether Morphine-6-β-glucuronide qualifies as an analgesic; this study provides the pharmacokinetic bases for such studies. Methods Plasma concentration-time data of Morphine-6-β-glucuronide and Morphine obtained from 20 healthy volunteers after short-term intravenous administration of either Morphine-6-β-glucuronide or Morphine were described by a biexponential disposition curve. Disposition parameters of Morphine-6-β-glucuronide and Morphine were estimated by nonlinear regression, and basic pharmacokinetic parameters (clearance, volume of distribution at steady state, and mean disposition residence time) were derived. A new model of metabolite kinetics was applied, and the disposition parameters of Morphine and Morphine-6-β-glucuronide were then used to fit the plasma concentration-time profile of Morphine-6-β-glucuronide formed from Morphine. Thereby the fraction of Morphine metabolized to Morphine-6β-glucuronide and the mean transit time of Morphine across the site of metabolism were estimated. Results The extent and time course of Morphine-6-β-glucuronide formation from Morphine could be well described by a parametric model, with a fraction of Morphine metabolized to Morphine-6-β-glucuronide of 7.55% ± 1.24% and a mean metabolic transit time for Morphine to Morphine-6-β-glucuronide of 0.28 ± 0.21 hour. The underlying disposition of Morphine and Morphine-6-β-glucuronide was characterized by clearance (Morphine clearance, 32.7 ± 6 ml · min−1 · kg−1, Morphine-6-β-glucuronide clearance, 2.2 ± 0.4 ml · min−1 · kg−1), volume of distribution at steady state (Morphine, 1.8 ± 0.3 L · hr−1; Morphine-6-β-glucuronide, 0.12 ± 0.02 L · hr−1), and mean disposition residence time (Morphine, 1.8 ± 0.4 hours; Morphine-6-β-glucuronide, 1.7 ± 0.4 hours). Conclusions The time course of Morphine-6-β-glucuronide formation kinetics was analyzed with use of the information on the disposition kinetics of both Morphine and preformed Morphine-6-β-glucuronide, which was obtained by separate data fits. The transformation of Morphine to Morphine-6-β-glucuronide could be described by two parameters characterizing the extent and delay of metabolite formation. The results of this study will serve as pharmacokinetic bases of future investigations of Morphine-6-β-glucuronide in human beings. Clinical Pharmacology & Therapeutics (1998) 63, 629–639; doi:
Jörn Lötsch - One of the best experts on this subject based on the ideXlab platform.
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analgesic effects of Morphine and Morphine 6 glucuronide in a transcutaneous electrical pain model in healthy volunteers
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Carsten Skarke, Gerd Geisslinger, Jutta Darimont, Helmut Schmidt, Jörn LötschAbstract:Objective Our objective was to quantify the extent and time course of the effects of Morphine-6-glucuronide and Morphine on pain threshold, pain tolerance, pupil diameter, and side effects. Methods In a double-blind, placebo-controlled, randomized, 3-way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of Morphine-6-glucuronide or 26 to 66 mg of Morphine as an intravenous bolus, followed by an infusion of the same medication for 1.8 to 6.4 hours. Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0–9.99 mA). Pupil diameter and side effects were recorded concomitantly. Results At the administered doses, Morphine-6-glucuronide and Morphine had comparable effects on pain tolerance, pupil diameter, and side effects. The delay between the time course of the plasma concentrations and the time course of the effects was longer for Morphine-6-glucuronide than for Morphine (transfer half-life, 8.2 hours versus 2.6 hours for pain tolerance and 7.7 hours versus 2.8 hours for pupil diameter). The slope of the linear concentration versus effect relationship for pain tolerance was flatter for Morphine-6-glucuronide than for Morphine (0.05% versus 0.6% increase in pain tolerance per nanomole per liter of Morphine-6-glucuronide and Morphine at effect site, respectively). Morphine-6-glucuronide was less potent than Morphine in producing pupil constriction (mean concentration at half-maximum effect, 745 nmol/L versus 26.4 nmol/L for Morphine-6-glucuronide and Morphine, respectively). In carriers of the mutated G118 allele of the μ-opioid receptor, the potency of the pupil-constricting effects of Morphine-6-glucuronide and Morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of Morphine-6-glucuronide. Conclusions Morphine-6-glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic Morphine-6-glucuronide needed to produce the same effects as Morphine suggest that Morphine-6-glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of Morphine. Clinical Pharmacology & Therapeutics (2003) 73, 107–121; doi: 10.1067/mcp.2003.5
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pharmacokinetics of Morphine 6 glucuronide and its formation from Morphine after intravenous administration
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Gerd Geisslinger, Jörn Lötsch, Michael Weiss, G KobalAbstract:Background Morphine-6-β-glucuronide is a primary Morphine metabolite with potent opioid action. However, its low and slow brain permeability eventually prevents its central opioid effects after short-term intravenous administration. Research is needed to establish whether Morphine-6-β-glucuronide qualifies as an analgesic; this study provides the pharmacokinetic bases for such studies. Methods Plasma concentration-time data of Morphine-6-β-glucuronide and Morphine obtained from 20 healthy volunteers after short-term intravenous administration of either Morphine-6-β-glucuronide or Morphine were described by a biexponential disposition curve. Disposition parameters of Morphine-6-β-glucuronide and Morphine were estimated by nonlinear regression, and basic pharmacokinetic parameters (clearance, volume of distribution at steady state, and mean disposition residence time) were derived. A new model of metabolite kinetics was applied, and the disposition parameters of Morphine and Morphine-6-β-glucuronide were then used to fit the plasma concentration-time profile of Morphine-6-β-glucuronide formed from Morphine. Thereby the fraction of Morphine metabolized to Morphine-6β-glucuronide and the mean transit time of Morphine across the site of metabolism were estimated. Results The extent and time course of Morphine-6-β-glucuronide formation from Morphine could be well described by a parametric model, with a fraction of Morphine metabolized to Morphine-6-β-glucuronide of 7.55% ± 1.24% and a mean metabolic transit time for Morphine to Morphine-6-β-glucuronide of 0.28 ± 0.21 hour. The underlying disposition of Morphine and Morphine-6-β-glucuronide was characterized by clearance (Morphine clearance, 32.7 ± 6 ml · min−1 · kg−1, Morphine-6-β-glucuronide clearance, 2.2 ± 0.4 ml · min−1 · kg−1), volume of distribution at steady state (Morphine, 1.8 ± 0.3 L · hr−1; Morphine-6-β-glucuronide, 0.12 ± 0.02 L · hr−1), and mean disposition residence time (Morphine, 1.8 ± 0.4 hours; Morphine-6-β-glucuronide, 1.7 ± 0.4 hours). Conclusions The time course of Morphine-6-β-glucuronide formation kinetics was analyzed with use of the information on the disposition kinetics of both Morphine and preformed Morphine-6-β-glucuronide, which was obtained by separate data fits. The transformation of Morphine to Morphine-6-β-glucuronide could be described by two parameters characterizing the extent and delay of metabolite formation. The results of this study will serve as pharmacokinetic bases of future investigations of Morphine-6-β-glucuronide in human beings. Clinical Pharmacology & Therapeutics (1998) 63, 629–639; doi:
Pierre Giusti - One of the best experts on this subject based on the ideXlab platform.
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Conditioned place preference: No tolerance to the rewarding properties of Morphine
Naunyn-Schmiedeberg's Archives of Pharmacology, 1997Co-Authors: ANGELO CONTARINO, Adriano Zanotti, Fabrizio Natolino, Maria Lipartiti, Filippo Drago, Pierre GiustiAbstract:The effect of repeated Morphine administration on conditioned place preference (CPP) using a novel treatment schedule, i.e., drug treatment was always contingent with the conditioned environmental stimuli, was investigated. We also examined whether changes in the mu- and kappa-opioid receptor binding occurred in the brain of Morphine-treated animals. Intraperitoneal (i.p.) administration of Morphine (2 and 10 mg/kg) induced a place preference after 8 daily conditioning trials (4 Morphine injections on alternate trials), the level of preference being the same with the two doses of the opiate. No change in place preference was observed in the Morphine-treated rats at 2 mg/kg, when animals were further trained up to a total of 32 conditioning trials (16 Morphine injections). Conversely, after 20 conditioning trials (10 Morphine injections), a stronger CPP response developed in the Morphine-treated rats at 10 mg/kg. Signs of Morphine withdrawal were never detected in Morphine-treated rats during the experiment. Loss of body weight (index of opiate dependence) was not observed either 24 h or 48 h after the last Morphine administration. mu- and kappa-opioid receptor density and affinity were not affected by repeated Morphine administrations at either dose. The results demonstrate that no tolerance develops to the rewarding properties of Morphine. Indeed, a sensitisation effect may occur at increasing doses of the opiate. Furthermore, changes in the rewarding effect of Morphine are not dependent upon alterations in opioid receptors involved in the reinforcing mechanisms.
