The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Graeme Henderson - One of the best experts on this subject based on the ideXlab platform.
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Evidence for an important role of protein phosphatases in the mechanism of Morphine Tolerance.
Brain Research, 2007Co-Authors: Bichoy H. Gabra, Forrest L. Smith, Christopher P. Bailey, Eamonn Kelly, Amanda V. Sanders, Graeme Henderson, William L. DeweyAbstract:Acute Morphine antinociception has been shown to be blocked by very low picogram doses of okadaic acid indicating that inhibition of protein phosphatase PP2A allows for increases in phosphorylation to inhibit antinociception. Comparative studies in Morphine tolerant animals have not been reported. In the present study, we showed a significant increase in the total phosphatase activity in the periaqueductal gray matter (PAG) from Morphine-pelleted versus placebo-pelleted mice, 72-h after pellet implantation. This supports our hypothesis that phosphatase activity is increased in Tolerance as a compensatory mechanism for the increase in kinase activity during the development of Tolerance. We also demonstrated that i.c.v. administration of the phosphatase inhibitor okadaic acid (3 pmol/mouse; a dose tested to be inert in placebo-pelleted mice) enhanced the level of Morphine antinociceptive Tolerance assessed by the tail immersion test, 72-h following pellet implantation. This was supported by the fact that the same treatment with okadaic acid blocked the increase in phosphatase activity in PAG of Morphine tolerant mice indicating that selective inhibition of PP2A contributes to enhanced levels of Morphine Tolerance. We have previously reported that PKC or PKA inhibitors reversed Morphine antinociceptive Tolerance in mice. The current study shows that i.c.v. administration of the PKC inhibitors bisindolylmaleimide I or Go6976 reversed the enhanced level of Morphine Tolerance induced by okadaic acid treatment to the same level of Tolerance observed in non-okadaic acid-treated tolerant mice. However, the PKA inhibitor PKI-(14-22)-amide only partially reversed the enhancement of Morphine Tolerance induced by okadaic acid. Our data suggest an important role for the balance between kinases and phosphatases in modulating Tolerance levels. Further studies will be directed towards a better understanding of the role of different phosphatase isoforms in Morphine Tolerance.
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how important is protein kinase c in μ opioid receptor desensitization and Morphine Tolerance
Trends in Pharmacological Sciences, 2006Co-Authors: Christopher P. Bailey, Forrest L. Smith, William L. Dewey, Eamonn Kelly, Graeme HendersonAbstract:The repeated administration of opiate drugs such as Morphine results in the development of Tolerance to their analgesic, rewarding (euphoric) and respiratory-depressant effects; thus, to obtain the same level of response with subsequent administrations, a greater dose must be used. Tolerance can limit the clinical efficacy of opiate drugs and enhance the social problems that are inherent in recreational opioid abuse. Surprisingly, the mechanism (or mechanisms) underlying the development of Morphine Tolerance remains controversial. Here, we propose that protein kinase C could have a crucial role in the desensitization of μ-opioid receptors by Morphine and that this cellular process could contribute to the development and maintenance of Morphine Tolerance in vivo.
Backil Sung - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the ubiquitin proteasome activity prevents glutamate transporter degradation and Morphine Tolerance
Pain, 2008Co-Authors: Liling Yang, Shuxing Wang, Backil Sung, Qing ZengAbstract:Glutamate transporters play a crucial role in physiological glutamate homeostasis and neurotoxicity. Recently, we have shown that downregulation of glutamate transporters after chronic Morphine exposure contributed to the development of Morphine Tolerance. In the present study, we examined whether regulation of the glutamate transporter expression with the proposed proteasome inhibitor MG-132 would contribute to the development of Tolerance to repeated intrathecal (twice daily × 7 days) Morphine administration in rats. The results showed that MG-132 (5 nmol) given intrathecally blocked Morphine-induced glutamate transporter downregulation and the decrease in glutamate uptake activity within the spinal cord dorsal horn. Co-administration of Morphine (15 nmol) with MG-132 (vehicle = 1 < 2.5 < 5 = 10 nmol) also dose-dependently prevented the development of Morphine Tolerance in rats. These findings suggest that prevention of spinal glutamate transporter downregulation may regulate the glutamatergic function that has been implicated in the development of Morphine Tolerance. The possible relationship between MG-132-mediated regulation of glutamate transporters, ubiquitin-proteasome system, and the cellular mechanisms of Morphine Tolerance is discussed in light of these findings.
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spinal glucocorticoid receptors contribute to the development of Morphine Tolerance in rats
Anesthesiology, 2005Co-Authors: Shuxing Wang, Qing Zeng, Backil SungAbstract:BACKGROUND: Opioid analgesic Tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid Tolerance. In a rat model of Morphine Tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of Tolerance to the antinociceptive effect of Morphine. METHODS: In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 microg), the mineralocorticoid receptor antagonist spironolactone (3 microg), or a vehicle, given intrathecally with Morphine (10 microg) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 microg Morphine plus 5 micromol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 microg) was given intrathecally twice daily in combination with 10 microg Morphine. For all experiments, the development of Morphine antinociceptive Tolerance was assessed using the tail-flick test. RESULTS: The development of Tolerance to the antinociceptive effect of Morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 microg > vehicle) but not spironolactone was coadministered with Morphine for 6 days. A single treatment with RU38486 did not affect Morphine antinociception, nor did it reverse Morphine Tolerance on day 7. A similar reduction of Morphine Tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of Morphine Tolerance. CONCLUSIONS: The results indicate an important role of spinal GRs in the cellular mechanisms of Morphine Tolerance in rats and may have significant implications in clinical opioid therapy.
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chronic Morphine induces downregulation of spinal glutamate transporters implications in Morphine Tolerance and abnormal pain sensitivity
The Journal of Neuroscience, 2002Co-Authors: Backil Sung, Rurong JiAbstract:Tolerance to the analgesic effects of an opioid occurs after its chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we examined the role of spinal glutamate transporters (GTs) in the development of both Morphine Tolerance and associated thermal hyperalgesia. Chronic Morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn. This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes. Morphine-induced GT downregulation reduced the ability to maintain in vivo glutamate homeostasis at the spinal level, because the hyperalgesic response to exogenous glutamate was enhanced, including an increased magnitude and a prolonged time course, in Morphine-treated rats with reduced spinal GTs. Moreover, the downregulation of spinal GTs exhibited a temporal correlation with the development of Morphine Tolerance and thermal hyperalgesia. Consistently, the GT inhibitorl- trans -pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both Morphine Tolerance and thermal hyperalgesia. The effects from regulating spinal GT activity by PDC were at least in part mediated through activation of the NMDA receptor (NMDAR), because the noncompetitive NMDAR antagonist MK-801 blocked both Morphine Tolerance and thermal hyperalgesia that were potentiated by PDC. These results indicate that spinal GTs may contribute to the neural mechanisms of Morphine Tolerance and associated abnormal pain sensitivity by means of regulating regional glutamate homeostasis.
Marc G. Caron - One of the best experts on this subject based on the ideXlab platform.
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μ opioid receptor desensitization by β arrestin 2 determines Morphine Tolerance but not dependence
Nature, 2000Co-Authors: Laura M Bohn, Robert J Lefkowitz, Raul R. Gainetdinov, Marc G. CaronAbstract:μ-Opioid receptor desensitization by β-arrestin-2 determines Morphine Tolerance but not dependence
Charles E Inturrisi - One of the best experts on this subject based on the ideXlab platform.
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d methadone blocks Morphine Tolerance and n methyl d aspartate induced hyperalgesia
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Antonia M Davis, Charles E InturrisiAbstract:Previous in vitro and in vivo studies have determined that the d isomer of methadone has N -methyl-d-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability of d -methadone to attenuate the development of Morphine Tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily Morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of Morphine which was prevented by s.c. coadministered d -methadone at 15 mg/kg. In rats, intrathecal (i.t.) Morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d -methadone at 160 μg/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 μg/rat NMDA was completely blocked by pretreatment with 160 μg/rat d -methadone. Thus, systemically coadministered d -methadone prevents systemically induced Morphine Tolerance in mice, i.t. d -methadone attenuates Tolerance produced by i.t. Morphine in rats, and i.t. d -methadone, at the same dose which modulates Morphine Tolerance, blocks NMDA-induced hyperalgesia. These results support the conclusion that d -methadone affects the development of Morphine Tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.
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ketamine attenuates and reverses Morphine Tolerance in rodents
Anesthesiology, 1996Co-Authors: Naohito Shimoyama, Megumi Shimoyama, Charles E Inturrisi, Kathryn J ElliottAbstract:Background : The development of Tolerance complicates the use of Morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse Morphine Tolerance. The authors studied ketamine's ability to modulate Morphine Tolerance. Method : Tolerance was produced in mice given Morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after Morphine to attenuate the development of Tolerance was assessed. The ability of 10 mg/kg ketamine to reverse Tolerance produced by the subcutaneous implantation of Morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal Morphine and the effects of the coadministration of 12 μg intraspinal ketamine were assessed. Results : Morphine given subcutaneously produced a fivefold increase in the median effective (ED 50 ) dose of Morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the Morphine ED 50 produced by Morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal Morphine produced a 46-fold increase in its ED 50 , which was almost completely attenuated by the coadministration of intraspinal ketamine. Conclusions : Systemically administered ketamine attenuates and reverses systemically induced Morphine Tolerance in mice, and intraspinal ketamine attenuates Tolerance produced by intraspinal Morphine in rats.
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attenuation and reversal of Morphine Tolerance by the competitive n methyl d aspartate receptor antagonist ly274614
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: P J Tiseo, Charles E InturrisiAbstract:The ability of a competitive (LY274614; (+-)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid) and a noncompetitive (MK801; [(+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate) N-methyl-D-aspartate receptor antagonist to modulate the development of Tolerance to Morphine's antinociceptive (analgesic) effects was assessed by using hot-plate latency in rats. Concurrent treatment with LY274614 or MK801 by continuous s.c. infusion significantly attenuated the development of Morphine Tolerance produced by twice daily injections of Morphine (10 mg/kg s.c.). This attenuation of Morphine Tolerance by LY274614 was dose-dependent, 12 or 24 mg/kg/24 hr s.c. infusion). Additionally, animals tested 1 week after the discontinuation of all drug treatments were observed to retain their analgesic sensitivity to Morphine, whereas control animals remained relatively tolerant. These results suggest that LY274614 and MK801 do not alter the expression of Tolerance but actually modify the development of Morphine Tolerance. Morphine-tolerant animals infused with LY274614 for 7 days regained their analgesic sensitivity to Morphine. Furthermore, LY274614 also reversed the development of Tolerance and restored Morphine sensitivity in tolerant animals that continued to receive Morphine. The demonstration that LY274614 can prevent and reverse the development of Morphine Tolerance without reducing the analgesic response suggests that the adaptive system involved in the development and maintenance of Tolerance requires a functional N-methyl-D-aspartate receptor. LY274614 lacks the phencyclidine-like side effects seen with MK801, and this may favor the clinical development of this competitive N-methyl-D-aspartate receptor antagonist as an adjunct for patients receiving chronic opioids for pain management.
David J Fink - One of the best experts on this subject based on the ideXlab platform.
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transgene mediated expression of tumor necrosis factor soluble receptor attenuates Morphine Tolerance in rats
Gene Therapy, 2012Co-Authors: Marina Mata, David J FinkAbstract:Opiate/narcotic analgesics are the most effective treatments for chronic severe pain, but their clinical utility is often hampered by the development of analgesic Tolerance. Recent evidence suggests chronic Morphine may activate glial cells to release proinflammatory cytokines. In this study, we used herpes simplex virus (HSV) vector-based gene transfer to dorsal root ganglion to produce a local release of p55 tumor necrosis factor (TNF) soluble receptor in the spinal cord in rats with Morphine Tolerance. Subcutaneous inoculation of HSV vectors expressing p55 TNF soluble receptor into the plantar surface of the hindpaws enhanced the antinociceptive effect of acute Morphine in rats. Subcutaneous inoculation of those vectors into hindpaws also delayed the development of chronic Morphine Tolerance in rats. TNF soluble receptor expressed by HSV vector reduced gene transcription of spinal TNFα and interleukin-1β (IL-1β) induced by repeated Morphine. Furthermore, we found that TNF soluble receptor mediated by HSV reversed the upregulation of protein level of TNFα and IL-1β and phosphorylation of p38 mitogen-activated protein kinase induced by repeated Morphine. These results support the concept that proinflammatory cytokines may have an important role in the pathogenesis induced by Morphine. This study provides a novel approach to treating Morphine Tolerance.