Using [11C]Diprenorphine to Image Opioid Receptor Occupancy by Methadone in Opioid Addiction: Clinical and Preclinical Studies

2004 ◽  
Vol 312 (1) ◽  
pp. 309-315 ◽  
Author(s):  
Jan K. Melichar ◽  
Susan P. Hume ◽  
Tim M. Williams ◽  
Mark R. C. Daglish ◽  
Lindsay G. Taylor ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Occupancy ◽  
Opioid Addiction ◽  
Preclinical Studies

scholarly journals μ-opioids activate phospholipase C in SH-SY5Y human neuroblastoma cells via calcium-channel opening

1995 ◽  
Vol 305 (2) ◽  
pp. 577-581 ◽  
Author(s):  
D Smart ◽  
G Smith ◽  
D G Lambert
Keyword(s):  
Phospholipase C ◽  
Opioid Receptor ◽  
Neuroblastoma Cells ◽  
Receptor Occupancy ◽  
Mu Opioid Receptor ◽  
Human Neuroblastoma ◽  
Mu Opioid ◽  
Inositol 1,4,5 Trisphosphate ◽  
Dependent Inhibition ◽  
Dose Dependent

We have recently reported that, in SH-SY5Y cells, mu-opioid receptor occupancy activates phospholipase C via a pertussis toxin-sensitive G-protein. In the present study we have further characterized the mechanisms involved in this process. Fentanyl (0.1 microM) caused a monophasic increase in inositol 1,4,5-trisphosphate mass formation, with a peak (20.5 +/- 3.6 pmol/mg of protein) at 15 s. Incubation in Ca(2+)-free buffer abolished this response, while Ca2+ replacement 1 min later restored the stimulation of inositol 1,4,5-trisphosphate formation (20.1 +/- 0.6 pmol/mg of protein). In addition, nifedipine (1 nM-0.1 mM), an L-type Ca(2+)-channel antagonist, caused a dose-dependent inhibition of inositol 1,4,5-trisphosphate formation, with an IC50 of 60.3 +/- 1.1 nM. Elevation of endogenous beta/gamma subunits by selective activation of delta-opioid and alpha 2 adrenoceptors failed to stimulate phospholipase C. Fentanyl also caused a dose-dependent (EC50 of 16.2 +/- 1.0 nM), additive enhancement of carbachol-induced inositol 1,4,5-trisphosphate formation. In summary, we have demonstrated that in SH-SY5Y cells activation of the mu-opioid receptor allows Ca2+ influx to activate phospholipase C. However, the possible role of this mechanism in the process of analgesia remains to be elucidated.

Influence of neonatal opioid blockade or injections of gonadotrophin-releasing hormone on the timing of puberty in female rats: correlation of opioid effects with occupation of hypothalamic μ-opioid receptors

1988 ◽  
Vol 119 (3) ◽  
pp. 447-452 ◽  
Author(s):  
K. M. Landymore ◽  
M. Wilkinson
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Sexual Maturation ◽  
Receptor Occupancy ◽  
Female Rats ◽  
Opioid Antagonist ◽  
Female Rat ◽  
Timing Of Puberty ◽  
Long Acting ◽  
Opioid Blockade

ABSTRACT Hypothalamic opioid peptides have been implicated in the timing of sexual maturation in several species. We have examined the effects of neonatal opioid blockade on the timing of puberty in the female rat and have compared these with the effects of neonatal GnRH injection. Intermittent naloxone (2·5 mg/kg) or GnRH (200 ng/100 g body wt) injected s.c. at 6-h intervals for the first 10 days of life only slightly advanced the mean day of vaginal opening (VO). However, the degree of precocity was significantly more marked in a subgroup of drug-injected rats. In contrast, injections of the long-acting opioid antagonist naltrexone (50 mg/kg) had no effect on the timing of VO. The results suggested that the duration of opioid receptor blockade is critical in determining the degree of opioid antagonist effect. Therefore, additional studies were performed to compare receptor occupancy of naloxone and naltrexone in 9-day-old rat pups. An exvivo binding assay was utilized to determine the availability of hypothalamic opioid-binding sites at various intervals following a single s.c. injection of antagonist. The time-course of inhibition of tritium labelled [d-Ala2-N-Me-Phe4,Gly5-ol]-enkephalin ([3H]DAGO) binding (μ-opioid sites) revealed that naloxone occupies the μ-receptor for a relatively short period of time. Naloxone (2·5 and 50 mg/kg) produced extensive inhibition of [3H]DAGO binding at 30 min following injection but binding was 100% of control at 1 h and 3·5 h respectively. In contrast, hypothalamic binding in naltrexone-treated (50 mg/kg) pups did not reach 50% of control values until 12 h and 100% of control values at 20 h after injection. The results are consistent with naltrexone's role as a long-acting antagonist but indicate that this blockade is not sustained for 24 h as previously indicated by indirect assessment with opiate challenge tests. Our data demonstrate that the duration of μ-opioid receptor occupancy is an important consideration in attempting to understand why intermittent, but not more continuous, blockade of opioid receptors induces some degree of sexual precocity in female rats. Also of interest is the observation that anterior pituitary stimulation with GnRH, during the first 10 days of life, can modify the timing of sexual maturation. J. Endocr. (1988) 119, 447–452

Reversibility of opioid receptor occupancy of buprenorphine in vivo

2006 ◽  
Vol 534 (1-3) ◽  
pp. 95-102 ◽  
Author(s):  
Werner Englberger ◽  
Babette Kögel ◽  
Elmar Friderichs ◽  
Wolfgang Straβburger ◽  
Tieno Germann
Keyword(s):  
Opioid Receptor ◽  
Receptor Occupancy

scholarly journals Brief Report: Higher Fentanyl Exposures Require Higher Doses of Naloxone for Successful Reversals in a Quantitative Systems Pharmacology Model

2021 ◽  
Author(s):  
Ronald B. Moss ◽  
Meghan McCabe Pryor ◽  
Rebecca Baillie ◽  
Katherine Kudrycki ◽  
Christina Friedrich ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Peak Concentration ◽  
Systemic Exposure ◽  
Receptor Occupancy ◽  
Systems Pharmacology ◽  
Dose Equivalent ◽  
Quantitative Systems Pharmacology ◽  
Synthetic Opioids ◽  
Higher Doses ◽  
Systems Pharmacology Model

Abstract Background: Previously, we reported on an opioid receptor quantitative systems pharmacology (QSP) model to evaluate naloxone dosing. Methods: In this study we extended our model to include higher systemic levels of fentanyl (up to 100 ng/ml) and the newly approved 8mg IN naloxone dose (equivalent to 4 mg)Results : As expected, at the lower peak fentanyl concentrations (25 ng/ml and 50 ng/ml), the simulations predicted that 2 mg, 4 mg, 5 mg, and 10 mg IM doses of naloxone displaced fentanyl and reached below the 50% receptor occupancy within 10 minutes. However, at the concentration of 75 ng/ml, the simulation predicted that the 2 mg dose of naloxone failed to reach below the 50% occupancy within 10 minutes. Interestingly, at the highest peak concentration of fentanyl studied (100 ng/ml), the model predicted that the 4 mg of naloxone IM (equivalent to 8 mg IN) failed to reach below the threshold of 50 % occupancy within 10 minutes or even within 15 minutes (Data not shown). In contrast, the model predicted successful reversals when 5 and 10 mg IM doses were utilized. Conclusion:These results support the notion that acutely administered higher doses of naloxone are needed for rapid and adequate clinical reversal, particularly when higher systemic exposure of the potent synthetic opioids occur.

Expression of mu opioid receptor splice variants mRNA in human blood lymphocytes: A peripheral marker for opioid addiction studies

2009 ◽  
Vol 9 (7-8) ◽  
pp. 1016-1020 ◽  
Author(s):  
Nasim Vousooghi ◽  
Ali Goodarzi ◽  
Farshad Roushanzamir ◽  
Tina Sedaghati ◽  
Mohammad-Reza Zarrindast ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Human Blood ◽  
Splice Variants ◽  
Mu Opioid Receptor ◽  
Opioid Addiction ◽  
Mu Opioid ◽  
Blood Lymphocytes ◽  
Human Blood Lymphocytes ◽  
Addiction Studies

scholarly journals Relationship Between Opioid-Receptor Occupancy and Stimulation of Low-KmGTPase in Brain Membranes

1989 ◽  
Vol 52 (4) ◽  
pp. 1162-1169 ◽  
Author(s):  
Mary J. Clark ◽  
Gordon L. Nordby ◽  
Fedor Medzihradsky
Keyword(s):  
Opioid Receptor ◽  
Receptor Occupancy ◽  
Brain Membranes ◽  
Stimulation Of

scholarly journals CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2–DOP receptor heterodimer

2008 ◽  
Vol 412 (2) ◽  
pp. 245-256 ◽  
Author(s):  
Geraldine Parenty ◽  
Shirley Appelbe ◽  
Graeme Milligan
Keyword(s):  
Opioid Receptor ◽  
Chemokine Receptors ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Receptor Occupancy ◽  
Α Subunit ◽  
Receptor Agonists ◽  
Opioid Agonists ◽  
Small Molecule Therapeutics ◽  
Cxcr2 Antagonist

Opioid agonists have a broad range of effects on cells of the immune system, including modulation of the inflammatory response, and opioid and chemokine receptors are co-expressed by many white cells. Hetero-oligomerization of the human DOP opioid and chemokine CXCR2 receptors could be detected following their co-expression by each of co-immunoprecipitation, three different resonance energy transfer techniques and the construction of pairs of individually inactive but potentially complementary receptor G-protein α subunit fusion proteins. Although DOP receptor agonists and a CXCR2 antagonist had no inherent affinity for the alternative receptor when either receptor was expressed individually, use of cells that expressed a DOP opioid receptor construct constitutively, and in which expression of a CXCR2 receptor construct could be regulated, demonstrated that the CXCR2 antagonist enhanced the function of DOP receptor agonists only in the presence of CXCR2. This effect was observed for both enkephalin- and alkaloid-based opioid agonists, and the effective concentrations of the CXCR2 antagonist reflected CXCR2 receptor occupancy. Entirely equivalent results were obtained in cells in which the native DOP opioid receptor was expressed constitutively and in which expression of the isolated CXCR2 receptor could be induced. These results indicate that a CXCR2 receptor antagonist can enhance the function of agonists at a receptor for which it has no inherent direct affinity by acting as an allosteric regulator of a receptor that is a heterodimer partner for the CXCR2 receptor. These results have novel and important implications for the development and use of small-molecule therapeutics.

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