morphinans and carfentanil

The presence of opioid peptides and receptors and their role in the regulation of cardiovascular function has been previously demonstrated in the mammalian heart. The aim of this study was to image micro and delta opioid receptors in the human heart using positron emission tomography (PET). Five subjects (three females, two males, 65+/-8 years old) underwent PET scanning of the chest with [(11)C]carfentanil ([(11)C]CFN) and [(11)C]- N-methyl-naltrindole ([(11)C]MeNTI) and the images were analyzed for evidence of opioid receptor binding in the heart. Either [(11)C]CFN or [(11)C]MeNTI (20 mCi) was injected i.v. with subsequent dynamic acquisitions over 90 min. For the blocking studies, either 0.2 mg/kg or 1 mg/kg of naloxone was injected i.v. 5 min prior to the injection of [(11)C]CFN and [(11)C]MeNTI, respectively. Regions of interest were placed over the left ventricle, left ventricular chamber, lung and skeletal muscle. Graphical analysis demonstrated average baseline myocardial binding potentials (BP) of 4.37+/-0.91 with [(11)C]CFN and 3.86+/-0.60 with [(11)C]MeNTI. Administration of 0.2 mg/kg naloxone prior to [(11)C]CFN produced a 25% reduction in BP in one subject in comparison with baseline values, and a 19% decrease in myocardial distribution volume (DV). Administration of 1 mg/kg of naloxone before [(11)C]MeNTI in another subject produced a 14% decrease in BP and a 21% decrease in the myocardial DV. These results demonstrate the ability to image these receptors in vivo by PET. PET imaging of cardiac opioid receptors may help to better understand their role in cardiovascular pathophysiology and the effect of abuse of opioids and drugs on heart function.

Topics: Aged; Carbon Radioisotopes; Feasibility Studies; Female; Fentanyl; Heart; Humans; Indoles; Lung; Male; Middle Aged; Morphinans; Muscle, Skeletal; Myocardium; Naloxone; Radiopharmaceuticals; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution; Tomography, Emission-Computed

SH-SY5Y (human neuroblastoma) cultured cells, known to have mu-opioid receptors, have been used to assess and compare the ability of eight representative mu-selective compounds from diverse opioid families to recognize and activate these receptors. A wide range of receptor affinities spanning a factor of 10,000 was found between the highest affinity fentanyl analogs (Ki = 0.1nM) and the lowest affinity analog, meperidine (Ki = 1 microM). A similar range was found for inhibition of PGE1-stimulated cAMP accumulation with a rank order of activities that closely paralleled binding affinities. Maximum inhibition of cAMP accumulation by each compound was about 80%. Maximum stimulation of GTPase activity (approximately 50%) was also similar for all compounds except the lowest affinity meperidine. Both effects were naloxone reversible. These results provide further evidence that mu-receptors are coupled to inhibition of adenylate cyclase and that the SH-SY5Y cell line is a good system for assessment of mu-agonists functional responses.

Topics: Alprostadil; Analgesics; Cyclic AMP; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Fentanyl; GTP Phosphohydrolases; Humans; Meperidine; Morphinans; Naloxone; Narcotics; Oxymorphone; Receptors, Opioid; Receptors, Opioid, mu; Tumor Cells, Cultured

The kinetics and regional distribution of [11C]carfentanil, a mu-selective opiate receptor agonist, and [11C]diprenorphine, a nonselective opiate receptor antagonist, were compared using paired positron emission tomography studies in two normal volunteers. Kinetics of total radioactivity (counts/mCi/pixel) was greater for [11C]diprenorphine than [11C]carfentanil in all regions. [11C]Carfentanil binding (expressed as the total/nonspecific ratio) reached near equilibrium at approximately 40 min, whereas [11C]diprenorphine showed a linear increase until approximately 60 min. Kinetics of specific binding demonstrated significant dissociation of [11C]carfentanil from opiate receptors, whereas little dissociation of [11C]diprenorphine was observed during the 90-min scan session. Regional distributions of [11C]carfentanil and [11C]diprenorphine were qualitatively and quantitatively different: Relative to the thalamus (a region with known predominance of mu-receptors), [11C]diprenorphine displayed greater binding in the striatum and cingulate and frontal cortex compared to [11C]carfentanil, consistent with labeling of additional, non-mu sites by [11C]diprenorphine. We conclude from these studies that [11C]diprenorphine labels other opiate receptor subtypes in addition to the mu sites selectively labeled by [11C]carfentanil. The nonselective nature of diprenorphine potentially limits its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases. Development of selective tracers for the delta- and kappa-opiate receptor sites, or alternatively use of unlabeled inhibitors to differentially displace mu, delta, and kappa subtypes, will help offset these limitations.

Topics: Adult; Brain; Diprenorphine; Fentanyl; Humans; Male; Morphinans; Receptors, Opioid; Tomography, Emission-Computed

The effects of chemical immobilisation on impala (Aepyceros melampus) were investigated. The results indicate that etorphine HCl or Carfentanil should not be used in isolation but that xylazine should be included in the immobilisation "cocktail". The highest dose possible, commensurate with safety, should be used in order to minimise time and distance to recumbency. Body temperature should be monitored and if cooling measures are not effective the animal should be aroused. Either diprenorphine HCl alone or in combination with yohimbine and 4-aminopyridine should be used as antidote/s.

Topics: Animals; Antelopes; Artiodactyla; Drug Combinations; Etorphine; Female; Fentanyl; Immobilization; Male; Morphinans; Thiazines; Time Factors; Xylazine

The displacement of 3H-diprenorphine from opiate receptors by mu-selective opiates was measured in the mouse striatum and thalamus in vivo. In addition, the regional distribution of opiate receptor binding using 3H-diprenorphine, 3H-naloxone and 3H-lofentanil was measured. The displacement of 3H-diprenorphine by naloxone and carfentanil in vivo showed no differences in the striatum and thalamus suggesting that 3H-diprenorphine binds only to one opiate receptor subtype in vivo. This finding is substantiated by the observation that the mu selective ligands 3H-naloxone and 3H-lofentanil have the same in vivo distribution of receptor binding as 3H-diprenorphine. The implication of these findings for PET imaging of opiate receptor subtypes is discussed.

Topics: Animals; Binding, Competitive; Corpus Striatum; Diprenorphine; Fentanyl; Kinetics; Male; Mice; Mice, Inbred ICR; Morphinans; Naloxone; Receptors, Opioid; Receptors, Opioid, mu; Thalamus; Tritium