Using CHO cells stably transfected with rat mu-opioid receptor cDNA, we show that the mu-agonists morphine and [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin are negatively coupled to adenylylcyclase and inhibit forskolin-stimulated cAMP accumulation. Chronic exposure of cells to morphine leads to the rapid development of tolerance. Withdrawal of morphine or [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin f...

BACKGROUND The aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a cell system expressing only mu opioid receptors. Receptor activation was assessed by measuring the inhibition of forskolin-stimulated cyclic adenosine mono phosphate (cAMP) production. Efficacies and potencies of these ligands were determined relative to the endogenous...

We have shown previously that acute morphine administration markedly enhances naloxone-induced increases in serum luteinizing hormone (LH) levels in the male rat. The purposes of the present studies were to determine whether this effect was opiate-specific and, if so, whether it was mediated by mu, kappa or sigma opiate receptors. In agreement with our previous reports, we found that naloxone-i...

The objective of this investigation was to characterize the role of complex biophase distribution kinetics in the pharmacokinetic-pharmacodynamic correlation of a wide range of opioids. Following intravenous infusion of morphine, alfentanil, fentanyl, sufentanil, butorphanol and nalbuphine the time course of the EEG effect was determined in conjunction with blood concentrations. Different bioph...

Investigation of central nervous system activity of phenylcyclohexylamines was continued by preparation of "reversed" analogues. Following the unexpected finding of analgesic activity with 1-(dimethylamino)-1-phenylcyclohexylamine, the SAR of the series was investigated. Synthesis starts by double Michael reaction of acrylate on arylacetonitriles. Following cyclization, decarboxylation, ketaliz...

The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in b-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the m-opioid receptor (MOR) to G proteins, but not b-arrestins, would result in higher analgesic efficacy, less...

We have examined the interaction between halothane and specific opioid agonists at mu (morphine and [D-ala2 N-mephe4, gly-ol5]-enkephalin (DAGO)), delta ([D-pen2,5]-enkephalin (DPDPE)) and kappa (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrroliknyl)cyclohexyl]- bencetamide methane sulphonate (U-50,488H)) receptors on the isolated right atria of the rat. All the opioid agonists tested decreased atria...

Working in a laboratory at the University of Michigan that was originally designed in the 1960s by Dr. Tomoji Yanagita, we have been evaluating opioid drugs for their ability to maintain behavior in rhesus monkeys. The animals are prepared with intravenous catheters that can be accessed from the outside of the cage. Inside the cage are two response levers and several stimulus lights. When one o...