2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and quadazocine

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 ligand beta-endorphin and the common mu agonist, morphine.. Among the ligands studied naltrexone, WIN 44,441 and SKF 10047, were classified as antagonists, while the remaining ligands were agonists. Agonist efficacy was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The rank order of efficacy of the agonists was fentanyl = hydromorphone = beta-endorphin > etorphine = lofentanil = butorphanol = morphine = nalbuphine = nalorphine > cyclazocine = dezocine = metazocine >or= xorphanol. The rank order of potency of these ligands was different from that of their efficacies; etorphine > hydromorphone > dezocine > xorphanol = nalorphine = butorphanol = lofentanil > metazocine > nalbuphine > cyclazocine > fentanyl > morphine >>>> beta-endorphin.. These results elucidate the relative activities of a set of opioid ligands at mu opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of opioid ligands at this receptor. Furthermore, these results can assist in understanding the physiological effect of many opioid ligands acting through mu opioid receptors.

Topics: Azocines; beta-Endorphin; Binding, Competitive; Butorphanol; Cell Line; Colforsin; Cyclic AMP; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Etorphine; Fentanyl; Humans; Hydromorphone; Ligands; Morphine; Naltrexone; Phenazocine; Radioligand Assay; Receptors, Opioid, mu; Tritium

The antinociception of opiates is mediated through the activation of opioid receptors in several mid brain and brain stem areas. This paper reports that the forebrain area termed area tempestas (AT), first identified as a convulsant trigger area, is also a component of the endogenous pain suppression system. Unilateral AT application of DAMGO, morphine and U-50,488H in rats at doses in the nanogram range produced marked and dose-dependent increases in the latency to respond to nociceptive stimuli. A lower effect is found after application of DPDPE and DADLE. Antinociception is more evident in the hot plate than in the tail flick test. In the former test, the effect was restricted to the paws contralateral to the hemisphere of injection. Unilateral AT application of naltrexone (4 ng) reduced in the contralateral paws the antinociceptive effect that the bilateral AT application of morphine (20 ng/hemisphere) had induced in both body sides. Unilateral application of naltrexone, (20 ng) ICI 154, 129 (20 ng) and Win 44,441-3 (8 ng) antagonized the antinociceptive effect elicited by the systemic injection of morphine (2.5 mg/kg s), DPDPE (20 mg/kg s) and U-50,488H (20 mg/kg s), respectively. In the hot plate test, the antagonism was found in the paws ipsilateral and contralateral to the hemisphere of injection of the antagonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anticonvulsants; Azocines; Bicuculline; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Escape Reaction; Foot; Hot Temperature; Male; Morphine; Naltrexone; Narcotic Antagonists; Olfactory Pathways; Pain; Phenazocine; Pressure; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid; Seizures; Tail

The effects of the administration of naloxone hydrochloride (NX) or WIN 44,441-3 (WIN), administered either alone or prior to the subsequent administration of the three prototypic multiple opiate receptor agonists morphine sulfate (MS), ethylketocyclazocine methanesulfonate (EKC) and N-allylnormetazocine hydrochloride (NANMT), on the release of anterior pituitary hormones were studied in the rat. Serum levels of corticosterone, growth hormone, prolactin and luteinizing hormone were measured by radioimmunoassay. The administration of WIN alone produced a pattern of hormone release similar to that seen following the administration of NX. Pretreatment with either NX or WIN blocked the MS-induced rise in serum levels of corticosterone whereas neither the EKC nor the NANMT-induced rises were blocked. Pretreatment with WIN blocked the EKC-induced rise in serum growth hormone but failed to block the MS-induced increase. Both antagonists blocked the rise in serum levels of prolactin induced by either MS or EKC but also blocked the NANMT-induced fall. The administration of either NX or WIN blocked the inhibition of luteinizing hormone release induced by either MS or NANMT and partially blocked the EKC-induced fall. The data indicate that multiple opiate receptors are involved in opiate-induced changes in anterior pituitary hormone release and suggest that the patterns of hormone release induced by various opiate agonists as well as their interaction with antagonists may be useful in classifying drugs with respect to their activity toward specific receptors.

Topics: Animals; Azocines; Corticosterone; Cyclazocine; Drug Interactions; Ethylketocyclazocine; Growth Hormone; Luteinizing Hormone; Male; Morphine; Naloxone; Narcotic Antagonists; Phenazocine; Pituitary Hormones, Anterior; Prolactin; Rats; Rats, Inbred Strains; Receptors, Opioid