title: Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated.
abstract: The role of central versus peripheral opioid receptors in mediating the aversive effects of opioids was examined by use of an unbiased place preference conditioning procedure in rats. The non-selective opioid antagonist naloxone (NLX) produced conditioned aversions for the drug-associated place after subcutaneous (SC) as well as intracerebroventricular (ICV) administration. Place aversions were also observed in response to the ICV administration of the selective mu-antagonist CTOP. In contrast, the selective delta-antagonist ICI 174,864 and the selective kappa-antagonist norbinaltorphimine (nor-BNI) (ICV) were without effect. Place aversions were also produced by central applications of the selective kappa-agonist U50,488H and the dynorphin derivative E-2078. For those opioid ligands tested, the doses required to produce place aversions were substantially lower following ICV as compared to SC administration. These data confirm that kappa-agonists and opioid antagonists produce aversive states in the drug-naive animal and demonstrate that this effect is centrally mediated. Furthermore, the ability of NLX and CTOP, in contrast to both ICI 174,864 and nor-BNI, to produce place aversions suggests that the aversive effects of opioid antagonists result from the blockade of mu-receptors.
authors.affiliation: Department of Neuropharmacology, Max Planck Institute for Psychiatry, Federal Republic of Germany.
authors.forename: R
authors.initials: R
authors.lastname: Bals-Kubik
authors.forename: A
authors.initials: A
authors.lastname: Herz
authors.forename: T S
authors.initials: TS
authors.lastname: Shippenberg
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D009294:Narcotics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D009270:Naloxone; C051844:norbinaltorphimine; D013004:Somatostatin; D004743:Enkephalin, Leucine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine