title: Comparison of the in vitro efficacy of mu, delta, kappa and ORL1 receptor agonists and non-selective opioid agonists in dog brain membranes.
abstract: Morphine and related opioid agonists are frequently used in dogs for their analgesic properties, their sedative effects and as adjuncts to anesthesia. Such compounds may be effective through a combined action at mu-, delta- and kappa-opioid receptors. In this work, the in vitro relative agonist efficacy of ligands selective for mu (DAMGO)-, delta (SNC80)- and kappa (U69593)-opioid receptors as well as the opioid receptor-like receptor ORL(1) (orphaninFQ/nociceptin) which may mediate nociceptive or antinociceptive actions was determined using the [35S]GTPgammaS binding assay in membrane homogenates from the frontal cortex, thalamus and spinal cord of beagle dogs. In addition, other analgesics commonly used in the dog were investigated. For the receptor-selective compounds, maximum stimulation of [35S]GTPgammaS binding decreased in the order kappa > ORL1 > delta > mu in cortical homogenates, compared with mu > ORL1 > kappa > delta in thalamic and spinal cord homogenates. For other opioids examined, efficacy decreased in the order etorphine >> morphine > fentanyl = oxymorphine > butorphanol = oxycodone = nalbuphine. There was no significant difference in the potency of compounds to stimulate [35S]GTPgammaS binding between cortex and thalamus, with the exception of etorphine. Buprenorphine, the partial mu-opioid receptor agonist and kappa-, delta-opioid receptor antagonist, which does have analgesic efficacy in the dog, showed no agonism in any tissue but was an effective mu-opioid receptor > ORL1 receptor antagonist. The results show that the ability of agonists to stimulate [35S]GTPgammaS binding relates to the receptor distribution of opioid and ORL1 receptors in the dog.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lester
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D002462:Cell Membrane / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D011868:Radioisotopes / Q000493:pharmacokinetics; D011869:Radioligand Assay / Q000379:methods; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D011868:Radioisotopes; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)