Comparison of the in vitro efficacy of μ, δ, κ and ORL1 receptor agonists and non-selective opioid agonists in dog brain membranes

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 μ-, δ- and κ-opioid receptors. In this work, the in vitro relative agonist efficacy of ligands selective for μ (DAMGO)-, δ (SNC80)- and κ (U69593)-opioid receptors as well as the opioid receptor-like receptor ORL1 (orphaninFQ/nociceptin) which may mediate nociceptive or antinociceptive actions was determined using the [35S]GTPγS 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]GTPγS binding decreased in the order κ > ORL1 > δ > μ in cortical homogenates, compared with μ > ORL1 > κ > δ 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]GTPγS binding between cortex and thalamus, with the exception of etorphine. Buprenorphine, the partial μ-opioid receptor agonist and κ-, δ-opioid receptor antagonist, which does have analgesic efficacy in the dog, showed no agonism in any tissue but was an effective μ-opioid receptor > ORL1 receptor antagonist. The results show that the ability of agonists to stimulate [35S]GTPγS binding relates to the receptor distribution of opioid and ORL1 receptors in the dog.