Thienorphine: receptor binding and behavioral effects in rhesus monkeys

Thienorphine is an oripavine with long-lasting antinociceptive effects in mice that are thought to be mediated by mu-opioid receptors. This study examined the receptor binding of thienorphine in cell membrane homogenates and its behavioral effects in rhesus monkeys (Macaca mulatta). Affinity and potency were determined using radioligand displacement and stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding in C6 (mu, delta) and Chinese hamster ovary (kappa) cell membranes. Thienorphine displayed high affinity for kappa-, mu-, and delta-opioid receptors with K(i) values of 0.14, 0.22, and 0.69 nM, respectively. Thienorphine partially stimulated kappa-opioid (75%) and mu-opioid (19%) receptors and not delta-opioid receptors. Thienorphine dose-dependently increased tail-withdrawal latency for 50 degrees C water and not 55 degrees C water with effects lasting for more than 7 days. The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (3.2 mg/kg) and a large dose (1.0 mg/kg) of naltrexone prevented thienorphine-induced antinociception. Thienorphine enhanced the antinociceptive effects of morphine and U50,488 [trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide] with 50 degrees C water; with 55 degrees C water, thienorphine enhanced the effects of morphine and attenuated the effects of U50,488. In other monkeys, thienorphine decreased responding in both components of a multiple schedule of food presentation and stimulus shock termination for up to 8 days; naltrexone and nor-BNI partially prevented these rate-decreasing effects. In morphine-treated monkeys discriminating naltrexone, thienorphine, and U50,488 neither substituted for nor modified the naltrexone discriminative stimulus. Thienorphine and U50,488 produced the same directly observable signs. These results show that thienorphine has long-lasting effects that seem to be mediated by low-efficacy agonism at kappa-opioid receptors, both in vitro and in vivo.