Stereoselective mu- and delta-opioid receptor-related antinociception and binding with (+)-thebaine

In vivo and in vitro binding studies with natural thebaine and its enantiom er, (+)-thebaine were conducted to elucidate further their interactions wit h the opioid system. (-)-Thebaine a key intermediate in the biosynthesis of morphine in the poppy plant (Papaver somnniferum) and in mammalian tissue, was poorly effective antinociceptively in mice at doses to 30 mg/kg. Its p rincipal behavioral manifestation was lethal convulsions. Naltrindole, at d oses of 1 and 10 mg/kg did not block either the convulsions or lethal effec ts, suggesting that the delta-opioid receptor system was not involved in th is action. Surprisingly, the dextrorotatory isomer exhibited significant an tinociceptive activity in the tail-flick [ED50 = 8.9 (3.4-22.1) mg/kg], hot -plate [ED50 = 22.9 (10.9-48.1) mg/kg] and phenylquinone [ED50 = 1.9 (1.6-9 .5) mg/kg] assays. Studies with opioid receptor-subtype antagonists, beta-f unaltrexamine, nor-binaltorphimine and naltrindole, indicated that antinoci ception was associated with mu- and delta-opioid receptors. Results of disp lacement experiments supported the in vivo data. Significant competition fo r [H-3]diprenorphine binding with both isomers for cloned mu- and delta-opi oid receptors was observed. However, (-)-thebaine was more effective at the delta-opioid receptor (K-i = 1.02+/-0.01 mu M) whereas (+)-thebaine was mo re effective at the mu-opioid receptor (K-i = 2.75+/-0.01 mu M). Opioid-ind uced antinociception associated with unnatural thebaine raises the possibil ity of additional mu- and delta-opioid receptor sites. (C) 1999 Elsevier Sc ience B.V. All rights reserved.