Stereoselective mu- and delta-opioid receptor-related antinociception and binding with (+)-thebaine.
In vivo and in vitro binding studies with natural thebaine and its enantiomer, (+)-thebaine were conducted to elucidate further their interactions with the opioid system. (-)-Thebaine a key intermediate in the biosynthesis of morphine in the poppy plant (Papaver somniferum) and in mammalian tissue, was poorly effective antinociceptively in mice at doses to 30 mg/kg. Its principal behavioral manifestation was lethal convulsions. Naltrindole, at doses of 1 and 10 mg/kg did not block either the convulsions or lethal effects, suggesting that the delta-opioid receptor system was not involved in this action. Surprisingly, the dextrorotatory isomer exhibited significant antinociceptive 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-funaltrexamine, nor-binaltorphimine and naltrindole, indicated that antinociception was associated with mu- and delta-opioid receptors. Results of displacement experiments supported the in vivo data. Significant competition for [3H]diprenorphine binding with both isomers for cloned mu- and delta-opioid receptors was observed. However, (-)-thebaine was more effective at the delta-opioid receptor (Ki = 1.02+/-0.01 microM) whereas (+)-thebaine was more effective at the mu-opioid receptor ( Ki = 2.75+/-0.01 microM). Opioid-induced antinociception associated with unnatural thebaine raises the possibility of additional mu- and delta-opioid receptor sites.
Aceto
M D
MD
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth Univeristy, Richmond 23298-0613, USA. maceto@hsc.vcu.edu
Harris
L S
LS
Abood
M E
ME
Rice
K C
KC
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D004827:Epilepsy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods*; D011957:Receptors, Opioid / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology; D013237:Stereoisomerism; D013797:Thebaine / Q000378:metabolism* / Q000494:pharmacology