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

Eur J Pharmacol. 1999 Jan 22;365(2-3):143-7. doi: 10.1016/s0014-2999(98)00862-0.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Binding, Competitive
  • Cells, Cultured
  • Epilepsy / physiopathology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain Measurement / methods*
  • Receptors, Opioid / physiology*
  • Receptors, Opioid, delta / physiology
  • Receptors, Opioid, mu / physiology
  • Stereoisomerism
  • Thebaine / metabolism*
  • Thebaine / pharmacology

Substances

  • Analgesics
  • Narcotic Antagonists
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Thebaine
  • norbinaltorphimine
  • Naltrexone
  • beta-funaltrexamine
  • naltrindole