Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects

Eur J Pharmacol. 2006 Dec 28;553(1-3):73-81. doi: 10.1016/j.ejphar.2006.09.031. Epub 2006 Sep 26.


Some studies, suggesting the involvement of I(2)-imidazoline binding sites (I(2)-IBS) in morphine analgesia modulation, prompted us to examine on mice antinociceptive assays the effect produced by 1 (phenyzoline), that in view of its high I(2)-IBS affinity and high I(2)-IBS selectivity with regard to I(1)-IBS, alpha(2)-adrenoreceptors and mu-opioid receptors might be considered the first interesting I(2)-IBS ligand. The study was also applied to its ortho phenyl derivative 2 (diphenyzoline), designed and prepared in order to produce a possible modification of the biological profile of 1. Diphenyzoline (2) retains a significant I(2)-IBS selectivity with regard to I(1)-IBS, alpha(2)-adrenoreceptors and mu-opioid receptors. Moreover, by the functional assays 1 and 2 proved inactive at all alpha(2)-adrenoreceptors subtypes up to 10(-3) M. As expected, phenyzoline and diphenyzoline, which are structurally related, highlighted an interesting "positive" or "negative", respectively, morphine analgesia modulatory effect. In fact, 1 (s.c. 10 mg/kg) enhanced morphine analgesia (60% and 40% in mouse tail-flick and mouse hot-plate, respectively), while 2 (s.c. 10 mg/kg) decreased it (-41% and -20%, respectively). The ability to decrease morphine analgesia had never been observed before in I(2)-IBS ligands. These effects were not affected by i.p. treatment of animals with yohimbine (a selective alpha(2)-adrenoreceptor antagonist, 0.625 mg/kg) or efaroxan (an I(1)-IBS/alpha(2)-adrenoreceptor antagonist, 1.0 mg/kg). In contrast, they were completely reversed by i.p. treatment of animals with idazoxan (an I(2)-IBS/alpha(2)-adrenoreceptor antagonist, 2 mg/kg). Moreover, compound 2, in mouse tail-flick test, was able to potentiate by 23% the naloxone-induced decrease of morphine analgesia. Therefore, the results of this study indicate the crucial involvement of I(2)-IBS in the morphine analgesia modulatory effects of 1 and 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / pharmacology
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Benzofurans / pharmacology
  • CHO Cells
  • Cricetinae
  • Idazoxan / chemistry
  • Idazoxan / pharmacology
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Imidazoline Receptors
  • Male
  • Mice
  • Models, Molecular
  • Morphine / pharmacology*
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain Measurement / drug effects
  • Radioligand Assay
  • Reaction Time / drug effects
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Drug / chemistry
  • Receptors, Drug / drug effects
  • Receptors, Drug / metabolism*
  • Receptors, Opioid, mu / drug effects
  • Yohimbine / pharmacology


  • Adrenergic alpha-Antagonists
  • Analgesics, Opioid
  • Benzofurans
  • Imidazoles
  • Imidazoline Receptors
  • Narcotic Antagonists
  • Receptors, Adrenergic, alpha-2
  • Receptors, Drug
  • Receptors, Opioid, mu
  • imidazoline receptor 2
  • Yohimbine
  • Naloxone
  • tracizoline
  • Morphine
  • efaroxan
  • Idazoxan