title: Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gentili
authors.forename: Claudia
authors.initials: C
authors.lastname: Cardinaletti
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Ghelfi
authors.forename: Laura
authors.initials: L
authors.lastname: Mattioli
authors.forename: Marina
authors.initials: M
authors.lastname: Perfumi
authors.forename: Cristian
authors.initials: C
authors.lastname: Vesprini
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D019329:Idazoxan / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D054755:Imidazoline Receptors; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011869:Radioligand Assay; D011930:Reaction Time / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D011955:Receptors, Drug / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000701:Analgesics, Opioid; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D009292:Narcotic Antagonists; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D017450:Receptors, Opioid, mu; C487767:imidazoline receptor 2; D015016:Yohimbine; D009270:Naloxone; C107863:tracizoline; D009020:Morphine; C062597:efaroxan; D019329:Idazoxan