title: Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation.
abstract: Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete Freund's adjuvant injection. To determine the ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of morphine tolerance, showing different potency and duration of action. Indeed, the selective imidazoline I2 receptor interaction (2) restored the analgesic response by maintaining the same time-dependent profile observed after a single morphine administration. Differently, the selective α2C-adrenoceptor activation (1) or the combination between α2C-adrenoceptor activation and imidazoline I2 receptor engagement (3) promoted a change in the temporal profile of morphine analgesia by maintaining a mild but long lasting analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance. Based on these observations, 1-3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by opioids.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Caprioli
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ricciutelli
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sagratini
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032 Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032 Camerino, Italy.
authors.forename: Esi
authors.initials: E
authors.lastname: Domi
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sabatini
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Galimberti
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy; PhD program in Neuroscience, University of Milan-Bicocca, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Milia
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy; PhD program in Neuroscience, University of Milan-Bicocca, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Comi
authors.affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., 20900 Monza, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lanza
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy. Electronic address: fabio.delbello@unicam.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
mesh_terms: D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D054755:Imidazoline Receptors / Q000378:metabolism; D048288:Imidazolines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism
chemical_list: D054755:Imidazoline Receptors; D048288:Imidazolines; D018341:Receptors, Adrenergic, alpha-2; C487767:imidazoline receptor 2; D009020:Morphine
keywords: 1. allyphenyline (PubChem CID 24906198); 2. (PubChem CID 3086491); 3. (PubChem CID 44269006); Bioavailability; Imidazoline I(2) receptors; Inflammatory pain; Morphine tolerance; morphine (PubChem CID 5288826); α(2)-adrenoceptors