title: Antinociceptive effects of imidazoline I2 receptor agonists in the formalin test in rats.
abstract: The imidazoline I2 receptor is an emerging drug target for analgesics. This study extended previous studies by examining the antinociceptive effects of three I2 receptor agonists (2-BFI, BU224, and CR4056) in the formalin test. The receptor mechanisms and anatomical mediation of I2 receptor agonist-induced antinociception were also examined. Formalin-induced flinching responses (2%, 50 μl) were quantified after treatment with I2 receptor agonists alone or in combination with the I2 receptor antagonist idazoxan. Anatomical mediation was studied by locally administering 2-BFI into the plantar surface or into the right lateral ventricle through cannulae (intracerebroventricular). The locomotor activity was also examined after central (intracerebroventricular) administration of 2-BFI. 2-BFI (1-10 mg/kg, intraperitoneal) and BU224 (1-10 mg/kg, intraperitoneal) attenuated the spontaneous flinching response observed during 10 min (phase 1) and 20-60 min (phase 2) following formalin treatment, whereas CR4056 (1-32 mg/kg, intraperitoneal) decreased only phase 2 flinching response. The I2 receptor antagonist idazoxan attenuated the antinociceptive effects of 2-BFI and BU224 during phase 1, but not phase 2. Peripheral administration of 2-BFI (1-10 mg/kg, intraplantar) to the hind paw of rats had no antinociceptive effect. In contrast, centrally delivered 2-BFI (10-100 µg, intracerebroventricular) dose-dependently attenuated phase 1 and phase 2 flinching at doses that did not reduce the locomotor activity. Together, these data revealed the differential antinociceptive effects of I2 receptor agonists and the differential antagonism profiles by idazoxan, suggesting the involvement of different I2 receptor subtypes in reducing different phases of formalin-induced pain-like behaviors. In addition, the results also suggest the central mediation of I2 receptor agonist-induced antinociceptive actions.
authors.affiliation: aDepartment of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York bDepartment of Anesthesiology, Yantai Affiliated Hospital, Binzhou Medical University, Binzhou, China cResearch Triangle Institute, Research Triangle Park, North Carolina, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Thorn
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qiu
authors.forename: Shushan
authors.initials: S
authors.lastname: Jia
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000819:agonists*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects; D008297:Male; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000700:Analgesics; C105826:BU 224; D001572:Benzofurans; C000596974:CR4056; D007093:Imidazoles; D054755:Imidazoline Receptors; D011799:Quinazolines; C487767:imidazoline receptor 2; C103723:2-(2-benzofuranyl)-2-imidazoline