Antinociceptive effects of imidazoline I-2 receptor agonists in the formalin test in rats
The imidazoline I-2 receptor is an emerging drug target for analgesics. This study extended previous studies by examining the antinociceptive effects of three I-2 receptor agonists (2-BFI, BU224, and CR4056) in the formalin test. The receptor mechanisms and anatomical mediation of I-2 receptor agonist-induced antinociception were also examined. Formalin-induced flinching responses (2%, 50 mu l) were quantified after treatment with I-2 receptor agonists alone or in combination with the I-2 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 I-2 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 mu g, 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 I-2 receptor agonists and the differential antagonism profiles by idazoxan, suggesting the involvement of different I-2 receptor subtypes in reducing different phases of formalin-induced pain-like behaviors. In addition, the results also suggest the central mediation of I-2 receptor agonist-induced antinociceptive actions. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.