Role of intracellular Ca2+ signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I2 receptor agonist 2-BFI in rats.

Abstract

Recent research has established the imidazoline I2 receptor as a promising target for the development of novel analgesics. However, despite an increasing understanding of imidazoline I2 receptor-mediated behavioral effects, little is known about post-I2-receptor signaling mechanisms. This study examined the effects of several inhibitors of Ca2+ signaling mechanisms on two behavioral effects of the prototypical imidazoline I2 receptor ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI). The von Frey filament test was used to examine the antinociceptive effects of 2-BFI in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6mg/kg (intraperitoneally) 2-BFI from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. The L-type Ca2+ channel blockers verapamil and nimodipine, the calmodulin antagonist W-7, and the internal Ca2+ release inhibitor ryanodine all attenuated the antinociceptive effects of 2-BFI. Oxycodone- and acetaminophen-induced antinociception was unaffected by pretreatment with the Ca2+ channel blockers. Rats learned to reliably discriminate 5.6mg/kg 2-BFI from saline. The I2 receptor agonists BU224, RS45041, tracizoline, and CR4056 all fully substituted for 5.6mg/kg 2-BFI while idazoxan, S22687, 2,5-dimethoxy-4-methylamphetamine (DOM), and phenyzoline produced partial or no substitution. Verapamil, nimodipine, and W-7 did not alter the discriminative stimulus effects of 2-BFI. These results indicate that the antinociceptive effects of 2-BFI involve intracellular Ca2+ elevation and/or downstream Ca2+/calmodulin signaling, whereas the discriminative stimulus effects of 2-BFI are mediated by a distinct, independent mechanism.