Justin N Siemian1, Yanyan Qiu1, Yanan Zhang2, Jun-Xu Li3. 1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. 2. Research Triangle Institute, Research Triangle Park, Durham, NC, USA. 3. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. junxuli@buffalo.edu.
Abstract
RATIONALE: 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. OBJECTIVE: 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). METHODS: 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 5.6 mg/kg (intraperitoneally) 2-BFI from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. RESULTS: 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 5.6 mg/kg 2-BFI from saline. The I2 receptor agonists BU224, RS45041, tracizoline, and CR4056 all fully substituted for 5.6 mg/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. CONCLUSION: 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.
RATIONALE: 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. OBJECTIVE: 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). METHODS: 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 5.6 mg/kg (intraperitoneally) 2-BFI from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. RESULTS: 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 5.6 mg/kg 2-BFI from saline. The I2 receptor agonists BU224, RS45041, tracizoline, and CR4056 all fully substituted for 5.6 mg/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. CONCLUSION: 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.
Authors: M Pigini; P Bousquet; A Carotti; M Dontenwill; M Giannella; R Moriconi; A Piergentili; W Quaglia; S K Tayebati; L Brasili Journal: Bioorg Med Chem Date: 1997-05 Impact factor: 3.641
Authors: C M Brown; A C MacKinnon; W S Redfern; A Williams; C Linton; M Stewart; R U Clague; R Clark; M Spedding Journal: Br J Pharmacol Date: 1995-09 Impact factor: 8.739