title: Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the μ-Opioid Receptor.
abstract: Although μ-opioids have been reported to interact favorably with imidazoline I2 receptor (I2R) ligands in animal models of chronic pain, the dependence on the μ-opioid receptor ligand efficacy on these interactions had not been previously investigated. This study systematically examined the interactions between the selective I2 receptor ligand 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) and three μ-opioid receptor ligands of varying efficacies: fentanyl (high efficacy), buprenorphine (medium-low efficacy), and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl) acetamido] morphine (NAQ; very low efficacy). The von Frey test of mechanical nociception and Hargreaves test of thermal nociception were used to examine the antihyperalgesic effects of drug combinations in complete Freund's adjuvant-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to examine the rate-suppressing effects of each drug combination. Dose-addition and isobolographical analyses were used to characterize the nature of drug-drug interactions in each assay. 2-BFI and fentanyl fully reversed both mechanical and thermal nociception, whereas buprenorphine significantly reversed thermal but only slightly reversed mechanical nociception. NAQ was ineffective in both nociception assays. When studied in combination with fentanyl, NAQ acted as a competitive antagonist (apparent pA2 value: 6.19). 2-BFI/fentanyl mixtures produced additive to infra-additive analgesic interactions, 2-BFI/buprenorphine mixtures produced supra-additive to infra-additive interactions, and 2-BFI/NAQ mixtures produced supra-additive to additive interactions in the nociception assays. The effects of all combinations on schedule-controlled responding were generally additive. Results consistent with these were found in experiments using female rats. These findings indicate that lower-efficacy μ-opioid receptor agonists may interact more favorably with I2R ligands than high-efficacy μ-opioid receptor agonists.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York (J.N.S., J.-X.L.); Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (S.O., Yan.Z.); and Research Triangle Institute, Research Triangle Park, North Carolina (Yanan.Z.).
authors.forename: Justin N
authors.initials: JN
authors.lastname: Siemian
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York (J.N.S., J.-X.L.); Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (S.O., Yan.Z.); and Research Triangle Institute, Research Triangle Park, North Carolina (Yanan.Z.).
authors.forename: Samuel
authors.initials: S
authors.lastname: Obeng
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York (J.N.S., J.-X.L.); Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (S.O., Yan.Z.); and Research Triangle Institute, Research Triangle Park, North Carolina (Yanan.Z.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York (J.N.S., J.-X.L.); Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (S.O., Yan.Z.); and Research Triangle Institute, Research Triangle Park, North Carolina (Yanan.Z.).
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York (J.N.S., J.-X.L.); Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (S.O., Yan.Z.); and Research Triangle Institute, Research Triangle Park, North Carolina (Yanan.Z.) junxuli@buffalo.edu.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000819:agonists*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D017450:Receptors, Opioid, mu; C487767:imidazoline receptor 2; C103723:2-(2-benzofuranyl)-2-imidazoline