title: Brain P450 epoxygenase activity is required for the antinociceptive effects of improgan, a nonopioid analgesic.
abstract: The search for the mechanism of action of improgan (a nonopioid analgesic) led to the recent discovery of CC12, a compound that blocks improgan antinociception. Because CC12 is a cytochrome P450 inhibitor, and brain P450 mechanisms were recently shown to be required in opioid analgesic signaling, pharmacological and transgenic studies were performed in rodents to test the hypothesis that improgan antinociception requires brain P450 epoxygenase activity. Intracerebroventricular (i.c.v.) administration of the P450 inhibitors miconazole and fluconazole, and the arachidonic acid (AA) epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) potently inhibited improgan antinociception in rats at doses that were inactive alone. MW06-25, a new P450 inhibitor that combines chemical features of CC12 and miconazole, also potently blocked improgan antinociception. Although miconazole and CC12 were weakly active at opioid and histamine H(3) receptors, MW06-25 showed no activity at these sites, yet retained potent P450-inhibiting properties. The P450 hypothesis was also tested in Cpr(low) mice, a viable knock-in model with dramatically reduced brain P450 activity. Improgan (145 nmol, i.c.v.) antinociception was reduced by 37% to 59% in Cpr(low) mice, as compared with control mice. Moreover, CC12 pretreatment (200 nmol, i.c.v.) abolished improgan action (70% to 91%) in control mice, but had no significant effect in Cpr(low) mice. Thus, improgan's activation of bulbospinal nonopioid analgesic circuits requires brain P450 epoxygenase activity. A model is proposed in which (1) improgan activates an unknown receptor to trigger downstream P450 activity, and (2) brainstem epoxygenase activity is a point of convergence for opioid and nonopioid analgesic signaling.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, NY, USA Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, USA Curragh Chemistries, Valley View, OH, USA Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA Leiden/Amsterdam Center for Drug Research, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Hough
authors.forename: Julia W
authors.initials: JW
authors.lastname: Nalwalk
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Conroy
authors.forename: Melissa A
authors.initials: MA
authors.lastname: VanAlstine
authors.forename: Weizhu
authors.initials: W
authors.lastname: Yang
authors.forename: Joseph
authors.initials: J
authors.lastname: Gargano
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Shan
authors.forename: Shao-Zhong
authors.initials: SZ
authors.lastname: Zhang
authors.forename: Mark P
authors.initials: MP
authors.lastname: Wentland
authors.forename: James G
authors.initials: JG
authors.lastname: Phillips
authors.forename: Brian I
authors.initials: BI
authors.lastname: Knapp
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bidlack
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002461:Cell Line, Transformed; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008825:Miconazole / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency; D009271:Naltrexone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000493:pharmacokinetics; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D058888:14-alpha Demethylase Inhibitors; C521071:4(5)-((4-iodobenzyl)thiomethyl)-1H-imidazole; D000577:Amides; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007093:Imidazoles; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D009292:Narcotic Antagonists; D018100:Receptors, Histamine H3; C099531:SKF 92374; D013440:Sulfides; D014316:Tritium; D009271:Naltrexone; D008825:Miconazole; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase; C055382:naltrindole