PMID- 21316152 OWN - NLM STAT- MEDLINE DCOM- 20110726 LR - 20211020 IS - 1872-6623 (Electronic) IS - 0304-3959 (Print) IS - 0304-3959 (Linking) VI - 152 IP - 4 DP - 2011 Apr TI - Brain P450 epoxygenase activity is required for the antinociceptive effects of improgan, a nonopioid analgesic. PG - 878-887 LID - 10.1016/j.pain.2011.01.001 [doi] AB - 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. CI - Copyright (c) 2011 International Association for the Study of Pain. All rights reserved. FAU - Hough, Lindsay B AU - Hough LB AD - 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. FAU - Nalwalk, Julia W AU - Nalwalk JW FAU - Yang, Jun AU - Yang J FAU - Conroy, Jennie L AU - Conroy JL FAU - VanAlstine, Melissa A AU - VanAlstine MA FAU - Yang, Weizhu AU - Yang W FAU - Gargano, Joseph AU - Gargano J FAU - Shan, Zhixing AU - Shan Z FAU - Zhang, Shao-Zhong AU - Zhang SZ FAU - Wentland, Mark P AU - Wentland MP FAU - Phillips, James G AU - Phillips JG FAU - Knapp, Brian I AU - Knapp BI FAU - Bidlack, Jean M AU - Bidlack JM FAU - Zuiderveld, Obbe P AU - Zuiderveld OP FAU - Leurs, Rob AU - Leurs R FAU - Ding, Xinxin AU - Ding X LA - eng GR - DA03816/DA/NIDA NIH HHS/United States GR - DA00360/DA/NIDA NIH HHS/United States GR - R01 ES007462-15/ES/NIEHS NIH HHS/United States GR - ES07462/ES/NIEHS NIH HHS/United States GR - R01 DA027835/DA/NIDA NIH HHS/United States GR - K05 DA000360/DA/NIDA NIH HHS/United States GR - R01 DA003816/DA/NIDA NIH HHS/United States GR - K05 DA000360-10/DA/NIDA NIH HHS/United States GR - R01 DA003816-21/DA/NIDA NIH HHS/United States GR - R01 ES007462/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Pain JT - Pain JID - 7508686 RN - 0 (14-alpha Demethylase Inhibitors) RN - 0 (4(5)-((4-iodobenzyl)thiomethyl)-1H-imidazole) RN - 0 (Amides) RN - 0 (Analgesics, Non-Narcotic) RN - 0 (Analgesics, Opioid) RN - 0 (Enzyme Inhibitors) RN - 0 (Imidazoles) RN - 0 (N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide) RN - 0 (Narcotic Antagonists) RN - 0 (Receptors, Histamine H3) RN - 0 (SKF 92374) RN - 0 (Sulfides) RN - 10028-17-8 (Tritium) RN - 5S6W795CQM (Naltrexone) RN - 7NNO0D7S5M (Miconazole) RN - 80061L1WGD (Cimetidine) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase) RN - G167Z38QA4 (naltrindole) SB - IM MH - 14-alpha Demethylase Inhibitors/pharmacology MH - Amides/pharmacology MH - Analgesics, Non-Narcotic/*pharmacology MH - Analgesics, Opioid/pharmacokinetics MH - Animals MH - Brain/*drug effects/metabolism MH - Cell Line, Transformed MH - Cimetidine/*analogs & derivatives/pharmacology MH - Cytochrome P-450 Enzyme System/*metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/pharmacology MH - Gene Expression Regulation, Enzymologic/*drug effects MH - Humans MH - Imidazoles/pharmacology MH - Injections, Intraventricular/methods MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Miconazole/pharmacology MH - NADPH-Ferrihemoprotein Reductase/deficiency MH - Naltrexone/analogs & derivatives/pharmacokinetics MH - Narcotic Antagonists/pharmacokinetics MH - Pain Measurement/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Reaction Time/drug effects MH - Receptors, Histamine H3/metabolism MH - Sulfides/pharmacology MH - Time Factors MH - Tritium/pharmacokinetics PMC - PMC3065546 MID - NIHMS275635 EDAT- 2011/02/15 06:00 MHDA- 2011/07/27 06:00 PMCR- 2012/04/01 CRDT- 2011/02/15 06:00 PHST- 2010/02/23 00:00 [received] PHST- 2010/12/01 00:00 [revised] PHST- 2011/01/04 00:00 [accepted] PHST- 2011/02/15 06:00 [entrez] PHST- 2011/02/15 06:00 [pubmed] PHST- 2011/07/27 06:00 [medline] PHST- 2012/04/01 00:00 [pmc-release] AID - 00006396-201104000-00026 [pii] AID - 10.1016/j.pain.2011.01.001 [doi] PST - ppublish SO - Pain. 2011 Apr;152(4):878-887. doi: 10.1016/j.pain.2011.01.001.