Brain P450 epoxygenase activity is required for the antinociceptive effects of improgan, a nonopioid analgesic

Lindsay B. Hough, Julia W. Nalwalk, Jun Yang, Jennie L. Conroy, Melissa A. Vanalstine, Weizhu Yang, Joseph Gargano, Zhixing Shan, Shao Zhong Zhang, Mark P. Wentland, James G. Phillips, Brian I. Knapp, Jean M. Bidlack, Obbe P. Zuiderveld, Rob Leurs, Xinxin Ding

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 (ICV) 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 H3 receptors, MW06-25 showed no activity at these sites, yet retained potent P450-inhibiting properties. The P450 hypothesis was also tested in Cprlow mice, a viable knock-in model with dramatically reduced brain P450 activity. Improgan (145 nmol, ICV) antinociception was reduced by 37% to 59% in Cprlow mice, as compared with control mice. Moreover, CC12 pretreatment (200 nmol, ICV) abolished improgan action (70% to 91%) in control mice, but had no significant effect in Cprlow 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. The present study found that the nonopioid analgesic drug improgan utilizes cytochrome P450 epoxygenase enzymes in the brain to produce its pain-relieving actions.

Original languageEnglish (US)
Pages (from-to)878-887
Number of pages10
JournalPain
Volume152
Issue number4
DOIs
StatePublished - Apr 2011
Externally publishedYes

Keywords

  • Analgesia
  • Cytochrome P450
  • Improgan
  • Nonopioid
  • Opioid
  • Pain

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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