Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of β-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray

Maia Terashvili, Leon F. Tseng, Hsiang En Wu, Jayashree Narayanan, Lucas M. Hart, John R. Falck, Phillip F. Pratt, David R. Harder

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Abstract

Cytochrome P450 genes catalyze formation of epoxyeicosatrienoic acids (EETs) from arachidonic acid. The effects of 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET microinjected into the ventrolateral periaqueductal gray (vlPAG) on the thermally produced tail-flick response were studied in male Sprague-Dawley rats. 14,15-EET microinjected into vlPAG (3-156 pmol) dose-dependently inhibited the tail-flick response (ED50 = 32.5 pmol). In contrast, 5,6-EET, 8,9-EET, and 11,12-EET at a dose of 156 pmol were not active when injected into the vlPAG. 14,15-EET failed to displace the radiobinding of [ 3H][D-Ala2,NHPe4, Gly-ol5]enkephalin (μ-opioid receptor ligand) or [3H]naltrindole (δ-opioid receptor ligand) in crude membrane fractions of rat brain. Tail-flick inhibition produced by 14,15-EET from vlPAG was blocked by intra-vlPAG pretreatment with antiserum against β-endorphin or Met-enkephalin or the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) or the δ-opioid receptor antagonist naltrindole but not with dynorphin A[1-17] antiserum or the κ-opioid receptor antagonist nor-binaltorphimine. In addition, tail-flick inhibition produced by 14,15-EET treatment was blocked by intrathecal pretreatment with Met-enkephalin antiserum, naltrindole, or CTOP but not with β-endorphin antiserum. It is concluded that 1) 14,15-EET itself does not have any affinity for μ- or δ-opioid receptors and 2) 14,15-EET activates β-endorphin and Met-enkephalin, which subsequently act on μ-and δ-opioid receptors to produce antinociception.

Original languageEnglish (US)
Pages (from-to)614-622
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume326
Issue number2
DOIs
StatePublished - Aug 1 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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