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

Research output: Contribution to journalArticle

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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 2008

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Endorphins
Methionine Enkephalin
Periaqueductal Gray
naltrindole
Opioid Receptors
Narcotic Antagonists
Tail
Immune Sera
Ligands
Dynorphins
14,15-epoxy-5,8,11-eicosatrienoic acid
Arachidonic Acid
Cytochrome P-450 Enzyme System
Sprague Dawley Rats
Acids
Membranes
Brain

ASJC Scopus subject areas

  • Pharmacology

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Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of β-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray. / Terashvili, Maia; Tseng, Leon F.; Wu, Hsiang En; Narayanan, Jayashree; Hart, Lucas M.; Falck, John R.; Pratt, Phillip F.; Harder, David R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 326, No. 2, 08.2008, p. 614-622.

Research output: Contribution to journalArticle

Terashvili, Maia ; Tseng, Leon F. ; Wu, Hsiang En ; Narayanan, Jayashree ; Hart, Lucas M. ; Falck, John R. ; Pratt, Phillip F. ; Harder, David R. / Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of β-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray. In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 326, No. 2. pp. 614-622.
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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.",
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AU - Terashvili, Maia

AU - Tseng, Leon F.

AU - Wu, Hsiang En

AU - Narayanan, Jayashree

AU - Hart, Lucas M.

AU - Falck, John R.

AU - Pratt, Phillip F.

AU - Harder, David R.

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N2 - 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.

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