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NEUROPHARMACOLOGY

Antinociception Produced by 14,15-Epoxyeicosatrienoic Acid Is Mediated by the Activation of β-Endorphin and Met-Enkephalin in the Rat Ventrolateral Periaqueductal Gray

Department of Physiology, Cardiovascular Research Center (M.T., J.N., L.M.H., D.R.H.) and Department of Anesthesiology (L.F.T., H.W., P.F.P.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Department of Biochemistry, University of Texas Southwestern Medical Center (J.R.F.), Dallas, Texas

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 (-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 -opioid receptor antagonist naltrindole but not with dynorphin A[1–17] antiserum or the -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 -opioid receptors and 2) 14,15-EET activates β-endorphin and Met-enkephalin, which subsequently act on µ-and -opioid receptors to produce antinociception.

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