Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of beta-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray. J Pharmacol Exp Ther 2008 Aug;326(2):614-22
Date
05/22/2008Pubmed ID
18492947Pubmed Central ID
PMC2567871DOI
10.1124/jpet.108.136739Scopus ID
2-s2.0-47949133301 (requires institutional sign-in at Scopus site) 83 CitationsAbstract
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 (mu-opioid receptor ligand) or [3H]naltrindole (delta-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 beta-endorphin or Met-enkephalin or the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) or the delta-opioid receptor antagonist naltrindole but not with dynorphin A[1-17] antiserum or the kappa-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 beta-endorphin antiserum. It is concluded that 1) 14,15-EET itself does not have any affinity for mu- or delta-opioid receptors and 2) 14,15-EET activates beta-endorphin and Met-enkephalin, which subsequently act on mu- and delta-opioid receptors to produce antinociception.
Author List
Terashvili M, Tseng LF, Wu HE, Narayanan J, Hart LM, Falck JR, Pratt PF, Harder DRMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAnalgesics
Animals
Dose-Response Relationship, Drug
Enkephalin, Methionine
Male
Microinjections
Pain Measurement
Periaqueductal Gray
Rats
Rats, Sprague-Dawley
Reaction Time
beta-Endorphin
