PMID- 19028872
OWN - NLM
STAT- MEDLINE
DCOM- 20090105
LR  - 20220310
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 105
IP  - 48
DP  - 2008 Dec 2
TI  - Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct 
      analgesic pathways.
PG  - 18901-6
LID - 10.1073/pnas.0809765105 [doi]
AB  - During inflammation, a large amount of arachidonic acid (AA) is released into the 
      cellular milieu and cyclooxygenase enzymes convert this AA to prostaglandins that 
      in turn sensitize pain pathways. However, AA is also converted to natural 
      epoxyeicosatrienoic acids (EETs) by cytochrome P450 enzymes. EET levels are 
      typically regulated by soluble epoxide hydrolase (sEH), the major enzyme 
      degrading EETs. Here we demonstrate that EETs or inhibition of sEH lead to 
      antihyperalgesia by at least 2 spinal mechanisms, first by repressing the 
      induction of the COX2 gene and second by rapidly up-regulating an acute 
      neurosteroid-producing gene, StARD1, which requires the synchronized presence of 
      elevated cAMP and EET levels. The analgesic activities of neurosteroids are well 
      known; however, here we describe a clear course toward augmenting the levels of 
      these molecules. Redirecting the flow of pronociceptive intracellular cAMP toward 
      up-regulation of StARD1 mRNA by concomitantly elevating EETs is a novel path to 
      accomplish pain relief in both inflammatory and neuropathic pain states.
FAU - Inceoglu, Bora
AU  - Inceoglu B
AD  - Department of Entomology and UC Davis Cancer Center, University of California, 
      Davis, CA 95616, USA.
FAU - Jinks, Steven L
AU  - Jinks SL
FAU - Ulu, Arzu
AU  - Ulu A
FAU - Hegedus, Christine M
AU  - Hegedus CM
FAU - Georgi, Katrin
AU  - Georgi K
FAU - Schmelzer, Kara R
AU  - Schmelzer KR
FAU - Wagner, Karen
AU  - Wagner K
FAU - Jones, Paul D
AU  - Jones PD
FAU - Morisseau, Christophe
AU  - Morisseau C
FAU - Hammock, Bruce D
AU  - Hammock BD
LA  - eng
GR  - R01 HL059699/HL/NHLBI NIH HHS/United States
GR  - HL 59699/HL/NHLBI NIH HHS/United States
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - P42 ES04699/ES/NIEHS NIH HHS/United States
GR  - GM 78167/GM/NIGMS NIH HHS/United States
GR  - R37 ES02710/ES/NIEHS NIH HHS/United States
GR  - R01 GM078167/GM/NIGMS NIH HHS/United States
GR  - R37 ES002710/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20081121
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Analgesics)
RN  - 0 (Eicosanoids)
RN  - 0 (Phosphoproteins)
RN  - 0 (steroidogenic acute regulatory protein)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Analgesics/*metabolism
MH  - Animals
MH  - Cyclic AMP/metabolism
MH  - Cyclooxygenase 2/genetics/metabolism
MH  - Eicosanoids/chemistry/*metabolism
MH  - Epoxide Hydrolases/antagonists & inhibitors/*metabolism
MH  - Gene Expression Regulation
MH  - Mice
MH  - Pain Measurement
MH  - Phosphoproteins/genetics/metabolism
MH  - Rats
MH  - Signal Transduction/*physiology
PMC - PMC2596245
COIS- Conflict of interest statement: B.D.H. founded Arete Therapeutics to move soluble 
      epoxide hydrolase inhibitors into the clinic. B.I., S.L.J., K.R.S., P.D.J., C.M., 
      and B.D.H. are authors on University of California patents in the area.
EDAT- 2008/11/26 09:00
MHDA- 2009/01/06 09:00
PMCR- 2009/06/02
CRDT- 2008/11/26 09:00
PHST- 2008/11/26 09:00 [pubmed]
PHST- 2009/01/06 09:00 [medline]
PHST- 2008/11/26 09:00 [entrez]
PHST- 2009/06/02 00:00 [pmc-release]
AID - 0809765105 [pii]
AID - 5625 [pii]
AID - 10.1073/pnas.0809765105 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18901-6. doi: 
      10.1073/pnas.0809765105. Epub 2008 Nov 21.