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Oxidized linoleic acid metabolite–cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain

Ruparel, Shivania,*; Hargreaves, Kenneth M.a,c; Eskander, Michaelc; Rowan, Spencera; de Almeida, Jose F.A.a; Roman, Lindab; Henry, Michael A.a

doi: 10.1016/j.pain.2013.07.011
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Summary The oxidized metabolites of linoleic acid (OLAM)-cytochrome P450 machinery may play a role in activating peripheral pain pathways even in human tissues such as the dental pulp under inflammatory conditions, thereby suggesting a novel strategy of targeting the OLAMs to inhibit inflammatory pain conditions.

Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [eg, cytochrome P450 (CYP)] are up-regulated after inflammation in the rat. However, it is not known whether such agonists are elevated in human inflammatory pain conditions. Because TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal vs inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues evoked significant inward currents in trigeminal ganglia neurons and were blocked by pretreatment with the TRPV1 antagonist IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in trigeminal ganglia neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of 2 CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicate that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.

aDepartment of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

bDepartment of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

cDepartment of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

*Corresponding author. Address: Department of Endodontics, Mail Code 7892, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. Tel.: +1 210 567 6668; fax: +1 210 567 3389.

E-mail: ruparels@uthscsa.edu

Submitted April 22, 2013; revised June 26, 2013; accepted July 10, 2013.

© 2013 Lippincott Williams & Wilkins, Inc.
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