title: The cPLA2α inhibitor efipladib decreases nociceptive responses without affecting PGE2 levels in the cerebral spinal fluid.
abstract: The contribution of central PGE(2) levels to the nociceptive response in rats was assessed and the effects of the selective cPLA(2)α inhibitor efipladib, and pain therapies of different classes on these responses was determined. An inflammatory pain model was optimized in rats so that PGE(2) levels in the cerebrospinal fluid (CSF) could be directly correlated to the nociceptive response. Since efipladib appears to have limited permeation of the blood-brain barrier, we used this compound to determine the extent of pain reversal resulting primarily from peripheral, but not central, inhibition of the arachidonic acid (AA) pathway. The nociceptive response was significantly inhibited by orally administered efipladib, yet spinal fluid levels of PGE(2) and temperature measurements were unaffected compared to vehicle-treated animals. Conversely, intrathecal (IT) administration of efipladib reduced PGE(2) levels in the CSF by 45-60%, yet there was no effect on the nociceptive response. With COX-2 selective inhibitors and ibuprofen, a return of the nociceptive response developed over time, despite complete inhibition of PGE(2) in the spinal fluid. The opposite was true with low doses of indomethacin: inhibition of the nociceptive response was observed despite the lack of effect on central PGE(2) levels. Our results demonstrate that levels of PGE(2) in the spinal fluid do not directly correlate with the nociceptive response and that blocking cPLA(2)α in the periphery significantly decreases inflammatory pain.
authors.affiliation: Department of Inflammation and Immunology, Pfizer, Cambridge, MA 02140, USA. cheryl.nickerson-nutter@pfizer.com
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Nickerson-Nutter
authors.forename: Debra
authors.initials: D
authors.lastname: Goodwin
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: Christy
authors.initials: C
authors.lastname: Damphousse
authors.forename: Weili
authors.initials: W
authors.lastname: Duan
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Samad
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lee
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: Nevena
authors.initials: N
authors.lastname: Mollova
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000134:cerebrospinal fluid*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D008297:Male; D010146:Pain / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; D054513:Group IV Phospholipases A2; D015232:Dinoprostone; C531068:efipladib