The cPLA2α inhibitor efipladib decreases nociceptive responses without affecting PGE2 levels in the cerebral spinal fluid

The contribution of central PGE2 levels to the nociceptive response in rats was assessed and the effects of the selective cPLA2α inhibitor efipladib, and pain therapies of different classes on these responses was determined. An inflammatory pain model was optimized in rats so that PGE2 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 PGE2 and temperature measurements were unaffected compared to vehicle-treated animals. Conversely, intrathecal (IT) administration of efipladib reduced PGE2 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 PGE2 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 PGE2 levels. Our results demonstrate that levels of PGE2 in the spinal fluid do not directly correlate with the nociceptive response and that blocking cPLA2α in the periphery significantly decreases inflammatory pain.