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.