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.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Nickerson-Nutter CL,Goodwin D,Shen MW,Damphousse C,Duan W,Samad TA,McKew JC,Lee KL,Zaleska MM,Mollova N,Clark JDdoi
10.1016/j.neuropharm.2010.11.025subject
Has Abstractpub_date
2011-03-01 00:00:00pages
633-41issue
4eissn
0028-3908issn
1873-7064pii
S0028-3908(10)00324-2journal_volume
60pub_type
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