Thus far, our data suggest a role for COX in LPS-induced changes in burrowing and open-field activity. To investigate the role of the different isoforms of COX we next compared the effect of
selective COX-1 and COX-2 inhibitors on LPS-induced behaviour changes. Fig. 5 shows the changes in burrowing tested 1–3 h after injection of LPS. Administration of LPS alone significantly decreased burrowing (Fig. 5, F(5,25) = 4.851, p = 0.0046) and mice pre-treated with the COX-1 selective inhibitors piroxicam and sulindac no longer differed from saline-treated mice. In contrast, pre-treatment with the selective COX-2 inhibitor nimesulide or niflumic acid had no effect and mice were still significantly impaired in the burrowing task. We next tested the effect of the inhibitors at CYC202 price various time points after injection of LPS to investigate the possibility that LPS-induced burrowing and open-field activity are differentially regulated over time as was previously reported for other behaviours (Swiergiel and Dunn, 2002). Fig. 6 shows the effect of LPS on burrowing and open-field activity at 2–4, 5–7 and 24 h after injection of LPS in mice pre-treated with the COX-1 specific inhibitor piroxicam or the COX-2 specific Selleckchem Ganetespib inhibitor nimesulide. The anti-inflammatory drugs were suspended in the same vehicle and given 30 min prior
to LPS. Administration of LPS significantly reduced burrowing at all time points tested. Piroxicam significantly reversed the effect of LPS on burrowing when tested between 2 and 4 h (Fig. 6, F(1,12) = 36.91, p < 0.0001). At later time points piroxicam was no longer protective, which may be explained by the short half life of drug in mice (T1/2 = 1.7 h) ( Milne and Twomey, 1980). Nimesulide (T1/2 = 2–3 h) ( Hull et al., 2005) did not significantly reverse the LPS-induced changes in burrowing at any time point tested ( Fig. 6). Similar results were observed for open-field activity: a clear trend towards protection of piroxicam at 2–4 h which disappeared at later time points. Pre-treatment
with the (-)-p-Bromotetramisole Oxalate drugs alone did not have an effect on burrowing or open-field activity. Interestingly, mice pre-treated with the COX-2 inhibitor appeared to recover better 24 h after LPS injection, compared to LPS-treated only or piroxicam pre-treated mice. The changes did not, however, reach significance. These results suggest that LPS-induced changes in burrowing and open-field activity between 2 and 4 h are largely mediated by COX-1 activity and show a minimal role for COX-2. Having established a key role of COX-1 in LPS-induced changes in burrowing and open-field activity, we next investigated the effect of piroxicam and nimesulide on cytokine and PG production. LPS increased serum IL-6 levels measured 3 h post challenge (Fig. 7A, F(3,16) = 5.893, p = 0.0091). Pre-treatment with piroxicam or nimesulide did not affect the serum levels of IL-6.