dministration . Baseline thermal paw withdrawal Camptothecin 7689-03-4 latencies did not differ between groups, therefore, baselines in the log dose response plots were averaged across all doses Camptothecin 7689-03-4 of the same drug for statistical analyses. Moreover, thermal paw withdrawal latencies and mechanical withdrawal thresholds did not differ based upon the order of thermal and mechanical testing at baseline, therefore, the two vehicle groups are combined for all studies presented. AM1241 induced seizure like activity in two animals tested. No other animals tested with AM1241 at this or lower doses showed evidence of similar symptoms.
Responses to Mechanical Stimulation Systemic administration of morphine increased paw withdrawal thresholds to von Frey stimulation relative to baseline preinjection thresholds.
By contrast, neither AM1241 nor AM1241 nor AM1241 altered mechanical withdrawal thresholds relative to either baseline or vehicle treatment at the same postinjection time point. Naloxone treatment completely buy Camptothecin blocked morphine induced antinociception to mechanical stimulation. However, naloxone, administered either locally buy Camptothecin or systemically, did not alter paw withdrawal thresholds when administered either alone or in combination with CB2 specific agonists relative to either baseline thresholds or vehicle treatment. Cannabinoid antagonist coadministration did not alter mechanical withdrawal thresholds in any study, with one exception.
Coadministration of rimonabant with AM1241 increased paw withdrawal thresholds relative to the vehicle condition, all other drug conditions, and baseline thresholds.
The Aminoalkylindole AM1241 and its Enantiomers AM1241 increased thermal paw withdrawal latencies relative to vehicle treatment at 30 min postinjection. AM1241 also increased paw withdrawal latencies relative to baseline at this time point. An inverted U shaped dose response curve was observed at the time point of maximal antinociception, AM1241 produced greater antinociception than either the two lowest or the highest doses. The entire dose range of AM1241 increased thermal paw withdrawal latencies relative to the vehicle condition at 30 min postinjection.
All doses of AM1241 also produced antinociception relative to baseline measurements. AM1241 increased thermal paw withdrawal latencies relative to vehicle at 30 min postinjection.
AM1241 also produced thermal antinociception relative to baseline at this time point. AM1241 and Its Enantiomers Comparisons were made between the antinociceptive effects of racemic AM1241 and the enantiomers and AM1241 across the entire dose range. At the time point of maximal antinociception, differences in the magnitude of antinociception, relative to baseline, were noted between groups. Planned comparisons at this time point revealed that the lowest doses of AM1241 produced greater antinociception than either AM1241 or AM1241 at the same doses. The highest dose of AM1241 also produced greater antinociception relative to the same dose of AM1241. Comparisons were subsequently made between the antinociceptive effects of AM1241, AM1241, and AM1241, relative to the DMSO control condition, across the full 120 min time course. The lowest, middle, and highest doses were selected for comparison. AM1241 produced antinociception relative