that antinociception could occur to noxious levels of stimulation. Moreover, AM1241 does suppress mechanical hypersensitivity to von Frey stimulation under conditions of injury, during which mechanical thresholds are lowered relative to baseline. Coadministration Celecoxib Celebra of rimonabant with AM1241 increased mechanical paw withdrawal thresholds. Celecoxib Celebra This observation parallels our recent finding of antiallodynia in paclitaxel treated animals that received rimonabant prior to administration of the CB2 agonist AM1714. Enhanced efficacy of a CB2 agonist following administration of a CB1 antagonist has also been reported in a cerebral ischemic injury model.
These data suggest that blockade of CB1 receptors with rimonabant may enhance the tone of the endogenous cannabinoid system, Celecoxib Inflammation thereby increasing the efficacy of the CB2 agonist.
Antinociceptive properties of the enantiomers of Celecoxib Inflammation AM1241 have not previously been evaluated in naive rats. This characterization is important because of the widespread use of AM1241 as a tool to study functional roles of CB2 receptor activation. Antihyperalgesic effects of AM1241 were previously reported in a visceral and inflammatory pain model. In our study, AM1241 presented a pharmacological profile which was nearly identical to racemic AM1241. We observed an inverted U shaped dose response curve following administration of either AM1241 or AM1241 at the time point of maximal antinociception.
Our data also illustrate that both the lowest and the highest doses of AM1241 produced greater antinociception than comparable doses of either AM1241 or AM1241.
At intermediate doses, the compounds produced similar antinociceptive effects. Previous in vitro work with the enantiomers noted that and AM1241 are inverse agonists for rat CB2 receptors in the cyclase assay, whereas AM1241 is a full agonist. Thus, it is possible that agonist activity in the cyclase assay predicts the antinociceptive efficacy of AM1241, thereby reconciling the in vivo observations with results from in vitro receptor binding assays. Both and AM1241 produced thermal antinociception that outlasted that of AM1241 at an identical dose.
This observation may be attributed to the combination of inverse agonist as well as agonist properties of the racemic compound. Differences in metabolic transformation of and AM1241 may also contribute to differences in in vivo efficacy of these enantiomers.
Although AM1241 was suggested to be the more active enantiomer in vivo in suppressing acute visceral and inflammatory pain, this observation may be dose dependent. In a chemotherapy model of neuropathic pain, AM1241, but not AM1241, was effective in suppressing neuropathic nociception when a high dose of AM1241 and AM1241 were evaluated. It is important to note that a high dose of AM1241 produced seizure like effects in two of the eight animals tested in our study, effects not observed with either AM1241 or AM1241. AM1241 was previously tested in a chemotherapy model of neuropathic pain and no similar side effects were observed. In addition, AM1241 was utilized by Bingham and colleagues in visceral and inflammatory pain models, and no similar effects were reported. These latter effects are, therefore, almost certainly due to off target binding. To our k