also CCT128930 CCT128930 885499-61-6 885499-61-6 effects of a higher, more efficacious dose of AM1241 relative to the vehicle condition. Under these conditions, naloxone did not alter paw withdrawal latencies in either the injected or noninjected paw relative to animals that received local injections of saline. Systemic administration of naloxone blocked thermal antinociception produced by morphine at 30 min postinjection, whereas naloxone alone did not alter paw withdrawal latencies. Morphine produced an antinociceptive effect at 120 min postinjection relative to both vehicle treatment and baseline preinjection thresholds. However, systemic naloxone failed to block these observed antinociceptive effects, suggesting that the duration of action of naloxone blockade was less than 2 h.
Data presented in Fig.
6 are consequently restricted to the 30 min time point. Naloxone, administered at buy CCT128930 buy CCT128930 a dose that completely blocked the antinociceptive effects of morphine in the same test, failed to block thermal antinociception produced by either AM1241, AM1241, or AM1241. Racemic AM1241 produces antinociception in the plantar test when administered systemically. In our study, AM1241 induced antinociception formed an inverted U shaped dose response curve at 30 min postinjection, lower and higher doses of the drug were less effective at producing antinociception than a dose of 1 mg/kg i.p.
Previous reports of AM1241 induced antinociception did not test higher doses of AM1241 in the plantar test and therefore did not observe this loss of efficacy.
However, the inverted U shaped dose response curve could potentially account for conflicting reports of AM1241,s limited antihyperalgesic efficacy. Previous work by our lab demonstrated that AM1241 was effective at suppressing neuropathic pain induced by administration of the chemotherapeutic agent paclitaxel, whereas a lower dose failed to produce an effect. Thus, it appears that drug efficacy and potency could also be influenced by the receptor state of the animal. As expected, the antinociceptive effects of AM1241 observed in our study were clearly CB2 mediated, these effects were blocked by the CB2 antagonist SR144528 but not by the CB1 antagonist rimonabant.
This observation is consistent with previous demonstrations of CB2 mediated antihyperalgesic effects produced by AM1241 in animal models of persistent, inflammatory, and neuropathic pain.
In contrast to the thermal antinociceptive effects of the CB2 agonists observed here in the plantar test, none of the aminoalkylindoles produced an antinociceptive effect to nonnoxious mechanical stimulation, assessed using a highly sensitive electrovonfrey device. This observation is in marked contrast to the opioid analgesic morphine, which produced reliable, naloxone sensitive antinociception to mechanical stimulation at the same postinjection time point. Our failure to observe a change in the basal mechanical threshold following administration of either AM1241 or its enantiomers in this test is unlikely to be attributed to selection of an inadequate postinjection time point for evaluation. Malan and colleagues reported robust CB2 mediated antinociception to thermal stimulation following systemic administration of AM1241 at 15 min postinjection. However, our results do not p