. Due to the inverted U shaped dose response curve observed for AM1241 induced antinociception, this high dose, in naive rats, might be expected to produce CHIR-124 CHIR-124 405168-58-3 405168-58-3 effects comparable to 0.1 or 10 mg/kg i.p. and be less efficacious at inducing antinociception compared to doses of 1 or 5 mg/kg. Moreover, it is also unclear whether this high dose is associated with off target activity as neither study demonstrated that effects of AM1241 were CB2 mediated. In our hands, systemic naloxone completely blocked the antinociceptive effects of systemic morphine in the plantar test. However, the same dose of naloxone, administered systemically, failed to block the antinociceptive effects of racemic AM1241 or either of its enantiomers.

Our studies suggest that activation of opioid receptors is not sufficient to account for the antinociceptive effects of either AM1241, buy CHIR-124 AM1241, or AM1241 in naive buy CHIR-124 animals. The aminoalkylindole AM1241 and its enantiomers AM1241 and AM1241 all produce CB2 mediated antinociception that is insensitive to blockade by naloxone and, consequently, is not dependent upon opioid receptor activation. These observations support the hypothesis that the antinociceptive effects of CB2 agonists do not require opioid receptor activation. Our data suggest that the CB2 receptor remains a promising therapeutic target for the treatment of pain.
The analgesic properties of herbal and synthetic cannabinoid agonists have been well established. However, undesirable psychotropic effects produced by these ligands have limited their therapeutic potential.
Cloning and functional characterization of cannabinoid receptors have led to a better understanding of the underlining physiological function of this receptor class. Two types of cannabinoid receptors, CB1 and CB2, have been characterized to date. Both are G protein coupled receptors coupling to Gi/o, whose activation leads to the inhibition of the adenylyl cyclase activity. Activation of CB1 and CB2 receptors has been demonstrated to activate extracellular signal regulated protein kinase. The CB1 receptor is predominantly located in the CNS and the peripheral CB2 receptor is abundant in the immune system.
The activation of the CB1 receptor subtype has been clearly linked to the sedation, anxiety, paranoia, increased appetite, mild euphoria and impaired short term memory associated with cannabis use.
However, activation of both the CB1 and CB2 receptor subtypes has been shown to be involved in the analgesic activity of nonselective cannabinoids. An increasing body of evidence supports the premise that the CB2 receptor may be the better target for the treatment of inflammatory and neuropathic pain, since CB2 receptor activation with receptor selective agonists has been shown in animals to be devoid of the centrallymediated side effects of hypothermia, catalepsy and loss of motor coordination associated with the nonselective cannabinoids. A possible third cannabinoid receptor has recently been recognized in the orphan receptor, GPR55, and is expressed in the smooth muscle cells surrounding the blood vessels, as well as in the CNS. Although some herbal and synthetic cannabinoid ligands exhibit affinity for GPR55, this receptor remains largely uncharacterized. A b