d argue against any expectation . It is noteworthy that our study is not the first reported example of a discrepancy between the in vitro characterization of cannabinoid ligands and their BMS-806 357263-13-9 in vivo effects. Formalin induced BMS-806 357263-13-9 hyperalgesia in mice was shown to be exacerbated by each of two fatty acid derived compounds whose in vitro properties indicate them to be CB1 partial agonists, an observation that is not consistent with the expectation of CB1 receptor agonism being antihyperalgesic. Expectations about the effects of cannabinoid receptor inverse agonist compounds are further confused by reports of anti inflammatory effects of CB2 inverse agonists.

Without direct in vivo measurements of the basal state of CB2 receptor activation, in particular, in cell types known to mediate the responses buy BMS-806 to exogenous CB2 ligands, the behavioural studies we report herein can at the best be viewed as a characterization of R,S AM1241 and its enantiomers, and not as a direct test of the protean agonist hypothesis. buy BMS-806 In summary, we have reported for the first time an in vitro functional characterization of R,S AM1241 in rodent CB2 heterologous expression systems. In addition, we have provided the first in vitro and in vivo pharmacological assessment of this compound,s resolved enantiomers.
Despite the observation that S AM1241, the enantiomer that displayed rodent CB2 receptor agonist properties, was more efficacious than either R AM1241 or the racemate in rodent pain models, a full understanding of the relevance of the species dependent and stereoisomer dependent pharmacology we present herein will require further characterization.
N Acylethanolamines are endogenous lipids involved in cell signaling and they are synthesized in response to cellular injury. The NAE, arachidonylethanolamide, is a cannabinoid exhibiting cytoprotective properties against a wide variety of pathological insults including excitotoxicity, oxidative stress and hypoxia. Cannabinoids activate the G protein coupled cannabinoid receptors leading to downregulation of PKA and activation of the ERK MAPK pathway, a neuroprotective signaling pathway.
Furthermore, the activation of Akt by cannabinoids fur ther supports their role as neuroprotectants. Interestingly, concentrations of AEA in various tissues including the brain are relatively low compared to other NAE species such as the non cannabinoid NAE, palmitoylethanolamine .
Some saturated and monounsaturated NAEs have been shown to activate ERK1/2 phosphorylation pathway through a CB1 independent mechanism. Interestingly, the yeast Saccharomyces cerevisiae, which does not express cannabinoid or vanilloid receptors, synthesizes various NAE species in response to oxidative stress. This result further substantiates a non cannabinoid receptor and a non vanilloid receptor mediated function for some NAEs. In the present study, we determined that the lipid PEA is neuroprotective against oxidative insult. PEA treatment can activate the ERK1/2 MAP kinase and Akt proteins as determined by microfluorimetric measurements. Here, we identified that PEA can increase ERK1/2 and Akt phosphorylation and nuclear translocation of phospho Akt which suggests that the neuroprotective effects of PEA may be mediated, i