All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2.In behavioral studies (i.e. analgesia, hypothermia) trans-oxime 8a exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ<sup>8</sup>-THC-DMH (>24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor.
CB2 receptors contained in peripheral immune tissue mediate analgesia by altering cytokine profiles, and thus have little adverse effects on central nervous systems (CNSs).
In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects.
Because glial activation opposes opioid analgesia and enhances opioid tolerance and dependence, we suggest that CB(2) receptors, by inhibiting microglial activity, may be potential targets to increase clinical efficacy of opioids.