PKCε Regulates Behavioral Sensitivity, Binding and Tolerance to the CB1 Receptor Agonist WIN55,212-2

The cannabinoid CB1 receptor (CB1) is one of the most abundant G protein-coupled receptors in the brain, but little is known about the mechanisms that modulate CB1 receptor signaling. Here we show that inhibition or null mutation of the epsilon isozyme of protein kinase C (PKCε) selectively enhances behavioral responses to the CB1 agonist WIN55,212-2 in mice, but not to the structurally unrelated CB1 agonist CP55,940. Binding affinity for [(3)H] WIN55,212-2 was increased in brain membranes from PKCε(-/-) mice compared with PKCε(+/+) mice. There was no difference in binding of the inverse agonist [(3)H] SR141716A. In addition, repeated administration of WIN55,212-2 produced greater analgesic and thermal tolerance in PKCε(-/-) mice compared with PKCε(+/+) mice. These results indicate that PKCε selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.