¹Department of Neurology, The Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA, USA

Correspondence: Dr RO Messing, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA. Tel: +510 985 3950; Fax: +510 985 3101; E-mail: romes@gallo.ucsf.edu

Received 7 July 2008; Revised 10 December 2008; Accepted 11 December 2008; Published online 21 January 2009.

Abstract

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 (PKC) 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 [³H] WIN55,212-2 was increased in brain membranes from PKC^-/- mice compared with PKC^+/+ mice. There was no difference in binding of the inverse agonist [³H] SR141716A. In addition, repeated administration of WIN55,212-2 produced greater analgesic and thermal tolerance in PKC^-/- mice compared with PKC^+/+mice. These results indicate that PKC selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.