The involvement of dynorphin on Delta-9-tetrahydrocannabinol (THC) and morphine responses has been investigated by using mice with a targeted inactivation of the prodynorphin (Pdyn) gene. Dynorphin-deficient mice show specific changes in the behavioral effects of THC, including a reduction of spinal THC analgesia and the absence of THC-induced conditioned place aversion. In contrast, acute and chronic opioid effects were normal. The lack of negative motivational effects of THC in the absence of dynorphin demonstrates that this endogenous opioid peptide mediates the dysphoric effects of marijuana.

This work was supported by European Commission BIOM ED-2 Grant 98-2227 (R.M.), Fondo de Investigaciones Sanitaria Grant 99/0624 (R.M.), Dr. Esteve S. A. Laboratories (R.M.), Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 400), and the Land Nordrhein-Westfalen (Innovationsprogramm Forschung) (A.Z.)