Absence of Δ-9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice

Abstract

The involvement of dynorphin on ⌬-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.Key words: cannabinoid; opioid; mice; mutation; withdrawal; addiction; place aversion Pharmacological and genetic evidence suggest important functional interactions between the endogenous brain cannabinoid and opioid systems (Hine et al

Involvement of κ/Dynorphin System in WIN 55,212-2 Self-Administration in Mice

“…Taken together, these findings give further support to the involvement of KORs in the dysphoric effects of cannabinoids, which would deter the acquisition of cannabinoid self-administration behavior in mice. Accordingly, the anxiogenic-like responses induced by CP 55,940 seem to be mediated by the release of dynorphins and the consequent activation of KORs (Marín et al, 2003), and nor-binaltorphimine administration prevented the establishment of THC-induced conditioned place aversion (Zimmer et al, 2001). Moreover, THC was able to induce conditioned place preference in mice lacking KORs without receiving any previous injection of the drug, whereas THCinduced place aversion was abolished in these mutant mice (Ghozland et al, 2002).…”

“…The generation of mice with a deletion of the dynorphin gene has been previously described (Zimmer et al, 2001). Knockout mice were backcrossed in a pure C57BL/6J genetic background for at least 10 generations.…”

“…Thus, conditioned place preference induced by THC or WIN 55, can only be revealed in mice if they received a previous injection of the drug 24 h before the first conditioning day (Valjent and Maldonado, 2000;Castañé et al, 2004). Studies with genetically modified animals have provided further support to this hypothesis and have revealed the specific involvement of the k/ dynorphin system in such an initial aversive response of cannabinoids (Zimmer et al, 2001;Ghozland et al, 2002;Cheng et al, 2004). Thus, conditioned place preference to THC could be revealed in k knockout mice without avoiding the dysphoric consequences of the first exposure to the drug (Ghozland et al, 2002).…”

“…The endogenous opioid system seems to play an important role in the different effects produced on the reward circuit after cannabinoid administration. Accordingly, both pharmacological and genetic studies have provided evidence that the rewarding effects of cannabinoids are mediated by the activation of m-opioid receptors, whereas the stimulation of k-opioid receptors (KORs) by opioid peptides derived from pro-dynorphin seem to mediate their aversive effects (Ghozland et al, 2002;Zimmer et al, 2001). Moreover, several studies suggest that the k/dynorphin system opposes drug-rewarding effects, giving support to the idea that KORs could act as a possible pharmacotherapy for drug dependence (for a review, see Hasebe et al, 2004).…”

Gene expression of opioid and dopamine systems in mouse striatum: effects of CB1 receptors, age and sex

“…PPDYN(−/−) mice are no different from WT C57BL/6 in the Δ 9 -THC-decreased locomotion response attributed to striatal neurons. However, PPDYN(−/ −) mice are characterized by the absence of Δ 9 -THC-induced conditioned place aversion (Zimmer et al 2001). This suggests that dynorphin-containing neurons are in the pathway for the Δ 9 -THC dysphoric response.…”