Lack of dependence and rewarding effects of deltorphin II in mu-opioid receptor-deficient mice

We have previously shown that the antinociceptive effects produced by the d elta opioid-selective agonist deltorphin II are preserved in mu-opioid rece ptor (MOR)-deficient mice. We have now investigated rewarding effects and p hysical dependence produced by deltorphin II in these animals. Wild-type an d MOR-deficient mice were implanted with a cannula into the third ventricle and deltorphin II was administered centrally. The rewarding effects induce d by deltorphin Ii were then investigated using the place preference paradi gm. Wild-type mice showed place preference for the compartment previously a ssociated with deltorphin Il and this effect was not observed in MOR-defici ent mice. In a second experiment, mice received a chronic perfusion of delt orphin Il over 6 days, via an Alzet minipump connected to the intraventricu lar cannula, and withdrawal was precipitated by naloxone administration. Wi ld-type animals showed a moderate but significant incidence of several soma tic signs of withdrawal. This withdrawal response was suppressed in MOR-def icient mice. Analysis of the immunoreactivity levels of PKC-alpha, PKC-beta (I and II) and PKC-gamma isozymes in the cerebral cortex of mice infused c hronically with deltorphin II showed a significant up-regulation of all the se isozymes in the soluble fraction in wild-type but not in MOR-deficient m ice. In conclusion, mu-opioid receptors, which are not involved in deltorph in II antinociception, appear to mediate the effects of chronic deltorphin II on rewarding responses, physical dependence and adaptive changes to PKC.